Updated on 2023/12/04

写真a

 
TAKASHIMA Hiroshi
 
Organization
Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area Graduate School of Medical and Dental Sciences Advanced Therapeutics Course Neurology Professor
University Hospital, Medical and Dental Sciences Area University Hospital Clinical Center Neurology Disease Center
Title
Professor
Profile
Hereditary neuropathy  Neurogenic muscular atrophy Spinocerebellar degeneration Charcot-Marie-Tooth disease Prion disease Mitochondrial disease Muscular dystrophy HTLV-I related myelopathy New infectious encephalitis  Autoimmune encephalitis Archaeal infection

Degree

  • 博士(医学) ( 1997.3   Kagoshima University )

Research Interests

  • 遺伝性ニューロパチー 神経原性筋萎縮症 脊髄小脳変性症 プリオン病 CMT

  • archea

  • 自己免疫性脳症

  • 分子人類遺伝学

  • 分子生物学

Research Areas

  • Life Science / Neurology

  • Life Science / Genetics

  • Life Science / Medical biochemistry

  • Life Science / Neurology

Research History

  • Kagoshima University   Professor

    2010.1

  • Kagoshima University

    2010.1

Professional Memberships

  • 日本神経学会

    1990.6

  • 日本内科学会

    1990.6

  • 米国人類遺伝学会

    2000.9

  • 日本難病ネットワーク学会

    2010

  • 日本人類遺伝学会

    2015.10

  • 日本脳卒中学会

    2015.10

  • 日本末梢神経学会

    2015.10

  • 日本神経治療学会

    2015.10

▼display all

Studying abroad experiences

  • 2000.4 - 2002.7   BCM  

Qualification acquired

  • Attending physician

 

Papers

  • Shohei Beppu 1, Kensuke Ikenaka 1, Taiki Yabumoto 1, Kenichi Todo, Akihiro Hashiguchi, Hiroshi Takashima, Hideki Mochizuki .  A case of sporadic amyotrophic lateral sclerosis (ALS) with Senataxin (SETX) gene variant .  clinicalneurol.62 ( 3 ) 205 - 210   2022.5A case of sporadic amyotrophic lateral sclerosis (ALS) with Senataxin (SETX) gene variant

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  • Yujiro Higuchi, Hiroshi Takashima .  Clinical genetics of Charcot-Marie-Tooth disease .  J Hum Genet   2022.5Clinical genetics of Charcot-Marie-Tooth disease

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  • Yu Hiramatsu, Yuji Okamoto, Akiko Yoshimura, Jun-Hui Yuan, Masahiro Ando, Yujiro Higuchi, Akihiro Hashiguchi, Eiji Matsuura, Fumihito Nozaki, Tomohiro Kumada, Kei Murayama, Mikiya Suzuki, Yuki Yamamoto, Naoko Matsui, Yoshimichi Miyazaki, Masamitsu Yamaguchi, Youji Suzuki, Jun Mitsui, Hiroyuki Ishiura, Masaki Tanaka, Shinichi Morishita, Ichizo Nishino, Shoji Tsuji, Hiroshi Takashima .  Complex hereditary peripheral neuropathies caused by novel variants in mitochondrial-related nuclear genes .  Journal of Neurology- ( 8 ) 4129 - 4140   2022.5Reviewed International journal

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    Mitochondrial disorders are a group of clinically and genetically heterogeneous multisystem disorders and peripheral neuropathy is frequently described in the context of mutations in mitochondrial-related nuclear genes. This study aimed to identify the causative mutations in mitochondrial-related nuclear genes in suspected hereditary peripheral neuropathy patients. We enrolled a large Japanese cohort of clinically suspected hereditary peripheral neuropathy patients who were mutation negative in the prescreening of the known Charcot-Marie-Tooth disease-causing genes. We performed whole-exome sequencing on 247 patients with autosomal recessive or sporadic inheritance for further analysis of 167 mitochondrial-related nuclear genes. We detected novel bi-allelic likely pathogenic/pathogenic variants in four patients, from four mitochondrial-related nuclear genes: pyruvate dehydrogenase beta-polypeptide (PDHB), mitochondrial poly(A) polymerase (MTPAP), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB), and succinate-CoA ligase ADP-forming beta subunit (SUCLA2). All these patients showed sensory and motor axonal polyneuropathy, combined with central nervous system or multisystem involvements. The pathological analysis of skeletal muscles revealed mild neurogenic changes without significant mitochondrial abnormalities. Targeted screening of mitochondria-related nuclear genes should be considered for patients with complex hereditary axonal polyneuropathy, accompanied by central nervous system dysfunctions, or with unexplainable multisystem disorders.

    DOI: 10.1007/s00415-022-11026-w

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  • Masahiro Ando, Yujiro Higuchi, Mika Takeuchi, Akihiro Hashiguchi, Hiroshi Takashima .  The first case of infantile-onset multisystem neurologic, endocrine, and pancreatic disease caused by novel PTRH2 mutation in Japan .  Neurol Sci .43 ( 3 ) 2133 - 2136   2022.5The first case of infantile-onset multisystem neurologic, endocrine, and pancreatic disease caused by novel PTRH2 mutation in Japan

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  • Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Ruriko Kitao, Takehiko Morimoto, Takaki Taniguchi, Mika Takeuchi, Jun Takei, Yu Hiramatsu, Yusuke Sakiyama, Akihiro Hashiguchi, Yuji Okamoto, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroshi Takashima .  Novel de novo POLR3B mutations responsible for demyelinating Charcot-Marie-Tooth disease in Japan .  Ann Clin Transl Neurol9 ( 5 ) 747 - 755   2022.5Novel de novo POLR3B mutations responsible for demyelinating Charcot-Marie-Tooth disease in Japan

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  • Maruta K, Nobuhara Y, Ijiri Y, Kojima F, Takashima H .  Right optic perineuritis and myelitis 6 years following left optic perineuritis in anti-myelin oligodendrocyte glycoprotein-associated disorder: a case report. .  Clinical neurology62 ( 4 ) 286 - 292   2022.4

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    Language:Japanese   Publisher:Societas Neurologica Japonica  

    <p>We report a patient with myelin oligodendrocyte glycoprotein (MOG) antibody positivity who manifested myelitis with right optic perineuritis (OPN) 6 years following left OPN. A 45-year-old man treated 6 years previously for left OPN developed ascending numbness in both legs, urinary dysfunctions, and constipation. Neurologic examination disclosed bilateral hypesthesia extending downward over the chest from the T8 level. No motor weakness was evident. Visual field testing showed dense peripheral constriction with intact central vision on the right and a smaller superior scotoma on the left. Visual acuity and funduscopic findings were normal. Results of routine serologic investigations and autoimmune antibody titers, including those of anti-aquaporin 4 antibody, were within normal limits, except that both serum and cerebrospinal fluid were positive for anti-MOG antibody. MRI displayed a longitudinal cord lesion extending from T2 to T9, as well as optic nerve sheath enhancement characteristic of OPN. The patient was diagnosed with myelitis in addition to OPN, both resulting from MOG antibody-associated demyelination. Patients with myelitis, require careful assessment of visual acuity and visual fields to detect possible accompanying OPN and ON. We suspect that OPN in some other patients may likewise be caused by anti-MOG antibody.</p>

    DOI: 10.5692/clinicalneurol.cn-001705

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  • Yujiro Higuchi, Hiroshi Takashima .  Clinical genetics of Charcot–Marie–Tooth disease .  J Hum Genet.   2022.3

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  • Tashiro Y, Matsuura E, Sagara Y, Nozuma S, Kodama D, Tanaka M, Koriyama C, Kubota R, Takashima H .  High Prevalence of HTLV-1 Carriers Among the Elderly Population in Kagoshima, a Highly Endemic Area in Japan. .  AIDS research and human retroviruses38 ( 5 ) 363 - 369   2022.2Reviewed International journal

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    Authorship:Last author   Language:English   Publisher:AIDS Research and Human Retroviruses  

    Japan is one of the world's highly endemic areas for human T cell leukemia virus type 1 (HTLV-1), and it is known that the infection rate of HTLV-1 increases with age. The infection rate among the elderly has been estimated based on data from blood donors under the age of 65, and the actual number and rate of infection among the elderly are unknown. Data of 26,090 preoperative HTLV-1 screening tests conducted at Kagoshima University Hospital from 2001 to 2020, including 2726 HTLV-1-positive patients, were used for calculating the decadal infection rates for the year of birth. Estimated infection rates by birth year and demographic tables were used to estimate the current number of infected people in Kagoshima. The estimated total numbers of people infected with HTLV-1 in Kagoshima prefecture were 139,436 in 2005 and 80,975 in 2019. The infection rate increased with age for both men and women, reaching 17.3% for women born before the 1920s. Next, we tried to clarify whether the increase in infection rates with age was due to post-school age infections. The age of birth with the greatest increase in infection rate after 10 years was women born in the 1970s, and the increase in infection rate was only 0.98%, which is not a statistically significant increase. The number of infected people in Kagoshima was >80,000 in 2019. No data were available in this study to point to the involvement of horizontal transmission after school age in the high infection rate among the elderly. The high infection rate among the elderly is thought to have been high even when they were infants.

    DOI: 10.1089/AID.2021.0164

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  • Masahiro Ando, Yujiro Higuchi, Yuji Okamoto, Junhui Yuan, Akiko Yoshimura, Jun Takei, Takaki Taniguchi, Yu Hiramatsu, Yusuke Sakiyama, Akihiro Hashiguchi, Eiji Matsuura, Hiroto Nakagawa, Ken Sonoda, Toru Yamashita, Akiko Tamura, Hideo Terasawa, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroshi Takashima .  An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families .  Journal of human genetics67 ( 7 ) 399 - 403   2022.1Reviewed International journal

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    BACKGROUND AND AIMS: Mutations in neurofilament genes have been linked to several neuromuscular disorders. The neurofilament heavy (NEFH) gene was identified as the causative gene of Charcot-Marie-Tooth disease type 2CC (CMT2CC) in 2016, with a toxic gain of function mechanism caused by the translation and aggregation of cryptic amyloidogenic element (CAE) in the 3' untranslated region (UTR). But the NEFH-related clinical and genetic spectrums are still unclear in Japan. METHODS: We analyzed all variants in the NEFH gene from our in-house whole-exome sequencing data, established from Japanese nationwide patients with neuromuscular disorders, including Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA). RESULTS: We identified a c.3017dup (p.Pro1007Alafs*56) variant in NEFH from three families clinically diagnosed with CMT, and one family with SMA. In addition to the patients presented with typical peripheral neuropathies, pyramidal signs were observed from one CMT patient. Whereas the SMA patients showed severe characteristic weakness of triceps brachii and quadriceps femoris. All of these four families reside in Kagoshima Prefecture of Japan, and a following haplotype analysis strongly suggests a founder effect. INTERPRETATION: This is the original report referring to a founder mutation in NEFH. The clinical diversity in our study, comprising CMT, with or without pyramidal signs, and SMA, suggest an extensive involvement of peripheral nerve, anterior horn cells, or both. Our findings broaden the phenotypic spectrum of NEFH-related disorders.

    DOI: 10.1038/s10038-022-01019-y

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  • Lee J., Iwasaki T., Kaida T., Chuman H., Yoshimura A., Okamoto Y., Takashima H., Miyata K. .  A case of adult-onset Wolfram syndrome with compound heterozygous mutations of the WFS1 gene .  American Journal of Ophthalmology Case Reports25   101315   2022.1International journal

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    Language:English   Publisher:American Journal of Ophthalmology Case Reports  

    Purpose: Wolfram syndrome is a rare genetic disorder characterized by juvenile onset of diabetes mellitus with bilateral optic atrophy. We report a case of adult onset Wolfram syndrome with diabetes mellitus at age 22 and optic atrophy after age 40. The WFS1 gene sequence was analyzed in the patient and her father. Observations: A 46-year-old woman presented with bilateral vision loss. She had developed diabetes mellitus at age 22 and underwent bilateral cataract surgery at age 37. Visual acuity was 20/50 in the right eye and 20/200 in the left eye. The pupillary light reflex was sluggish in both eyes. Fundus examination showed bilateral optic atrophy, but there was no diabetic retinopathy. Cecocentral scotoma of both eyes was observed in Goldmann perimetry. There were no intracranial lesions on magnetic resonance imaging. Audiometry demonstrated high-frequency sensorineural hearing loss. Sequence analysis of the WFS1 gene revealed compound heterozygous mutation: c.908T>C p.L303P and c.1232_1233del, p.S411Cfs*131 in the patient and heterozygous mutation c. 908 T>C, p. L303P in her father. Conclusions and importance: The patient was diagnosed with adult-onset Wolfram syndrome with compound heterozygous mutations of the WFS1 alleles. Wolfram syndrome must be ruled out even in adult-onset diabetic patients with optic atrophy.

    DOI: 10.1016/j.ajoc.2022.101315

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  • Takaki Taniguchi, Masahiro Ando, Yuji Okamoto, Akiko Yoshimura, Yujiro Higuchi, Akihiro Hashiguchi, Nozomu Matsuda, Mamoru Yamamoto, Eisuke Dohi, Makoto Takahashi, Masanao Yoshino, Taichi Nomura, Masaaki Matsushima, Ichiro Yabe, Yui Sanpei, Hiroyuki Ishiura, Jun Mitsui, Masanori Nakagawa, Shoji Tsuji, Hiroshi Takashima .  Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments .  J Hum Genet.67 ( 6 ) 353 - 362   2022.1Reviewed International journal

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    BACKGROUND AND AIMS: Some hereditary transthyretin (ATTRv) amyloidosis patients are misdiagnosed as Charcot-Marie-Tooth disease (CMT) at onset. We assess the findings to identify ATTRv amyloidosis among patients with suspected CMT to screen transthyretin gene variants for treatments. METHODS: We assessed clinical, cerebrospinal fluid, and electrophysiological findings by comparing ATTRv amyloidosis patients with suspected CMT (n = 10) and CMT patients (n = 489). RESULTS: The median (interquartile range) age at onset of neurological symptoms was 69 (64.2-70) years in the ATTRv amyloidosis vs 12 (5-37.2) years in CMT group (Mann-Whitney U, p < 0.01). The proportion of patients with initial sensory symptoms was 70% in the ATTRv amyloidosis group vs 7.1% in CMT group (Fisher's exact, p < 0.01). The proportion of patients with histories of suspected chronic inflammatory demyelinating polyneuropathy (CIDP) were 50% in the ATTRv amyloidosis group vs 8.7% in CMT group (Fisher's exact, p < .01). Other measures and outcomes were not different between the two groups. Five of the six patients with ATTRv amyloidosis received treatment and survived. INTERPRETATION: For effective treatments, the transthyretin gene should be screened in patients with suspected CMT with old age at onset of neurological symptoms, initial sensory symptoms, and histories of suspected CIDP.

    DOI: 10.1038/s10038-021-01005-w

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  • M.D. Beppu Shohei, M.D. Ph.D. Ikenaka Kensuke, M.D. Ph.D. Yabumoto Taiki, M.D. Ph.D. Todo Kenichi, M.D. Ph.D. Hashiguchi Akihiro, M.D. Ph.D. Takashima Hiroshi, M.D. Ph.D. Mochizuki Hideki .  A case of sporadic amyotrophic lateral sclerosis (ALS) with Senataxin (<i>SETX</i>) gene variant .  Rinsho Shinkeigakuadvpub ( 0 ) 205 - 210   2022A case of sporadic amyotrophic lateral sclerosis (ALS) with Senataxin (<i>SETX</i>) gene variant

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    Language:Japanese   Publisher:Societas Neurologica Japonica  

    <p>A 67-year-old man presented slowly progressive weakness of the extremities visited our hospital. Nerve conduction study showed axonal neuropathy and needle electromyography showed neurogenic changes with denervation findings in multiple limb muscles. While he was diagnosed as Probable amyotrophic lateral sclerosis (ALS), which is defined by the Awaji criteria for diagnosis of ALS, he did not develop either respiratory muscle paralysis or bulbar palsy, which are characteristic symptoms of sporadic ALS. Genetic testing revealed a novel gene variant in senataxin (<i>SETX</i>), the causative gene of ALS4. We could not make a definite diagnosis of ALS4 because he had no relatives who could perform genetic testing (segregation study). However, we considered the variant can be pathogenic because it was not previously reported and absent in at least 1,000 healthy control individuals, the variant site was highly conserved in mammals, and it may impair the function of senataxin protein (<i>in silico</i> analysis).</p>

    DOI: 10.5692/clinicalneurol.cn-001675

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  • Shirakawa Shunichi, Murakami Tatufumi, Hashiguchi Akihiro, Takashima Hiroshi, Hasegawa Hiroshi, Ichida Kimiyoshi, Sunada Yoshihide .  A Novel PRPS1 Mutation in a Japanese Patient with CMTX5 .  Internal Medicine61 ( 11 ) 1749 - 1751   2021.12Reviewed

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    Language:English   Publisher:The Japanese Society of Internal Medicine  

    <p>The PRPS1 gene encodes phosphoribosyl pyrophosphate synthetase 1 (PRS-1). The phenotypes associated with <i>PRPS1</i> mutations include DFN2 (mild PRS-1 deficiency), X-linked Charcot-Marie-Tooth disease type 5 (CMTX5) (moderate PRS-1 deficiency), Arts syndrome (severe PRS-1 deficiency), and PRS-1 superactivity1. CMTX5 is a very rare hereditary neuropathy characterized by deafness, optic atrophy, and polyneuropathy. We herein report a Japanese patient with CMTX5 who had a novel hemizygous mutation c.82 G>C in <i>PRPS1</i>. Despite showing a typical clinical picture, the decrease in enzyme activity measured in the patient's erythrocytes was milder than in previously reported cases. </p>

    DOI: 10.2169/internalmedicine.8029-21

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  • Kimura Yasuyoshi, Naka Takashi, Nishikawa Akira, Hashiguchi Akihiro, Etoh Masaki, Yoshimura Akiko, Asai Kanako, Miyashita Noriko, Takashima Hiroshi, Sumi Hisae .  An MFN2-related Charcot-Marie-Tooth Disease Patient with Optic Nerve Atrophy, Neurogenic Bladder Dysfunction, and Diaphragmatic Weakness .  Internal Medicine61 ( 11 ) 1743 - 1747   2021.12Reviewed

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    <p>Charcot-Marie-Tooth disease (CMT) is a common hereditary peripheral polyneuropathy encompassing distinct monogenetic disorders. Pathogenic mutations in <i>mitofusin 2</i> (<i>MFN2</i>) are the most frequent cause of its axonal type, CMT type 2A, with diverse phenotypes. We herein report a Japanese patient with a novel heterozygous <i>MFN2</i> pathogenic variant (c.740 G>C, p.R247P) and severe CMT phenotypes, including progressive muscle weakness, optic atrophy, urinary inconsistency, and restrictive pulmonary dysfunction with eventration of the diaphragm that developed over her 60-year disease course. Our case expands the clinico-genetic features of<i> MFN2</i>-related CMT and highlights the need to evaluate infrequent manifestations during long-term care of CMT patients. </p>

    DOI: 10.2169/internalmedicine.6487-20

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  • Aoki Sho, Nagashima Kazuaki, Shibata Makoto, Kasahara Hiroo, Fujita Yukio, Hashiguchi Akihiro, Takashima Hiroshi, Ikeda Yoshio .  Sibling Cases of Charcot-Marie-Tooth Disease Type 4H with a Homozygous FGD4 Mutation and Cauda Equina Thickening(和訳中) .  Internal Medicine60 ( 24 ) 3975 - 3981   2021.12Sibling Cases of Charcot-Marie-Tooth Disease Type 4H with a Homozygous FGD4 Mutation and Cauda Equina Thickening(和訳中)Reviewed International journal

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    Language:English   Publisher:(一社)日本内科学会  

    症例1は62歳女性で、51歳時に神経障害が疑われ、紹介受診していた。本再受診時には瞳孔の著明な縮瞳を認め、両眼の瞳孔光反射が認められなかった。四肢の遠位筋優位の筋力低下と萎縮を認め、足関節の背屈が重度に障害されて鶏歩をきたしていた。遠位下肢の感覚鈍麻、痛覚鈍麻、振動覚低下を認め、バビンスキー反射のない全身性反射消失が判明した。腰椎MRIでは、著明な馬尾肥厚が明らかとなった。遺伝子検査では、シャルコー・マリー・トゥース病4H型の原因遺伝子であるFGD4遺伝子にホモ接合ミスセンス変異(c.1730G>A[p.Arg577Gln])が認められた。症例2は68歳男性(症例1の兄)で、症例1と同様の症状を認め、腰椎MRIで馬尾肥厚が示された。FGD4遺伝子の解析では、症例1と同一のホモ接合ミスセンス変異が認められた。

  • Shota Hirakata, Yusuke Sakiyama, Akiko Yoshimura, Mei Ikeda, Katsunori Takahata, Yuichi Tashiro, Michiyoshi Yoshimura, Hitoshi Arata, Hajime Yonezawa, Mari Kirishima, Michiyo Higashi, Miho Hatanaka, Takuro Kanekura, Kenji Yagita, Eiji Matsuura, Hiroshi Takashima .  The application of shotgun metagenomics to the diagnosis of granulomatous amoebic encephalitis due to Balamuthia mandrillaris: a case report .    21 ( 1 ) 392   2021.10International journal

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    DOI: 10.1186/s12883-021-02418-y

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  • Yujiro Higuchi, Masahiro Ando, Akiko Yoshimura, Satoshi Hakotani, Yuki Koba, Yusuke Sakiyama, Yu Hiramatsu, Yuichi Tashiro, Yoshimitsu Maki3, Akihiro Hashiguchi, Junhui Yuan, Yuji Okamoto, Eiji Matsuura, Hiroshi Takashima .  Prevalence of Fragile X‑Associated Tremor/Ataxia Syndrome in Patients with Cerebellar Ataxia in Japan .  The Cerebellum21 ( 5 ) 851 - 860   2021.9Reviewed International journal

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  • Inada R, Hirano M, Oka N, Samukawa M, Saigoh K, Suzuki H, Udaka F, Hashiguchi A, Takashima H, Hamada Y, Nakamura Y, Kusunoki S. .  Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan .  J Neurol.268 ( 8 ) 2933 - 2942   2021.8Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan

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    DOI: 10.1007/s00415-021-10467-z.

  • Kengo Maeda, Yutaka Yamamoto, Masatsugu Ohuchi, Takuto Sakashita, Masanori Shiohara, Tomo Namura, Masayuki Shintaku, Eiji Matsuura, Hiroshi Takashima .  Pathological evidence of demyelination in the recurrent laryngeal, phrenic, and oculomotor nerves in Charcot-Marie-Tooth disease 4F .  eNeurologicalSci .   2021.7Pathological evidence of demyelination in the recurrent laryngeal, phrenic, and oculomotor nerves in Charcot-Marie-Tooth disease 4F

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  • Sho Aoki, Kazuaki Nagashima, Makoto Shibata, Hiroo Kasahara, Yukio Fujita, Akihiro Hashiguchi, Hiroshi Takashima, Yoshio Ikeda .  Sibling Cases of Charcot-Marie-Tooth Disease Type 4H with a Homozygous FGD4 Mutation and Cauda Equina Thickening .  Intern Med .   2021.6Sibling Cases of Charcot-Marie-Tooth Disease Type 4H with a Homozygous FGD4 Mutation and Cauda Equina Thickening

  • Yazawa S, Tsuruta K, Sugimoto A, Suzuki Y, Yagi K, Matsuhashi M, Yoshimura .  Appearance of bitemporal periodic EEG activity in the last stage of Gerstmann-Sträussler-Scheinker syndrome (Pro102Leu): A case report .    204   106602   2021.5

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    DOI: 10.1016/j.clineuro.2021.106602

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  • Inherited Creutzfeldt-Jakob disease with four-octapeptide repeat insertional .  Inherited Creutzfeldt-Jakob disease with four-octapeptide repeat insertional .  Rinsho Shinkeigaku.61 ( 5 ) 314 - 318   2021.5Inherited Creutzfeldt-Jakob disease with four-octapeptide repeat insertional

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    DOI: 10.5692/clinicalneurol.cn-001558

  • Penova M, Kawaguchi S, Yasunaga JI, Kawaguchi T, Sato T, Takahashi M, Shimizu M, Saito M, Tsukasaki K, Nakagawa M, Takenouchi N, Hara H, Matsuura E, Nozuma S, Takashima H, Izumo S, Watanabe T, Uchimaru K, Iwanaga M, Utsunomiya A, Tabara Y, Paul R, Yamano Y, Matsuoka M, Matsuda F. .  Genome wide association study of HTLV-1-associated myelopathy/tropical spastic paraparesis in the Japanese population .  Proceedings of the National Academy of Sciences of the United States of America118 ( 11 )   2021.3Reviewed International journal

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    HTLV-1-associated myelopathy (HAM/TSP) is a chronic and progressive inflammatory disease of the central nervous system. The aim of our study was to identify genetic determinants related to the onset of HAM/TSP in the Japanese population. We conducted a genomewide association study comprising 753 HAM/TSP patients and 899 asymptomatic HTLV-1 carriers. We also performed comprehensive genotyping of HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1 genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in HLA class I (P = 1.54 × 10-9) and class II (P = 1.21 × 10-8) loci with HAM/TSP. Association analysis using HLA genotyping results showed that HLAC∗ 07:02 (P = 2.61 × 10-5), HLA-B∗07:02 (P = 4.97 × 10-10), HLADRB1∗ 01:01 (P = 1.15 × 10-9) and HLA-DQB1∗05:01 (P = 2.30 × 10-9) were associated with disease risk, while HLA-B∗40:06 (P = 3.03 × 10-5), HLA-DRB1∗15:01 (P = 1.06 × 10-5) and HLA-DQB1∗06:02 (P = 1.78 × 10-6) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP (P = 9.52 × 10-10); individuals homozygous for leucine had an associated increased risk of HAM/TSP (odds ratio, 9.57), and proline was protective (odds ratio, 0.65). Both associations were independent of the known risk associated with proviral load. DRB1-GB-7-Leu was not significantly associated with proviral load. We have identified DRB1-GB-7-Leu as a genetic risk factor for HAM/TSP development independent of proviral load. This suggests that the amino acid residue may serve as a specific marker to identify the risk of HAM/ TSP even without knowledge of proviral load. In light of its allele frequency worldwide, this biomarker will likely prove useful in HTLV-1 endemic areas across the globe.

    DOI: 10.1073/pnas.2004199118

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  • Takaki Taniguchi , Masahiro Ando , Yuji Okamoto , Akiko Yoshimura , Yujiro Higuchi , Akihiro Hashiguchi , Kensuke Shiga , Arisa Hayashida , Taku Hatano , Hiroyuki Ishiura , Jun Mitsui , Nobutaka Hattori , Toshiki Mizuno , Masanori Nakagawa , Shoji Tsuji , Hiroshi Takashima .  Genetic spectrum of Charcot–Marie–Tooth disease associated with myelin protein zero gene variants in Japan .  Clinical Genetics99 ( 3 ) 359 - 375   2021.3Reviewed International journal

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    We aimed to reveal the genetic features associated with MPZ variants in Japan. From April 2007 to August 2017, 64 patients with 23 reported MPZ variants and 21 patients with 17 novel MPZ variants were investigated retrospectively. Variation in MPZ variants and the pathogenicity of novel variants was examined according to the American College of Medical Genetics standards and guidelines. Age of onset, cranial nerve involvement, serum creatine kinase (CK), and cerebrospinal fluid (CSF) protein were also analyzed. We identified 64 CMT patients with reported MPZ variants. The common variants observed in Japan were different from those observed in other countries. We identified 11 novel pathogenic variants from 13 patients. Six novel MPZ variants in eight patients were classified as likely benign or uncertain significance. Cranial nerve involvement was confirmed in 20 patients. Of 30 patients in whom serum CK levels were evaluated, eight had elevated levels. Most of the patients had age of onset >20 years. In another subset of 30 patients, 18 had elevated CSF protein levels; four of these patients had spinal diseases and two had enlarged nerve root or cauda equina. Our results suggest genetic diversity across patients with MPZ variants.

    DOI: 10.1111/cge.13881

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  • Inada R, Hirano M, Oka N, Samukawa M, Saigoh K, Suzuki H, Udaka F, .  Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan .    268 ( 8 ) 2933 - 2942   2021.2Invited Reviewed International journal

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  • M.D. Douzono Mika, M.D. Ph.D. Nobuhara Yasuyuki, M.D. Ph.D. Maruta Kyouko, M.D. Ph.D. Okamoto Yuji, M.D. Ph.D. Sonoda Yoshito, M.D. Ph.D. Takashima Hiroshi .  Inherited Creutzfeldt–Jakob disease with four-octapeptide repeat insertional mutation in the prion gene .  Rinsho Shinkeigaku61 ( 5 ) 314 - 318   2021

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    <p>We report a case of a 60-year-old man who presented with symptoms of memory loss, gait disorder, and sluggish movement. We considered both Parkinson's disease and multiple system atrophy as possible diagnoses and consequently hospitalized the patient owing to the worsening symptoms and the development of consciousness disorder. During the course of the disease, dementia, loss of consciousness, and movement disorders worsened rapidly within one year after admission, and the patient eventually developed mutism. The significant clinical characteristics of our case included no myoclonus and involuntary tremors in the extremities. There was no periodic synchronous discharge on electro­encephalography and cranial MRI with diffusion-weighted images showed no high-intensity findings in cortex. Prion protein genetic analysis identified four repeated insertional mutations in the octapeptide repeat (OPR) region, and the patient was diagnosed with inherited Creutzfeldt–Jakob disease. Cases of OPR insertional mutations are a few in Japan and occur in about 10% of population in Europe. Creutzfeldt–Jakob disease with OPR insertional mutation shows various clinical manifestations and atypical findings on electroencephalography and cranial MRI. Diagnosing for Creutzfeldt–Jakob disease with OPR insertional mutation is important in Prion protein<i> </i>genetic analysis.</p>

    DOI: 10.5692/clinicalneurol.cn-001558

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  • Satomi D. .  Limits to the exaggeration and diversification of a male sexual trait in the false blister beetle Oedemera sexualis .  Entomological Science   2021

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    DOI: 10.1111/ens.12469

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  • 髙嶋 博 .  脊髄性筋萎縮症の遺伝子治療の実際とその未来 .  神経治療学38 ( 6 ) S178 - S178   2021

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    DOI: 10.15082/jsnt.38.6_S178

  • Aoki Sho, Nagashima Kazuaki, Shibata Makoto, Kasahara Hiroo, Fujita Yukio, Hashiguchi Akihiro, Takashima Hiroshi, Ikeda Yoshio .  Sibling Cases of Charcot-Marie-Tooth Disease Type 4H with a Homozygous <i>FGD4</i> Mutation and Cauda Equina Thickening .  Internal Medicine60 ( 24 ) 3975 - 3981   2021

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    <p>Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive inherited demyelinating neuropathy caused by an FYVE, RhoGEF, and a PH domain-containing protein 4 (<i>FGD4</i>) gene mutation. CMT4H is characterized by an early onset, slow progression, scoliosis, distal muscle atrophy, and foot deformities. We herein present sibling cases of CMT4H with a homozygous mutation in the <i>FGD4</i> gene. Both patients exhibited cauda equina thickening on magnetic resonance imaging, which had not been reported among the previous CMT4H cases. This is the first report of CMT4H with a homozygous <i>FGD4</i> c.1730G>A (p.Arg577Gln) mutation showing mild progression and cauda equina thickening. </p>

    DOI: 10.2169/internalmedicine.7247-21

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  • Yamagishi Y. .  Serum IgG anti-GD1a antibody and mEGOS predict outcome in Guillain-Barré syndrome .  Journal of Neurology, Neurosurgery and Psychiatry91 ( 12 ) 1339 - 1342   2020.12Reviewed International journal

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    DOI: 10.1136/jnnp-2020-323960

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  • Sakiyama Yusuke, Matsuura Eiji, Shigehisa Ayano, Hamada Yuki, Dozono Mika, Nozuma Satoshi, Nakamura Tomonori, Higashi Keiko, Hashiguchi Akihiro, Takahashi Yukitoshi, Takashima Hiroshi .  Cryptococcus Meningitis Can Co-occur with Anti-NMDA Receptor Encephalitis .    59 ( 18 ) 2301 - 2306   2020.9Cryptococcus Meningitis Can Co-occur with Anti-NMDA Receptor Encephalitis

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    DOI: 10.2169/internalmedicine.4629-20.

  • Kodama D. .  Inhibition of abl1 tyrosine kinase reduces htlv-1 proviral loads in peripheral blood mononuclear cells from patients with htlv-1-associated myelopathy/tropical spastic paraparesis .  PLoS Neglected Tropical Diseases14 ( 7 ) 1 - 21   2020.7Reviewed International journal

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    DOI: 10.1371/journal.pntd.0008361

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  • Ishihara S, Okamoto Y, Tanabe H, Yoshimura A, Higuchi Y, Yuan JH, Hashiguchi .  Clinical features of inherited neuropathy with BSCL2 mutations in Japan .  Journal of the peripheral nervous system : JPNS25 ( 2 ) 125 - 131   2020.6Reviewed International journal

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    Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene have been reported with different clinical phenotypes including Silver syndrome (SS)/spastic paraplegia 17 (SPG17), distal hereditary motor neuropathy type V (dHMN-V), and Charcot-Marie-Tooth (CMT) disease type 2. We screened 407 Japanese patients who were clinically suspected of having CMT by exome sequencing and searched mutations in BSCL2. As a result, we identified five patients with heterozygous mutations in BSCL2. We confirmed three cases of known mutations (p.N88S and p.S90L) and two cases of novel mutations (p.N88T and p.S141A). The clinical features of the cases with known mutations in Japan were similar to those previously reported in other countries. In particular, there were many cases with sensory disturbance. The case with p.N88T mutation showed severe phenotype such as early onset age and prominent vocal cord paresis. The case with p.S141A mutation showed characteristics of demyelinating neuropathy such as CMT disease type 1 by electrophysiological examination. In this article, we report the clinical features and spread of cases with BSCL2 mutation in a Japanese cohort.

    DOI: 10.1111/jns.12369

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  • Yamagishi Y, Samukawa M, Kuwahara M, Takada K, Saigoh K, Mitsui Y, Oka N, Hashiguchi A, Takashima H, Kusunoki S. .  Charcot-Marie-Tooth Disease With a Mutation in FBLN5 Accompanying With the Small Vasculitis and Widespread Onion-Bulb Formations .  J Neurol Sci. 410   2020.3Charcot-Marie-Tooth Disease With a Mutation in FBLN5 Accompanying With the Small Vasculitis and Widespread Onion-Bulb FormationsReviewed

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    DOI: doi.org/10.1016/j.jns.2019.116623

  • Nishizawa M, Onodera O, Hirakawa A, Shimizu Y, Yamada M; Rovatirelin Study .  Effect of rovatirelin in patients with cerebellar ataxia: two randomised .  J Neurol Neurosurg Psychiatry.91 ( 3 ) 254 - 262   2020.3Effect of rovatirelin in patients with cerebellar ataxia: two randomised

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  • Sawada Jun, Yoshimura Akiko, Takashima Hiroshi, Hasebe Naoyuki, Katayama Takayuki, Tokashiki Takashi, Kikuchi Shiori, Kano Kohei, Takahashi Kae, Saito Tsukasa, Adachi Yoshiki, Okamoto Yuji .  The First Case of Spinocerebellar Ataxia Type 8 in Monozygotic Twins .  Internal Medicine59 ( 2 ) 277 - 283   2020.1Reviewed

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    <p>Spinocerebellar ataxia type 8 (SCA8) is a rare hereditary cerebellar ataxia showing mainly pure cerebellar ataxia. We herein report cases of SCA8 in Japanese monozygotic twins that presented with nystagmus, dysarthria, and limb and truncal ataxia. Their <i>ATXN8OS</i> CTA/CTG repeats were 25/97. They showed similar manifestations, clinical courses, and cerebellar atrophy on magnetic resonance imaging. Some of their pedigrees had nystagmus but not ataxia. These are the first monozygotic twins with SCA8 to be reported anywhere in the world. Although not all subjects with the <i>ATXN8OS</i> CTG expansion develop cerebellar ataxia, these cases suggest the pathogenesis of <i>ATXN8OS</i> repeat expansions in hereditary cerebellar ataxia. </p>

    DOI: 10.2169/internalmedicine.2905-19

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  • Takashima Hiroshi .  Symptoms of autoimmune encephalopathy ―Differentiation from hysteria― .  Neurological Therapeutics37 ( 4 ) 636 - 639   2020Reviewed

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    Authorship:Lead author, Last author, Corresponding author   Language:Japanese   Publisher:Japanese Society of Neurological Therapeutics  

    <p>Autoimmune encephalopathies are clinically and immunologically heterogeneous disorders. Many different types of autoimmune encephalopathy have been discovered, and most common type may be Hashimoto encephalopathy in it. In clinical situations, we often recognize that patients with autoimmune encephalopathy are misdiagnosed as exhibiting functional psychogenic movement, conversion, or somatoform disorders. Most patients with autoimmune encephalopathy showed motor disturbance mostly with unsustained and/or give–way weakness. About 70% of patients showed sensory abnormalities that was not explainable anatomically. One–fourth of patients exhibited involuntary movements such as tremor entrainment, dystonia, or coarse involuntary movement. Although give–way weakness, anatomically unexplainable pain, and strange involuntary movements were thought to be psychogenic, the presence of one of these three symptoms was indicative of autoimmune encephalopathy. As autoimmune encephalitis exhibits diffuse involvement with the whole brain, these symptoms were entirely understandable. Except for the presence of organic disease, most patients were classified into somatoform disorders or functional movement disorders. Without first excluding autoimmune encephalopathy, physicians should not diagnose somatoform disorders.</p>

    DOI: 10.15082/jsnt.37.4_636

  • Yoshimura A, Yuan JH, Hashiguchi A, Ando M, Higuchi Y, Nakamura T, Okamoto Y, Nakagawa M, Takashima H .  Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan. .  Journal of neurology, neurosurgery, and psychiatry90 ( 2 ) 195 - 202   2019.2Reviewed International journal

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    DOI: 10.1136/jnnp-2018-318839

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  • Takashima Hiroshi .  Clinical symptoms of autoimmune encephalopathy ―Differentiation from hysteria― .  Neurological Therapeutics36 ( 4 ) 341 - 344   2019Reviewed

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    Authorship:Lead author   Language:Japanese   Publisher:Japanese Society of Neurological Therapeutics  

    <p>Autoimmune encephalopathies are clinically and immunologically heterogeneous disorders. Many different types of autoimmune encephalopathy have been discovered, and most common type may be Hashimoto encephalopathy in it. We often recognize that patients with autoimmune encephalopathy are often misdiagnosed as functional psychogenic movement or somatoform disorders. We have reported 63 patients with autoimmune encephalopathy. Two–thirds of patients showed motor disturbance mostly with unsustained or give–way weakness. About 70% of patients showed sensory abnormalities that was not explainable anatomically. 27% of patients exhibited involuntary movements such as tremor entrainment, dystonia, or coarse involuntary movement. Although give–way weakness, anatomically unexplainable pain, and strange involuntary movements were thought to be psychogenic, the presence of one of these three symptoms was indicative of autoimmune encephalopathy. As autoimmune encephalitis exhibits diffuse involvement with the whole brain, these symptoms were entirely understandable. Except for the presence of organic disease, most patients were classified into somatoform disorders or functional movement disorders. Without first excluding autoimmune encephalopathy, physicians should not diagnose somatoform disorders.</p>

    DOI: 10.15082/jsnt.36.4_341

  • Yuan J.H. .  Genetic and phenotypic profile of 112 patients with X-linked Charcot–Marie–Tooth disease type 1 .  European Journal of Neurology25 ( 12 ) 1454 - 1461   2018.12Reviewed International journal

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:European Journal of Neurology  

    DOI: 10.1111/ene.13750

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  • Michiyoshi Yoshimura, Jun-Hui Yuan, Keiko Higashi, Akiko Yoshimura, Hitoshi Arata, Ryuichi Okubo, Yoshiaki Nakabeppu, Takashi Yoshiura, Hiroshi Takashima .  Correlation between clinical and radiologic features of patients with Gerstmann-Sträussler-Scheinker syndrome (Pro102Leu) .  Journal of the Neurological Sciences391   15 - 21   2018.8Reviewed International journal

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    Background and purpose: Gerstmann-Sträussler-Scheinker syndrome is a rare hereditary neurodegenerative disorder with clinical heterogeneity. This study is aim to demonstrate the clinical spectrum and radiologic characteristics of patients caused by Pro102Leu mutation in PRNP. Materials and methods: We retrospect clinical manifestations of five patients from four Japanese families, and comprehensively analyzed their brain MRI, SPECT (N-isopropyl-p-[123I] iodoamphetamine), and PET (18F-2-fluoro-2-deoxy-D-glucose) images. Results: All patients developed ataxia of lower limbs and trunk, gait disturbance, dysesthesia in legs, and lower limb hyporeflexia. In the early clinical stage before dementia began, no noticeable abnormalities could be observed from brain MRI, but SPECT and PET revealed mosaic-like pattern of blood flow and glucose metabolism of the brain. Predominant abnormalities were found in the occipital and frontal lobes on SPECT and PET analysis, respectively. In SPECT analysis, blood flow of the anterior cerebellar lobes was lower than that of the posterior cerebellar lobes. Conclusions: Clinical symptoms resulting from failure of dorsal horn of spinal cord and spinocerebellar tracts were observed in all cases. Radiologic findings revealed individual differences of involved region in their brain, which could produce clinical diversity. We identified a downtrend of blood flow in the anterior cerebellar lobes, a projection field of the spinocerebellar tracts, which is an important feature of Gerstmann-Sträussler-Scheinker syndrome.

    DOI: 10.1016/j.jns.2018.05.012

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  • Yujiro Higuchi, Ryuta Okunushi, Taichi Hara, Akihiro Hashiguchi, Junhui Yuan, Akiko Yoshimura, Kei Murayama, Akira Ohtake, Masahiro Ando, Yu Hiramatsu, Satoshi Ishihara, Hajime Tanabe, Yuji Okamoto, Eiji Matsuura, Takehiro Ueda, Tatsushi Toda, Sumimasa Yamashita, Kenichiro Yamada, Takashi Koide, Hiroaki Yaguchi, Jun Mitsui, Hiroyuki Ishiura, Jun Yoshimura, Koichiro Doi, Shinichi Morishita, Ken Sato, Masanori Nakagawa, Masamitsu Yamaguchi, Shoji Tsuji, Hiroshi Takashima .  Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy. .  Brain : a journal of neurology141 ( 6 ) 1622 - 1636   2018.6Reviewed International journal

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    Several genes related to mitochondrial functions have been identified as causative genes of neuropathy or ataxia. Cytochrome c oxidase assembly factor 7 (COA7) may have a role in assembling mitochondrial respiratory chain complexes that function in oxidative phosphorylation. Here we identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or other inherited peripheral neuropathies, including complex forms of CMT. We also found that all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy, and some patients showed leukoencephalopathy or spinal cord atrophy on MRI scans. Validated mutations were located at highly conserved residues among different species and segregated with the disease in each family. Nerve conduction studies showed axonal sensorimotor neuropathy. Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres. An immunohistochemical assay with an anti-COA7 antibody in the sural nerve from the control patient showed the positive expression of COA7 in the cytoplasm of Schwann cells. We also observed mildly elevated serum creatine kinase levels in all patients and the presence of a few ragged-red fibres and some cytochrome c oxidase-negative fibres in a muscle biopsy obtained from one patient, which was suggestive of subclinical mitochondrial myopathy. Mitochondrial respiratory chain enzyme assay in skin fibroblasts from the three patients showed a definitive decrease in complex I or complex IV. Immunocytochemical analysis of subcellular localization in HeLa cells indicated that mutant COA7 proteins as well as wild-type COA7 were localized in mitochondria, which suggests that mutant COA7 does not affect the mitochondrial recruitment and may affect the stability or localization of COA7 interaction partners in the mitochondria. In addition, Drosophila COA7 (dCOA7) knockdown models showed rough eye phenotype, reduced lifespan, impaired locomotive ability and shortened synaptic branches of motor neurons. Our results suggest that loss-of-function COA7 mutation is responsible for the phenotype of the presented patients, and this new entity of disease would be referred to as spinocerebellar ataxia with axonal neuropathy type 3.

    DOI: 10.1093/brain/awy104

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  • Jun-Hui Yuan, Akihiro Hashiguchi, Yuji Okamoto, Akiko Yoshimura, Masahiro Ando, Kazutaka Shiomi, Kayoko Saito, Makoto Takahashi, Keiko Ichinose, Takuma Ohmichi, Kazushi Ichikawa, Adachi Tadashi, Hiroshi Takigawa, Hidehiro Shibayama, Hiroshi Takashima .  Clinical and mutational spectrum of Japanese patients with recessive variants in SH3TC2. .  Journal of human genetics63 ( 3 ) 281 - 287   2018.3Reviewed International journal

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    SH3TC2, known as the causative gene of autosomal recessive demyelinating Charcot-Marie-Tooth type 4C (CMT4C), was also found linked to a mild mononeuropathy of the median nerve with an autosomal dominant inheritance pattern. Using DNA microarray, Illumina MiSeq, and Ion proton, we carried out gene panel sequencing among 1483 Japanese CMT patients, containing 397 patients with demyelinating CMT. From seven patients with demyelinating CMT, we identified eight recessive variants in the SH3TC2 gene, consisting of five novel (pathogenic/likely pathogenic) and three reported variants. Additionally, from two patients with axonal CMT, we detected a reported recessive variant, p.Arg77Trp, which was herein reclassified as variant with unknown significance. Of the seven CMT4C patients (six females and one male), 2/7 patients developed symptoms at their first decade, and 5/7 patients lost their ambulation around age 50. Scoliosis was observed from more than half (4/7) of these patients, whereas hearing loss is the most common symptom of central nervous system (6/7). No median nerve mononeuropathy was recorded from their family members. We identified recessive variants in SH3TC2 from 1.76% of demyelinating CMT patients. An uncommon gender difference was recognized and the wild spectrum of these variants suggests mutational diversity of SH3TC2 in Japan.

    DOI: 10.1038/s10038-017-0388-5

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  • Hajime Tanabe, Yujiro Higuchi, Jun-Hui Yuan, Akihiro Hashiguchi, Akiko Yoshimura, Satoshi Ishihara, Satoshi Nozuma, Yuji Okamoto, Eiji Matsuura, Hiroyuki Ishiura, Jun Mitsui, Ryotaro Takashima, Norito Kokubun, Kengo Maeda, Yuri Asano, Yoko Sunami, Yu Kono, Yasunori Ishigaki, Shosaburo Yanamoto, Jiro Fukae, Hiroshi Kida, Mitsuya Morita, Shoji Tsuji, Hiroshi Takashima .  Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan .  Journal of the Peripheral Nervous System23 ( 1 ) 40 - 48   2018.3Reviewed International journal

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Blackwell Publishing Inc.  

    Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.

    DOI: 10.1111/jns.12252

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  • Yuan Jun-Hui, Hashiguchi Akihiro, Okamoto Yuji, Yoshimura Akiko, Ando Masahiro, Shiomi Kazutaka, Saito Kayoko, Takahashi Makoto, Ichinose Keiko, Ohmichi Takuma, Ichikawa Kazushi, Adachi Tadashi, Takigawa Hiroshi, Shibayama Hidehiro, Takashima Hiroshi .  SH3TC2遺伝子に劣性多様体を有する日本人患者の臨床および変異スペクトル(Clinical and mutational spectrum of Japanese patients with recessive variants in SH3TC2) .  Journal of Human Genetics63 ( 3 ) 281 - 287   2018.3SH3TC2遺伝子に劣性多様体を有する日本人患者の臨床および変異スペクトル(Clinical and mutational spectrum of Japanese patients with recessive variants in SH3TC2)Reviewed International journal

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    Authorship:Last author, Corresponding author   Language:English   Publisher:Nature Publishing Group  

    2007年〜2016年9月に当院に来院したシャルコー・マリー・トゥース病(CMT)の日本人患者1483例のうち、劣性SH3TC2多様体を有する患者を後ろ向きに調査して、SH3TC2の臨床および電気生理学的特徴と変異スペクトルを評価した。その結果、9例(男性1例、女性8例、年齢11〜85歳)で10の劣性SH3TC2多様体を同定した。9例中7例は脱髄性CMTで、SH3TC2遺伝子で八つ劣性多様体を同定し、そのうち五つは新規多様体であった。2例は軸索CMTで、既報告の劣性多様体p.Arg77Trpが検出された。脱髄性CMT患者では3例が10〜20歳、4例は成人になってから発症した。脱髄性CMT患者の1.76%でSH3TC2に劣性多様体が同定された。

  • Natsumi Fujisaki, Shugo Suwazono, Masahito Suehara, Ryo Nakachi, Miwako Kido, Yoshihisa Fujiwara, Saki Oshiro, Takashi Tokashiki, Hiroshi Takashima, Masanori Nakagawa .  The natural history of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) in 97 Japanese patients. .  Intractable & rare diseases research7 ( 1 ) 7 - 12   2018Reviewed International journal

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    Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is a motor and sensory neuronopathy with autosomal dominant inheritance, adult onset, slowly progressive course, and is associated with TRK-fused gene (TFG) mutation. At advanced stages, respiratory failure and dysphagia becomes life-threatoning, and patients typically die by their 70s. Although there is currently no evidence for effective treatment, a therapy may be found by elucidation of the function of TFG. Recently its pathomechanism has been proposed to be associated with abnormalities in protein transfer from the endoplasmic reticulum. Such pathomechanisms might involve a similar process in amyotrophic lateral sclerosis; thus, its pathomechanisms and treatment strategy might make it a good model for neurodegenerative disorders. It is of great value to clarify the natural history of HMSN-P, in oder to judge the treatment effect. By evaluating 97 patients (79 out of 97 were examined and all confirmed with p.Pro 285 Leu mutation) in this study, it was confirmed that this disease follows a uniform course in the earlier stages, and there are individual differences in the onset between 20 and 30 years. Such uniformity might be due to the proposed single gene abnormality. At advanced stages, there are larger individual differences in the progression, but the reasons for these are unknown. Longer survival might be achieved with a better care for respiratory failure and dysphagia if such cares were undertaken at appropriate times.

    DOI: 10.5582/irdr.2017.01084

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  • Takashima Hiroshi .  Why are neurological symptoms after human papillomavirus vaccination mistaken for psychogenic diseases? .  Neurological Therapeutics35 ( 4 ) 536 - 542   2018Invited

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    Authorship:Lead author   Language:Japanese   Publisher:Japanese Society of Neurological Therapeutics  

    <p>Many patients present with extremely serious problems such as headache, photophobia, acoustic hyperresponsiveness, severe pain, menstrual disorders, various sleep disorders, and POTS after human papillomavirus vaccination (HPV vaccine). In addition, patients exhibit various neurological symptoms such as movement disorders, walking disturbance, involuntary movement, abnormal sensation, memory disturbance, and so on. However, these symptoms are variable and have been considered to be symptoms of hysteria (somatoform disorder, somatic symptoms). Immunosuppressive treatments were not administered because many cases were considered to be of neurological origin. In such cases, the disease condition is objectively evaluated to diagnose and treat patients with neurological symptoms. In conclusion, the wide–ranging symptoms of the central nervous system include those caused by disseminated autoimmune encephalitis and also symptoms of the peripheral small fibers. Thus, according to the obtained findings, the neurological symptoms caused by HPV vaccination are related to immunological diseases, and not psychogenic diseases. In addition, the cause of misdiagnosis has also been described.</p>

    DOI: 10.15082/jsnt.35.4_536

  • Yuan JH, Hashiguchi A, Yoshimura A, Sakai N, Takahashi MP, Ueda T, Taniguchi A, Okamoto S, Kanazawa N, Yamamoto Y, Saigoh K, Kusunoki S, Ando M, Hiramatsu Y, Okamoto Y, Takashima H .  WNK1/HSN2 Founder Mutation in Patients with Hereditary Sensory and Autonomic Neuropathy: a Japanese cohort study. .  Clin Genet92 ( 6 ) 659 - 663   2017.12Reviewed International journal

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    DOI: 10.1111/cge.13037

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  • Tashiro Y. .  Motor symptoms of autoimmune encephalopathies .  Brain and Nerve69 ( 12 ) 1387 - 1399   2017.12Reviewed

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    Authorship:Last author, Corresponding author   Language:Japanese   Publisher:Brain and Nerve  

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  • Honda H, Sasaki K, Takashima H, Mori D, Koyama S, Suzuki SO, Iwaki T .  Different Complicated Brain Pathologies in Monozygotic Twins With Gerstmann-Sträussler-Scheinker Disease. .  Journal of neuropathology and experimental neurology76 ( 10 ) 854 - 863   2017.10Different Complicated Brain Pathologies in Monozygotic Twins With Gerstmann-Sträussler-Scheinker Disease.International journal

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    DOI: 10.1093/jnen/nlx068

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  • Maki Y, Takashima H .  [Differential Diagnosis of Immune-Mediated Encephalopathies: "Neurological Symptoms of Diffuse Brain Damage": A New Concept]. .  Brain and nerve = Shinkei kenkyu no shinpo69 ( 10 ) 1131 - 1141   2017.10[Differential Diagnosis of Immune-Mediated Encephalopathies: "Neurological Symptoms of Diffuse Brain Damage": A New Concept].Reviewed

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    DOI: 10.11477/mf.1416200881

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  • Maki Y. .  Differential diagnosis of immune-mediated encephalopathies: Neurological symptoms of diffuse brain damage: A new concept .  Brain and Nerve69 ( 10 ) 1131 - 1141   2017.10Reviewed

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  • M. Ando, Y. Okamoto, A. Yoshimura, J. -H. Yuan, Y. Hiramatsu, Y. Higuchi, A. Hashiguchi, J. Mitsui, H. Ishiura, S. Fukumura, M. Matsushima, N. Ochi, J. Tsugawa, S. Morishita, S. Tsuji, H. Takashima .  Clinical and mutational spectrum of Charcot-Marie-Tooth disease type 2Z caused by MORC2 variants in Japan .  EUROPEAN JOURNAL OF NEUROLOGY24 ( 10 ) 1274 - 1282   2017.10Reviewed International journal

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY  

    Background and purpose: The microrchidia family CW-type zinc finger 2 gene (MORC2) was newly identified as a causative gene of Charcot-Marie-Tooth disease (CMT) type 2Z in 2016. We aimed to describe the clinical and mutational spectrum of patients with CMT harboring MORC2 mutations in Japan.
    Methods: We analyzed samples from 781 unrelated patients clinically diagnosed with CMT using deoxyribonucleic acid microarray or targeted resequencing by next-generation sequencing, and samples from 434 mutation-negative patients were subjected to whole-exome sequencing. We extracted MORC2 variants from these whole-exome sequencing data and classified them according to American College of Medical Genetics standards and guidelines.
    Results: We identified MORC2 variants in 13 patients. As the second most common causative gene of CMT type 2 after MFN2, MORC2 variants were detected in 2.7% of patients with CMT type 2. The mean age of onset was 10.3 +/- 8.7 years, and the inheritance pattern was mostly sporadic (11/13 patients, 84.6%). The clinical phenotype was typically length-dependent polyneuropathy, and electrophysiological studies revealed sensory-dominant axonal neuropathy. Mental retardation was identified in 4/13 patients (30.8%). p.Arg190Trp, as a mutational hotspot, was observed in eight unrelated families. We also identified two novel probably pathogenic variants, p.Cys345Tyr and p.Ala369Val, and one novel uncertain significance variant, p.Tyr332Cys.
    Conclusions: Our study is the largest report of patients harboring MORC2 variants. We revealed a clinical and mutational spectrum of Japanese patients with MORC2 variants. More attention should be paid to cognitive impairment, and the responsible mechanism requires further research for elucidation.

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  • Daisuke Kondo, Koji Shinoda, Ken-ichiro Yamashita, Ryo Yamasaki, Akihiro Hashiguchi, Hiroshi Takashima, Jun-ichi Kira .  A novel mutation in FGD4 causes Charcot-Marie-Tooth disease type 4H with cranial nerve involvement .  NEUROMUSCULAR DISORDERS27 ( 10 ) 959 - 961   2017.10Reviewed International journal

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    Charcot Marie Tooth disease type 4H (CMT4H) is a rare variant of autosomal recessive hereditary neuropathy. It is caused by FGD4 mutations and characterized by early infantile onset, slowly progressive distal muscle weakness, scoliosis, and myelin outfoldings visible in nerve biopsy samples. Here, we report a 65-year-old male born to consanguineous parents, who carries a novel homozygous FGD4 c.724C&gt;T nonsense mutation. He developed lower limb weakness in his teens, which progressed slowly and was accompanied by diplopia, bilateral hearing loss, and erectile dysfunction from his twenties. At the age of 65, he was wheelchair-bound and had mild scoliosis, bilateral ophthalmoplegia, facial muscle weakness, inner ear hearing loss, distal-dominant weakness, and sensory disturbance, but no cognitive deterioration. Magnetic resonance imaging revealed enlarged bilateral trigeminal and facial nerves. Accordingly, we believe that this mutation causes slowly progressive sensorimotor neuropathy with apparent cranial nerve involvement, thereby. further expanding the clinical spectrum of CMT4H. (C) 2017 Elsevier B.V. All rights reserved.

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  • Togawa J, Ohi T, Yuan JH, Takashima H, Furuya H, Takechi S, Fujitake J, Hayashi S, Ishiura H, Naruse H, Mitsui J, Tsuji S .  New familial amyotrophic lateral sclerosis with benign progression and myoclonus in lower extremities .  J. Neurol. Sci.381 ( Supplement ) 716   2017.10Reviewed International journal

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    DOI: 10.1016/j.jns.2017.08.2017

  • Togawa J, Ohi T, Yuan JH, Takashima H, Furuya H, Takechi S, Fujitake J, Hayashi S, Ishiura H, Naruse H, Mitsui J, Tsuji S .  New familial amyotrophic lateral sclerosis with benign progression and myoclonus in lower extremities .  J. Neurol. Sci.381 ( Supplement ) 716   2017.10Reviewed International journal

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    DOI: 10.1016/j.jns.2017.08.2017

  • Masahiro Ando, Akihiro Hashiguchi, Yuji Okamoto, Akiko Yoshimura, Yu Hiramatsu, Junhui Yuan, Yujiro Higuchi, Jun Mitsui, Hiroyuki Ishiura, Ayako Umemura, Koichi Maruyama, Takeshi Matsushige, Shinichi Morishita, Masanori Nakagawa, Shoji Tsuji, Hiroshi Takashima .  Clinical and genetic diversities of Charcot-Marie-Tooth disease with MFN2 mutations in a large case study .  JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM22 ( 3 ) 191 - 199   2017.9Reviewed International journal

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    Charcot-Marie-Tooth disease (CMT) constitutes a heterogeneous group affecting motor and sensory neurons in the peripheral nervous system. MFN2 mutations are the most common cause of axonal CMT. We describe the clinical and mutational spectra of CMT patients harboring MFN2 mutations in Japan. We analyzed 1,334 unrelated patients with clinically suspected CMT referred by neurological and neuropediatric departments throughout Japan. We conducted mutation screening using a DNA microarray, targeted resequencing, and whole-exome sequencing. We identified pathogenic or likely pathogenic MFN2 variants from 79 CMT patients, comprising 44 heterozygous and 1 compound heterozygous variants. A total of 15 novel variants were detected. An autosomal dominant family history was determined in 43 cases, and the remaining 36 cases were reported as sporadic with no family history. The mean onset age of CMT in these patients was 12 +/- 14 (range 0-59) years. We observed neuropathic symptoms in all patients. Some had optic atrophy, vocal cord paralysis, or spasticity. We detected a compound heterozygous MFN2 mutation in a patient with a severe phenotype and the co-occurrence of MFN2 and PMP22 mutations in a patient with an uncommon phenotype. MFN2 is themost frequent causative gene of CMT2 in Japan. We present 15 novel variants and broad clinical and mutational spectra of Japanese MFN2-related CMT patients. Regardless of the onset age and inheritance pattern, MFN2 gene analysis should be performed. Combinations of causative genes should be considered to explain the phenotypic diversity.

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  • A. Yoshimura, J. -H. Yuan, A. Hashiguchi, Y. Hiramatsu, M. Ando, Y. Higuchi, T. Nakamura, Y. Okamoto, K. Matsumura, T. Hamano, N. Sawaura, Y. Shimatani, S. Kumada, Y. Okumura, J. Miyahara, Y. Yamaguchi, S. Kitamura, K. Haginoya, J. Mitsui, H. Ishiura, S. Tsuji, H. Takashima .  Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants .  CLINICAL GENETICS92 ( 3 ) 274 - 280   2017.9Reviewed International journal

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    BackgroundMutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes of Charcot-Marie-Tooth disease (CMT), with autosomal dominant or recessive inheritance pattern. The aim of this study is to identify the clinical and mutational spectrum of CMT patients with GDAP1 variants in Japan.
    Materials and MethodsFrom April 2007 to October 2014, using three state-of-art technologies, we conducted gene panel sequencing in a cohort of 1,030 patients with inherited peripheral neuropathies (IPNs), and 398 mutation-negative cases were further analyzed with whole-exome sequencing.
    ResultsWe identified GDAP1 variants from 10 patients clinically diagnosed with CMT. The most frequent recessive variant in our cohort (5/10), c.740C&gt;T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C&gt;T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G&gt;A (p.E126K) in Case 8. Nerve conduction study or sural nerve biopsy of all 10 patients indicated axonal type peripheral neuropathy.
    ConclusionWe identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan.

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  • Jun-Hui Yuan, Akihiro Hashiguchi, Akiko Yoshimura, Hiroshi Yaguchi, Koji Tsuzaki, Azusa Ikeda, Kenji Wada-Isoe, Masahiro Ando, Tomonori Nakamura, Yujiro Higuchi, Yu Hiramatsu, Yuji Okamoto, Hiroshi Takashima .  Clinical diversity caused by novel IGHMBP2 variants .  JOURNAL OF HUMAN GENETICS62 ( 6 ) 599 - 604   2017.6Reviewed International journal

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    Immunoglobulin helicase mu-binding protein 2 (IGHMBP2) gene is responsible for Charcot-Marie-Tooth disease (CMT) type 2S and spinal muscular atrophy with respiratory distress type 1 (SMARD1). From June 2014 to December 2015, we collected 408 cases, who referred to our genetic laboratory for genetic analysis, suspected with CMT disease or other inherited peripheral neuropathies (IPNs) on the basis of clinical manifestations and electrophysiological studies. Mutation screening was performed using Ion AmpliSeq Custom Panels, which comprise 72 disease-causing or candidate genes of IPNs. We identified novel homozygous or compound heterozygous variants of IGHMBP2 in four patients. Three patients presented with childhood-onset axonal predominant sensorimotor polyneuropathies, whereas the other case was diagnosed with SMARD1, manifesting as low birth weight, weak cry, reduced spontaneous movement and developed respiratory distress 4 months after birth. We present the original report of CMT type 2S in Japan, and illustrate that recessive IGHMBP2 variants account for similar to 1.6% of axonal CMT in our cohort.

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  • Yuan Jun-Hui, Hashiguchi Akihiro, Yoshimura Akiko, Yaguchi Hiroshi, Tsuzaki Koji, Ikeda Azusa, Wada-Isoe Kenji, Ando Masahiro, Nakamura Tomonori, Higuchi Yujiro, Hiramatsu Yu, Okamoto Yuji, Takashima Hiroshi .  新規IGHMBP2変異による臨床的多様性(Clinical diversity caused by novel IGHMBP2 variants) .  Journal of Human Genetics62 ( 6 ) 599 - 604   2017.6新規IGHMBP2変異による臨床的多様性(Clinical diversity caused by novel IGHMBP2 variants)Reviewed International journal

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    2014年6月〜2015年12月に、臨床症状と電気生理学的検査でCharcot-Marie-Tooth病(CMT)やその他の遺伝性末梢ニューロパシー(IPS)と疑われた408例を対象に、次世代配列分析システムにて変異スクリーニングを行った。72種の原因遺伝子または疑いのある遺伝子が検出された。4名の患者で免疫グロブリンヘリカーゼμ結合性蛋白質2(IGHMBP2)の新規ホモ接合性または複合ヘテロ接合性変異が見つかった。3名は幼児発症性軸索型優性感覚運動性多発性神経障害であった。他の1名は呼吸窮迫を伴う脊髄性筋萎縮症1型(SMARD1)と診断した。低出生時体重、弱い泣き声、自発運動低下と出生4ヵ月後には呼吸窮迫を起こした。日本におけるCMT2S型の報告を調べたところ、劣性IGHMBP2変異は軸索型CMTの約1.6%にすぎなかった。臨床症状が多様であり、遺伝的因子の同定が必須であると考えられた。

  • Masayuki Wakita, Ran Takei, Fumio Miyashita, Yuki Hamada, Satoshi Ohyama, Hideki Matsuoka, Hiroshi Takashima .  Carotid ultrasound features of anomalous left vertebral artery originating from the aortic arch proximal to the left subclavian artery .  Neuroradiology Journal30 ( 2 ) 168 - 171   2017.4Reviewed International journal

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    We present three cases of anomalous origin of the left vertebral artery (LVA) detected during the evaluation of stroke. The VA usually enters the transverse foramen of the sixth cervical vertebra (C6), but an anomalous LVA originating from the aorta frequently enters at a higher level. In our series, ultrasound of the LVA showed entry at C4 in two patients and at C5 in one patient. These findings suggested anomalous LVA origin, and three-dimensional computed tomography demonstrated the LVA arising from the aorta proximal to the left subclavian arteries. Carotid duplex ultrasound is useful for the diagnosis of this anomaly.

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  • Hideaki Nishihara, Masatoshi Omoto, Masaki Takao, Yujiro Higuchi, Michiaki Koga, Motoharu Kawai, Hiroo Kawano, Eiji Ikeda, Hiroshi Takashima, Takashi Kanda .  Autopsy case of the C12orf65 mutation in a patient with signs of mitochondrial dysfunction. .  Neurology. Genetics3 ( 4 ) e171   2017Reviewed International journal

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    OBJECTIVE: To describe the autopsy case of a patient with a homozygous 2-base deletion, c171_172delGA (p.N58fs), in the C12orf65 gene. METHODS: We described the clinical history, neuroimaging data, neuropathology, and genetic analysis of the patients with C12orf65 mutations. RESULTS: The patient was a Japanese woman with a history of delayed psychomotor development, primary amenorrhea, and gait disturbance in her 20s. She was hospitalized because of respiratory failure at the age of 60. Pectus excavatum, long fingers and toes, and pes cavus were revealed by physical examination. Her IQ score was 44. Neurologic examination revealed ophthalmoplegia, optic atrophy, dysphagia, distal dominant muscle weakness and atrophy, hyperreflexia at patellar tendon reflex, hyporeflexia at Achilles tendon reflex, and extensor plantar reflexes. At age 60, she died of pneumonia. Lactate levels were elevated in the patient's serum and CSF. T2-weighted brain MRI showed symmetrical hyperintense brainstem lesions. At autopsy, axial sections exposed symmetrical cyst formation with brownish lesions in the upper spinal cord, ventral medulla, pons, dorsal midbrain, and medial hypothalamus. Microscopic analysis of these areas demonstrated mild gliosis with rarefaction. Cell bodies in the choroid plexuses were eosinophilic and swollen. Electron microscopic examination revealed that these cells contained numerous abnormal mitochondria. Whole-exome sequencing revealed the 2-base deletion in C12orf65. CONCLUSIONS: We report an autopsy case of the C12orf65 mutation, and findings suggest that mitochondrial dysfunction may underlie the unique clinical presentations.

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  • 髙嶋 博, 荒田 仁, 東 桂子, 松浦 英治 .  子宮頸がんワクチンに関連した自己免疫脳症 .  神経治療学34 ( 6 ) S136 - S136   2017

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    DOI: 10.15082/jsnt.34.6_S136

  • Takashima Hiroshi, Kuwabara Satoshi, Kuriyama Masaru, Iizuka Takahiro .  Discussion on Clinical Diversity of Various Encephalitis/Encephalopathy .  Nihon Naika Gakkai Zasshi106 ( 8 ) 1598 - 1610   2017International journal

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    DOI: 10.2169/naika.106.1598

  • Takashima Hiroshi .  Diagnostic tips and treatment of autoimmune encephalopathy .  Neurological Therapeutics34 ( 3 ) 160 - 162   2017Reviewed

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    <p>Autoimmune encephalopathies are clinically and immunologically heterogeneous disorders. Many different types of autoimmune encephalopathy have been discovered, and most common type may be Hashimoto encephalopathy in it. In clinical situations, we often recognize that patients with autoimmune encephalopathy are often misdiagnosed as exhibiting functional psychogenic movement, conversion, or somatoform disorders. We clinically analyzed 63 patients with autoimmune encephalopathy. Two–thirds of patients showed motor disturbance mostly with give–way weakness. About 70% of patients showed sensory abnormalities such as strong pain, deep muscle pain, dysesthesia, paresthesia, or fast neurologic pain. Most pain was distributed in manner that was not explainable anatomically. 27% of patients exhibited involuntary movements such as tremor entrainment, dystonia, or coarse involuntary movement. We observed memory loss, PNES (psychogenic non–epileptic seizure), dissociative amnesia, hyperventilation, opsoclonus, epilepsy, or autonomic symptoms amongst our patients. Although give–way weakness, anatomically unexplainable pain, and strange involuntary movements were thought to be psychogenic, the presence of one of these three symptoms was indicative of autoimmune encephalopathy. As autoimmune encephalitis exhibits diffuse involvement with the whole brain, these symptoms were entirely understandable. Except for the presence of organic disease, most patients were classified into somatoform disorders or functional movement disorders. Without first excluding autoimmune encephalopathy, physicians should not diagnose somatoform disorders.</p>

    DOI: 10.15082/jsnt.34.3_160

  • HAMADA Yuki, MIYASHITA Fumio, MATSUOKA Hideki, NISHINAKAMA Yuki, KAI Yusuke, YAMASHITA Yusuke, IKEDA Mei, TAKAGUCHI Go, MASUDA Keisuke, KUBO Fumikatsu, TAKASHIMA Hiroshi .  Alternative Proximal Protection Method during Carotid Artery Stenting Using Combined Transbrachial and Transradial Artery Approaches .  NMC Case Report Journal10 ( 0 ) 273 - 278   2023.12Alternative Proximal Protection Method during Carotid Artery Stenting Using Combined Transbrachial and Transradial Artery Approaches

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    <p>Herein, we report a case of carotid artery stenting with proximal flow protection for severe stenosis of the left internal carotid artery using transbrachial and transradial artery approaches. Because an abdominal aortic aneurysm was present, we avoided the transfemoral approach. The procedure was successfully performed with a combination of an 8-Fr balloon guide catheter and microballoon catheter on separate axes. No complications such as pseudoaneurysm, thrombosis, or dissection were observed at the puncture site. The patient was discharged without complications and showed good outcomes at 3 months. This technique may offer a useful alternative for patients with severe stenosis who cannot be treated using a femoral artery approach.</p>

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  • Matsuura E., Nozuma S., Shigehisa A., Dozono M., Nakamura T., Tanaka M., Kubota R., Hashiguchi A., Takashima H. .  HTLV-1-associated myelopathy/tropical spastic paraplegia with sporadic late-onset nemaline myopathy: a case report .  BMC Musculoskeletal Disorders24 ( 1 ) 355   2023.12

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    Background: Sporadic late onset nemaline myopathy (SLONM) is a muscle disorder characterized by the presence of nemaline rods in muscle fibers. SLONM has no known genetic cause but has been associated with monoclonal gammopathy of undetermined significance and with human immunodeficiency virus (HIV) infection. Human T-cell leukemia virus-1 (HTLV-1) is a known causative agent of adult T-cell leukemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraplegia (HAM/TSP), a chronic inflammatory neurological disease. HTLV-1 has been reported to be implicated in inflammatory myopathies, as well as in HIV infection.; however, there have been no reports of an association between HTLV-1 infection and SLONM to date. Case presentation: A 70-year-old Japanese woman presented with gait disturbance, lumbar kyphosis, and respiratory dysfunction. The diagnosis of HAM/TSP with SLONM was made based on characteristic clinical symptoms of HAM/TSP, such as spasticity in the lower extremities, and cerebrospinal fluid test results; and of SLONM, such as generalized head drooping, respiratory failure, and muscle biopsy results. Steroid treatment was initiated and improvement in her stooped posture was observed after 3 days of treatment. Conclusion: This is the first case report of SLONM combined with HTLV-1 infection. Further studies are needed to elucidate the relationship between retroviruses and muscle diseases.

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  • Hirano M, Kuwahara M, Yamagishi Y, Samukawa M, Fujii K, Yamashita S, Ando M, Oka N, Nagano M, Matsui T, Takeuchi T, Saigoh K, Kusunoki S, Takashima H, Nagai Y .  CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy. .  Scientific reports13 ( 1 ) 17801   2023.10

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    Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy.

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  • Takahashi Nobutaka, Mishima Takayasu, Fujioka Shinsuke, Izumi Kohtarou, Ando Masahiro, Higuchi Yujiro, Takashima Hiroshi, Tsuboi Yoshio .  Siblings with Cockayne Syndrome B Type III Presenting with Slowly Progressive Cerebellar Ataxia .  Internal Medicine62 ( 15 ) 2253 - 2259   2023.8

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    <p>Two patients, 48- and 50-year-old sisters, presented with a characteristic facial appearance with slowly progressive deafness and cerebellar ataxia starting in their 30s. Genetic testing identified compound heterozygous pathogenic variants in the <i>ERCC6</i> gene: c.1583G>A (p.G528E) and c.1873T>G (p.Y625D). A diagnosis of Cockayne syndrome (CS) B type III was made. CS is usually diagnosed in childhood with well-defined facial characteristics and photosensitivity. This case report describes rare cases of adulthood CS with a primary presentation of slowly progressing deafness and cerebellar ataxia. CS should be considered in adults with characteristic facial and skin findings, deafness, and cerebellar ataxia. </p>

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  • Takahashi Nobutaka, Mishima Takayasu, Fujioka Shinsuke, Izumi Kohtarou, Ando Masahiro, Higuchi Yujiro, Takashima Hiroshi, Tsuboi Yoshio .  Siblings with Cockayne Syndrome B Type III Presenting with Slowly Progressive Cerebellar Ataxia(タイトル和訳中) .  Internal Medicine62 ( 15 ) 2253 - 2259   2023.8Siblings with Cockayne Syndrome B Type III Presenting with Slowly Progressive Cerebellar Ataxia(タイトル和訳中)

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  • Okamoto Y., Takashima H. .  The Current State of Charcot–Marie–Tooth Disease Treatment .  Genes14 ( 7 )   2023.7

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    Charcot–Marie–Tooth disease (CMT) and associated neuropathies are the most predominant genetically transmitted neuromuscular conditions; however, effective pharmacological treatments have not established. The extensive genetic heterogeneity of CMT, which impacts the peripheral nerves and causes lifelong disability, presents a significant barrier to the development of comprehensive treatments. An estimated 100 loci within the human genome are linked to various forms of CMT and its related inherited neuropathies. This review delves into prospective therapeutic strategies used for the most frequently encountered CMT variants, namely CMT1A, CMT1B, CMTX1, and CMT2A. Compounds such as PXT3003, which are being clinically and preclinically investigated, and a broad array of therapeutic agents and their corresponding mechanisms are discussed. Furthermore, the progress in established gene therapy techniques, including gene replacement via viral vectors, exon skipping using antisense oligonucleotides, splicing modification, and gene knockdown, are appraised. Each of these gene therapies has the potential for substantial advancements in future research.

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  • Matsuura E., Nozuma S., Dozono M., Kodama D., Tanaka M., Kubota R., Takashima H. .  Iliopsoas Muscle Weakness as a Key Diagnostic Marker in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) .  Pathogens12 ( 4 )   2023.4

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    Human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive neurological disease that arises from HTLV-1 infection. Pathologically, the condition is characterized by diffuse myelitis, which is most evident in the thoracic spinal cord. Clinical manifestations of the infectious disease, HAM/TSP, are empirically known to include weakness of the proximal muscles of the lower extremities and atrophy of the paraspinal muscles, which is characteristic of the distribution of disturbed muscles usually seen in muscular diseases, except that the upper extremities are almost normal. This unique clinical presentation is useful information for physicians and physical therapists involved in diagnosing and rehabilitating patients with HAM/TSP, as well as critical information for understanding the pathogenesis of HAM/TSP. However, the precise pattern of muscle involvement in this condition has yet to be reported. The purpose of this study was to identify the muscles affected by HAM/TSP in order to understand the pathogenesis of HAM/TSP as well as to aid in the diagnosis and rehabilitation of HAM/TSP. A retrospective review of medical records was conducted on 101 consecutively admitted patients with HAM/TSP at Kagoshima University Hospital. Among 101 patients with HAM/TSP, all but three had muscle weakness in the lower extremities. Specifically, the hamstrings and iliopsoas muscle were the most frequently affected in over 90% of the patients. Manual muscle testing (MMT) revealed that the iliopsoas was the weakest of the muscles assessed, a consistent feature from the early to advanced stages of the disease. Our findings demonstrate a unique distribution of muscle weakness in HAM/TSP, with the proximal muscles of the lower extremities, particularly the iliopsoas muscle, being the most frequently and severely affected.

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  • Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Mika Dozono, Takahiro Hobara, Fumikazu Kojima, Yutaka Noguchi, Mika Takeuchi, Jun Takei, Yu Hiramatsu, Satoshi Nozuma, Tomonori Nakamura, Yusuke Sakiyama, Akihiro Hashiguchi, Eiji Matsuura, Yuji Okamoto, Jun Sone, Hiroshi Takashima .  Clinical phenotypic diversity of NOTCH2NLC-related disease in the largest case series of inherited peripheral neuropathy in Japan. .  Journal of neurology, neurosurgery, and psychiatry94 ( 8 ) 622 - 630   2023.3International journal

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    BACKGROUND: NOTCH2NLC GGC repeat expansions have been associated with various neurogenerative disorders, including neuronal intranuclear inclusion disease and inherited peripheral neuropathies (IPNs). However, only a few NOTCH2NLC-related disease studies in IPN have been reported, and the clinical and genetic spectra remain unclear. Thus, this study aimed to describe the clinical and genetic manifestations of NOTCH2NLC-related IPNs. METHOD: Among 2692 Japanese patients clinically diagnosed with IPN/Charcot-Marie-Tooth disease (CMT), we analysed NOTCH2NLC repeat expansion in 1783 unrelated patients without a genetic diagnosis. Screening and repeat size determination of NOTCH2NLC repeat expansion were performed using repeat-primed PCR and fluorescence amplicon length analysis-PCR. RESULTS: NOTCH2NLC repeat expansions were identified in 26 cases of IPN/CMT from 22 unrelated families. The mean median motor nerve conduction velocity was 41 m/s (range, 30.8-59.4), and 18 cases (69%) were classified as intermediate CMT. The mean age of onset was 32.7 (range, 7-61) years. In addition to motor sensory neuropathy symptoms, dysautonomia and involuntary movements were common (44% and 29%). Furthermore, the correlation between the age of onset or clinical symptoms and the repeat size remains unclear. CONCLUSIONS: These findings of this study help us understand the clinical heterogeneity of NOTCH2NLC-related disease, such as non-length-dependent motor dominant phenotype and prominent autonomic involvement. This study also emphasise the importance of genetic screening, regardless of the age of onset and type of CMT, particularly in patients of Asian origin, presenting with intermediate conduction velocities and dysautonomia.

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  • Hamada Yuki, Shigehisa Ayano, Kanda Yoshiki, Ikeda Mei, Takaguchi Go, Matsuoka Hideki, Takashima Hiroshi .  Enhancement of the Ivy Sign during an Ischemic Event in Moyamoya Disease(タイトル和訳中) .  Internal Medicine62 ( 4 ) 617 - 621   2023.2Enhancement of the Ivy Sign during an Ischemic Event in Moyamoya Disease(タイトル和訳中)

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    症例は67歳女性。突然に左片麻痺、左同名半盲、左半側空間無視が出現した。頭部MRI検査で右頭頂葉に脳梗塞を認めた。Fluid-attenuated inversion recovery(FLAIR)画像ではクモ膜下腔にivy signを認め、それらは梗塞領域の拡大とともに増加・拡大した。脳血管造影所見からもやもや病と診断し、抗血栓療法は回避して、ドパミン点滴静注による血圧コントロールと濃グリセリン・果糖点滴静注による脳浮腫の拡大予防を継続したところ、神経症状と脳梗塞の進行は抑止され、ivy signも消失した。ivy signは脳梗塞の拡大とともに増強し、虚血の解除とともに消失したことから、血行力学的変化が起こったことが示唆された。

  • Hamada Yuki, Matsuoka Hideki, Takashima Hiroshi .  Development of Ivy Sign and Infarction in the Lateral Part of the Hemisphere or the Middle Cerebral Artery Territory in Association with Steno-occlusive Involvement of the Posterior Cerebral Artery in Moyamoya Disease .  Internal Medicineadvpub ( 0 ) 1703 - 1704   2023

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    DOI: 10.2169/internalmedicine.0969-22

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  • Yuan JH, Higuchi Y, Hashiguchi A, Ando M, Yoshimura A, Nakamura T, Hiramatsu Y, Sakiyama Y, Takashima H .  Gene panel analysis of 119 index patients with suspected periodic paralysis in Japan. .  Frontiers in neurology14   1078195   2023

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    Introduction: Genetic factors are recognized as the major reason for patients with periodic paralysis. The goal of this study was to determine the genetic causes of periodic paralysis in Japan. Methods: We obtained a Japanese nationwide case series of 119 index patients (108 men and 11 women) clinically suspected of periodic paralysis, and a gene panel analysis, targeting CACNA1S, SCN4A, and KCNJ2 genes, was conducted. Results: From 34 cases, 25 pathogenic/likely pathogenic/unknown significance variants were detected in CACNA1S (nine cases), SCN4A (19 cases), or KCNJ2 (six cases), generating a molecular diagnostic rate of 28.6%. In total, seven variants have yet been found linked to periodic paralysis previously. The diagnostic yield of patients with hypokalemic and hyperkalemic periodic paralyzes was 26.2 (17/65) and 32.7% (17/52), respectively. A considerably higher yield was procured from patients with than without positive family history (18/25 vs. 16/94), onset age ≤20 years (24/57 vs. 9/59), or recurrent paralytic attacks (31/94 vs. 3/25). Discussion: The low molecular diagnostic rate and specific genetic proportion of the present study highlight the etiological complexity of patients with periodic paralysis in Japan.

    DOI: 10.3389/fneur.2023.1078195

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  • Nagata R, Matsuura E, Nozuma S, Dozono M, Noguchi Y, Ando M, Hiramatsu Y, Kodama D, Tanaka M, Kubota R, Yamakuchi M, Higuchi Y, Sakiyama Y, Arata H, Higashi K, Hashiguchi T, Nakane S, Takashima H .  Anti-ganglionic acetylcholine receptor antibodies in functional neurological symptom disorder/conversion disorder. .  Frontiers in neurology14   1137958   2023

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    Objective: Autoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by autonomic failure associated with the presence of anti-ganglionic acetylcholine receptor (gAChR) antibodies; however, several studies have reported that individuals with anti-gAChR antibodies present with central nervous system (CNS) symptoms such as impaired consciousness and seizures. In the present study, we investigated whether the presence of serum anti-gAChR antibodies correlated with autonomic symptoms in patients with functional neurological symptom disorder/conversion disorder (FNSD/CD). Methods: Clinical data were collected for 59 patients presenting with neurologically unexplained motor and sensory symptoms at the Department of Neurology and Geriatrics between January 2013 and October 2017 and who were ultimately diagnosed with FNSD/CD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Correlations between serum anti-gAChR antibodies and clinical symptoms and laboratory data were analyzed. Data analysis was conducted in 2021. Results: Of the 59 patients with FNSD/CD, 52 (88.1%) exhibited autonomic disturbances and 16 (27.1%) were positive for serum anti-gAChR antibodies. Cardiovascular autonomic dysfunction, including orthostatic hypotension, was significantly more prevalent (75.0 vs. 34.9%, P = 0.008), whereas involuntary movements were significantly less prevalent (31.3 vs. 69.8%, P = 0.007), among anti-gAChR antibody-positive compared with -negative patients. Anti-gAChR antibody serostatus did not correlate significantly with the frequency of other autonomic, sensory, or motor symptoms analyzed. Conclusions: An autoimmune mechanism mediated by anti-gAChR antibodies may be involved in disease etiology in a subgroup of FNSD/CD patients.

    DOI: 10.3389/fneur.2023.1137958

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  • Mitsui J., Matsukawa T., Uemura Y., Kawahara T., Chikada A., Porto K.J.L., Naruse H., Tanaka M., Ishiura H., Toda T., Kuzuyama H., Hirano M., Wada I., Ga T., Moritoyo T., Takahashi Y., Mizusawa H., Ishikawa K., Yokota T., Kuwabara S., Sawamoto N., Takahashi R., Abe K., Ishihara T., Onodera O., Matsuse D., Yamasaki R., Kira J.I., Katsuno M., Hanajima R., Ogata K., Takashima H., Matsushima M., Yabe I., Sasaki H., Tsuji S. .  High-dose ubiquinol supplementation in multiple-system atrophy: a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial .  eClinicalMedicine59   101920   2023

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    Background: Functionally impaired variants of COQ2, encoding an enzyme in biosynthesis of coenzyme Q10 (CoQ10), were found in familial multiple system atrophy (MSA) and V393A in COQ2 is associated with sporadic MSA. Furthermore, reduced levels of CoQ10 have been demonstrated in MSA patients. Methods: This study was a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Patients with MSA were randomly assigned (1:1) to either ubiquinol (1500 mg/day) or placebo. The primary efficacy outcome was the change in the unified multiple system atrophy rating scale (UMSARS) part 2 at 48 weeks. Efficacy was assessed in all patients who completed at least one efficacy assessment (full analysis set). Safety analyses included patients who completed at least one dose of investigational drug. This trial is registered with UMIN-CTR (UMIN000031771), where the drug name of MSA-01 was used to designate ubiquinol. Findings: Between June 26, 2018, and May 27, 2019, 139 patients were enrolled and randomly assigned to the ubiquinol group (n = 69) or the placebo group (n = 70). A total of 131 patients were included in the full analysis set (63 in the ubiquinol group; 68 in the placebo group). This study met the primary efficacy outcome (least square mean difference in UMSARS part 2 score (−1.7 [95% CI, −3.2 to −0.2]; P = 0.023)). The ubiquinol group also showed better secondary efficacy outcomes (Barthel index, Scale for the Assessment and Rating of Ataxia, and time required to walk 10 m). Rates of adverse events potentially related to the investigational drug were comparable between ubiquinol (n = 15 [23.8%]) and placebo (n = 21 [30.9%]). Interpretation: High-dose ubiquinol was well-tolerated and led to a significantly smaller decline of UMSARS part 2 score compared with placebo. Funding: Japan Agency for Medical Research and Development.

    DOI: 10.1016/j.eclinm.2023.101920

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  • Hiramatsu Yu, Sakiyama Yusuke, Takashima Hiroshi .  Neuroinfection and preventive medicine .  Neurological Therapeutics40 ( 2 ) 99 - 103   2023Neuroinfection and preventive medicine

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    <p>The discovery and approval of novel treatments and vaccines are altering the trajectory of neuroinfectious illnesses.</p><p>As for bacterial meningitis, the pneumococcal vaccine and Haemophilus influenzae type b vaccine have reduced the incidence of bacterial meningitis in children. The pneumococcal vaccine is now routinely administered to adults as well to prevent pneumonia, but problems of serotype substitution have arisen, including for children. Additionally, recently approved medications for the treatment of systemic myasthenia gravis and neuromyelitis optica spectrum diseases, such as eculizumab and labulizumab, increase the risk of meningococcal infection in adults and may result in meningitis. As a result, it is critical to immunize patients against meningococcal meningitis before administration and to describe the risks to the patient and family.</p><p>For tetanus, additional immunization with absorbed tetanus toxoid or concomitant use of human tetanus immune globulin should be taken into account, depending on the condition of the wound. According to an evaluation of contamination, wound depth, and consequences from neuropathy or ischemia, aggressive debridement should be taken into consideration for non–open wounds.</p><p>Vaccines for shingles have been approved for patients over 50 years of age, both live attenuated vaccines and genetically engineered vaccines. Given that both are successful in avoiding the disease's start, it is important to recognize the benefits and drawbacks of each and employ them appropriately.</p><p>The Japanese encephalitis virus, a flavivirus, is subject to routine vaccination in childhood, but it is known that the antibody retention rate declines in adults, and additional vaccination should be considered for those who work in rural areas in endemic areas. Although Japan has not licensed a vaccine for the tick–borne encephalitis virus, the administration should be taken into account if the individual will be living in an area where it is common or will be visiting a forest.</p><p>There is also disagreement over the effectiveness of long–term SARS–CoV–2 vaccines, and further understanding of the etiology is preferred.</p>

    DOI: 10.15082/jsnt.40.2_99

  • Nozuma S., Matsuura E., Tanaka M., Kodama D., Matsuzaki T., Yoshimura A., Sakiyama Y., Nakahata S., Morishita K., Enose-Akahata Y., Jacoboson S., Kubota R., Takashima H. .  Identification and tracking of HTLV-1-infected T cell clones in virus-associated neurologic disease .  JCI Insight8 ( 7 )   2023

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    Human T lymphotropic virus type 1-assoicated (HTLV-1-associated) myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory disease caused by the persistent proliferation of HTLV-1-infected T cells. Here, we performed a T cell receptor (TCR) repertoire analysis focused on HTLV-1-infected cells to identify and track the infected T cell clones that are preserved in patients with HAM/TSP and migrate to the CNS. TCRβ repertoire analysis revealed higher clonal expansion in HTLV-1-infected cells compared with noninfected cells from patients with HAM/TSP and asymptomatic carriers (ACs). TCR clonality in HTLV-1-infected cells was similar in patients with HAM/TSP and ACs. Longitudinal analysis showed that the TCR repertoire signature in HTLV-1-infected cells remained stable, and highly expanded infected clones were preserved within each patient with HAM/TSP over years. Expanded HTLV-1-infected clones revealed different distributions between cerebrospinal fluid (CSF) and peripheral blood and were enriched in the CSF of patients with HAM/TSP. Cluster analysis showed similarity in TCRβ sequences in HTLV-1-infected cells, suggesting that they proliferate after common antigen stimulation. Our results indicate that exploring TCR repertoires of HTLV-1-infected cells can elucidate individual clonal dynamics and identify potential pathogenic clones expanded in the CNS.

    DOI: 10.1172/jci.insight.167422

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  • Nozaki Ichiro, Hashiguchi Akihiro, Takashima Hiroshi, Yamashita Yoko, Higashide Tomomi, Iwasa Kazuo, Ono Kenjiro .  Charcot-Marie-Tooth Disease with A Novel Variant in <i>Gap Junction Protein Beta 1</i> Presenting with Visual Field Defects .  Internal Medicineadvpub ( 0 ) 3033 - 3036   2023

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    <p>Pathogenic variants in<i> Gap Junction Protein Beta 1</i> (<i>GJB1)</i> cause X-linked Charcot-Marie-Tooth (CMT) disease type 1 (CMTX1), which is a common hereditary motor and sensory neuropathy. A 45-year-old man presented with progressive muscle weakness, atrophy, sensory disturbance of all limbs from childhood, and visual field defects in both eyes at 40 years old. A segregation analysis revealed a novel variant, c.173 C>A (p. P58H), in the <i>GJB1</i> gene. Patients with variants at codon 58 in <i>GJB1</i> showed clinically varied phenotypes, ranging from demyelinating neuropathy to cerebellar ataxia. This patient may represent one of the various clinical phenotypes of <i>GJB1</i> variants. </p>

    DOI: 10.2169/internalmedicine.1403-22

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  • M.D. Imoto Makiko, M.D. Nakamura Kota, M.D. Inoue Kimiko, M.D. Ph.D. Ando Masahiro, M.D. Ph.D. Higuchi Yujiro, M.D. Ph.D. Takashima Hiroshi, M.D. Ph.D. Okuda Shiho .  Involvement of autonomic nervous system since middle age in elderly patient with giant axonal neuropathy caused by novel genetic mutation .  Rinsho Shinkeigaku63 ( 9 ) 566 - 571   2023

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    <p>A 69-year-old man began to experience difficulty with walking at the age of 5 years and started use of a cane at around 13 years, then finally started using a wheelchair at 17 years old. A diagnosis of Charcot-Marie-Tooth disease was previously determined at another hospital, though neither peripheral nerve biopsy nor gene analysis was conducted. He visited our institution at the age of 54 years and irregular outpatient examinations were started, which indicated slowly progressive muscle weakness and sensory disturbance of the limbs, leading to a decline in activities of daily living. Gene analysis at 60 years old identified a novel homozygous missense mutation in the gigaxonin gene, c.1478A>C, p.E493A. Intellectual capacity was preserved and kinky hair was not present, though complications such as vocal cord paralysis, paralytic ileus, and dysarthria were noted starting at age 61. Based on these findings, the patient was diagnosed with a mild form of giant axonal neuropathy.</p>

    DOI: 10.5692/clinicalneurol.cn-001822

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  • Yoshimoto Yukiyo, Yoshimoto Shoko, Kakiuchi Kensuke, Miyagawa Rumina, Ota Shin, Hosokawa Takafumi, Ishida Shimon, Higuchi Yujiro, Hashiguchi Akihiro, Takashima Hiroshi, Arawaka Shigeki .  Spatial Fluctuation of Central Nervous System Lesions in X-linked Charcot-Marie-Tooth Disease with a Novel <i>GJB1</i> Mutation .  Internal Medicineadvpub ( 0 )   2023Spatial Fluctuation of Central Nervous System Lesions in X-linked Charcot-Marie-Tooth Disease with a Novel <i>GJB1</i> Mutation

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    <p>X-linked Charcot-Marie-Tooth disease type 1 (CMTX1), the most common form of CMTX, is caused by gap-junction beta 1 (<i>GJB1</i>) mutations. We herein report a 25-year-old Japanese man with disorientation, right hemiparesis, and dysarthria. Brain magnetic resonance imaging (MRI) showed high signal intensities in the bilateral cerebral white matter on diffusion-weighted imaging. He had experienced 2 episodes of transient central nervous system symptoms (at 7 and 13 years old). A genetic analysis identified a novel <i>GJB1</i> mutation, c.169 C>T, p.Gln57*. MRI abnormalities shifted from the cerebral white matter to the corpus callosum and had disappeared at the five-month follow-up. Transient changes between these lesions may indicate CMTX1. </p>

    DOI: 10.2169/internalmedicine.1713-23

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  • Takei J., Higuchi Y., Ando M., Yoshimura A., Yuan J.H., Fujisaki N., Tokashiki T., Kanzato N., Jonosono M., Sueyoshi T., Kanda N., Matsuoka H., Okubo R., Suehara M., Matsuura E., Takashima H. .  Microbleed clustering in thalamus sign in CADASIL patients with NOTCH3 R75P mutation .  Frontiers in Neurology14   1241678   2023

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    Background and objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microvascular disease characterized by the development of vascular dementia and lacunar infarctions. This study aimed to identify the genetic and clinical features of CADASIL in Japan. Methods: We conducted genetic analysis on a case series of patients clinically diagnosed with CADASIL. Clinical and imaging analyses were performed on 32 patients with pathogenic mutations in the NOTCH3 gene. To assess the presence of cerebral microbleeds (CMBs), we utilized several established rating scales including the Fazekas scale, Scheltens rating scale, and Microbleed Anatomical Rating Scale, based on brain MRI images. Results: Among the 32 CADASIL patients, 24 cases were found carrying the R75P mutation in NOTCH3, whereas the remaining eight cases had other NOTCH3 mutations (R75Q, R110C, C134F, C144F, R169C, and R607C). The haplotype analysis of the R75P mutation uncovered the presence of a founder effect. A brain MRI analysis revealed that cases with the R75P mutation had a significantly higher total number of CMBs, particularly in the thalamus when compared to patients with other NOTCH3 mutations. Among 15 out of 24 cases with the R75P mutation, we observed a notable clustering of CMBs in the thalamus, termed microbleed clustering in thalamus sign (MCT sign). Conclusion: We propose that the MCT sign observed in NOTCH3 R75P-related CADASIL patients may serve as a potentially characteristic imaging feature. This finding offers further insights into the interactions between genotypes and phenotypes between NOTCH3 and CADASIL.

    DOI: 10.3389/fneur.2023.1241678

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  • Yuan J.H., Cheng X., Matsuura E., Higuchi Y., Ando M., Hashiguchi A., Yoshimura A., Nakachi R., Mine J., Taketani T., Maeda K., Kawakami S., Kira R., Tanaka S., Kanai K., Dib-Hajj F., Dib-Hajj S.D., Waxman S.G., Takashima H. .  Genetic, electrophysiological, and pathological studies on patients with SCN9A-related pain disorders .  Journal of the Peripheral Nervous System   2023

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    Background and Aims: Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis. Methods: We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system. Results: From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p <.001) and slow inactivation (5.5 mV, p <.001), but no effect on channel activation was observed. Interpretation: Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype–phenotype association caused by Nav1.7 gain-of-function mutations.

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  • Masuda Aiko, Hamada Yuki, Matsuoka Hideki, Takashima Hiroshi .  Eagle Syndrome Induced by the Head Retroflexion .  Internal Medicineadvpub ( 0 )   2023Eagle Syndrome Induced by the Head Retroflexion

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    DOI: 10.2169/internalmedicine.2704-23

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  • Higuchi Y., Ando M., Kojima F., Yuan J., Hashiguchi A., Yoshimura A., Hiramatsu Y., Nozuma S., Fukumura S., Yahikozawa H., Abe E., Toyoshima I., Sugawara M., Okamoto Y., Matsuura E., Takashima H. .  Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum .  Journal of Neurology   2023

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    Background and objective: Biallelic mutations in the COA7 gene have been associated with spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3), and a notable clinical diversity has been observed. We aim to identify the genetic and phenotypic spectrum of COA7-related disorders. Methods: We conducted comprehensive genetic analyses on the COA7 gene within a large group of Japanese patients clinically diagnosed with inherited peripheral neuropathy or cerebellar ataxia. Results: In addition to our original report, which involved four patients until 2018, we identified biallelic variants of the COA7 gene in another three unrelated patients, and the variants were c.17A > G (p.D6G), c.115C > T (p.R39W), and c.449G > A (p.C150Y; novel). Patient 1 presented with an infantile-onset generalized dystonia without cerebellar ataxia. Despite experiencing an initial transient positive response to levodopa and deep brain stimulation, he became bedridden by the age of 19. Patient 2 presented with cerebellar ataxia, neuropathy, as well as parkinsonism, and showed a slight improvement upon levodopa administration. Dopamine transporter SPECT showed decreased uptake in the bilateral putamen in both patients. Patient 3 exhibited severe muscle weakness, respiratory failure, and feeding difficulties. A haplotype analysis of the mutation hotspot in Japan, c.17A > G (p.D6G), uncovered a common haplotype block. Conclusion: COA7-related disorders typically encompass a spectrum of conditions characterized by a variety of major (cerebellar ataxia and axonal polyneuropathy) and minor (leukoencephalopathy, dystonia, and parkinsonism) symptoms, but may also display a dystonia-predominant phenotype. We propose that COA7 should be considered as a new causative gene for infancy-onset generalized dystonia, and COA7 gene screening is recommended for patients with unexplained dysfunctions of the central and peripheral nervous systems.

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  • 髙嶋 博 .  Discovery 新・感染症学−真の脳炎・脳症の原因を求めて− .  神経感染症28 ( 1 ) 1   2023Discovery 新・感染症学−真の脳炎・脳症の原因を求めて−

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  • Ishikawa R., Nakamori M., Takenaka M., Aoki S., Yamazaki Y., Hashiguchi A., Takashima H., Maruyama H. .  Case report: Mitochondrial trifunctional protein deficiency caused by HADHB gene mutation (c.1175C&gt;T) characterized by higher brain dysfunction followed by neuropathy, presented gadolinium enhancement on brain imaging in an adult patient .  Frontiers in Neurology14   1187822   2023

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    Mitochondrial trifunctional protein (MTP) deficiency is an autosomal recessive disorder caused by impaired metabolism of long-chain fatty acids (LCFAs). Childhood and late-onset MTP deficiency is characterized by myopathy/rhabdomyolysis and peripheral neuropathy; however, the features are unclear. A 44-year-old woman was clinically diagnosed with Charcot-Marie-Tooth disease at 3 years of age due to gait disturbance. Her activity and voluntary speech gradually decreased in her 40s. Cognitive function was evaluated and brain imaging tests were performed. The Mini-Mental State Examination and frontal assessment battery scores were 25/30 and 10/18, respectively, suggesting higher brain dysfunction. Peripheral nerve conduction studies revealed axonal impairments. Brain computed tomography showed significant calcification. Magnetic resonance imaging revealed an increased gadolinium contrast-enhanced signal in the white matter, suggesting demyelination of the central nervous system (CNS) due to LCFAs. The diagnosis of MTP deficiency was confirmed through genetic examination. Administration of L-carnitine and a medium-chain fatty triglyceride diet was initiated, and the progression of higher brain dysfunction was retarded within 1 year. This patient's presentation was suggestive of CNS demyelination. The presence of brain calcification, higher brain dysfunction, or gadolinium enhancement in the white matter in patients with peripheral neuropathy may be suggestive of MTP deficiency.

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  • Nozuma S., Yuji-Takeuchi M., Nakamura T., Saigo R., Masuda M., Ando M., Sakiyama Y., Miyata R., Tabata K., Matsuura E., Takashima H. .  A case of severe paraneoplastic glutamic acid decarboxylase antibody-spectrum disorder with improvement through prior immunotherapy before surgical intervention .  Clinical and Experimental Neuroimmunology14 ( 4 ) 202 - 206   2023

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    Background: Initially associated with stiff-person syndrome, antibodies to glutamic acid decarboxylase (GAD) antibodies are now recognized as indicators of GAD antibody-spectrum disorders (GAD-SD), which encompass cerebellar ataxia, autoimmune epilepsy and limbic encephalitis. Paraneoplastic neurological syndromes associated with GAD-SD are rare, and optimal timing of surgical intervention and impact on neurological symptoms remain poorly understood. Case Presentation: We present the case of a 65-year-old woman who developed overlapping symptoms of cerebellar ataxia and stiff-person syndrome detected through high-titer GAD antibodies in both serum and cerebrospinal fluid, alongside the presence of a thymoma. Due to severe dysphagia and gait ataxia that rendered her bedridden on admission, surgical intervention was initially deferred. Instead, she received immunotherapies including intravenous methylprednisolone and intravenous immunoglobulin, which remarkably improved neurological symptoms. However, a decline in symptoms occurred on tapering oral prednisolone. Subsequently, a thoracoscopic thymectomy was carried out 27 months after symptom onset, leading to further neurological improvement and successful reduction of prednisolone. Conclusion: In paraneoplastic GAD-SD cases with severe symptoms at presentation, prioritizing immunotherapy and considering surgical intervention once the symptoms have stabilized might be advantageous.

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  • Numahata Kyoko, Sugawara Miki, Watanabe Kazuyoshi, Takizawa Yoshinori, Katayanagi Junya, Ogawa Tomohiro, Onoue Hiroyuki, Akaiwa Yasuhisa, Hashiguchi Akihiro, Takashima Hiroshi, Miyamoto Tomoyuki .  A Case of Idiopathic Scoliosis with Intraoperative Neurophysiological Monitoring Abnormalities Leading to the Diagnosis of Charcot-Marie-Tooth Disease 1B .  Dokkyo Medical Journaladvpub ( 0 )   2023A Case of Idiopathic Scoliosis with Intraoperative Neurophysiological Monitoring Abnormalities Leading to the Diagnosis of Charcot-Marie-Tooth Disease 1B

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    <p>The current case report describes the clinical and genetic characteristics of a 16-year-old female proband. She did not have any subjective neurological symptoms preoperatively and who was incidentally diagnosed due to abnormal intraoperative neurophysiological monitoring (IONM) using transcranial electrical stimulation motor evoked potentials (TES-MEP) and somatosensory evoked potentials (SEP) for idiopathic scoliosis, leading to the diagnosis of Charcot-Marie-Tooth disease (CMT) 1B. There was no similar disease in her family history. Nerve conduction velocity testing revealed decreased conduction velocity of the median nerve, and genetic testing indicated myelin protein zero (<i>MPZ</i>) mutation (c242A > G), leading to the diagnosis of demyelinating type CMT1B. The parents had no genetic mutation, and this was a case of de novo mutation. CMT1B is an important differential diagnosis because, similar to our case, there may not be any clinical symptoms. The disease was discovered during a careful evaluation of the patient's scoliosis and other complications. TES-MEP was more useful than SEP for IONM of scoliosis with CMT1B.</p>

    DOI: 10.51040/dkmj.2023-005

  • M.D. Yamashiro Masataka, M.D. Ohnari Keiko, M.D. Higuchi Yujiro, M.D. Hashiguchi Hiroaki, M.D. Takashima Hiroshi, M.D. Okada Kazumasa .  A case of Charcot–Marie–Tooth disease type 2 caused by homozygous <i>MME</i> gene mutation .  Rinsho Shinkeigaku63 ( 11 ) 743 - 747   2023A case of Charcot–Marie–Tooth disease type 2 caused by homozygous <i>MME</i> gene mutation

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    <p>The patient is a 44-year-old man. His parents are consanguineous. He experienced muscle weakness in his toe and distal tingling sensation in his feet at 42 years of age, which gradually progressed. Additionally, a marked cyanotic discoloration of the feet appeared and worsened progressively. Neurological examination revealed loss of tendon reflexes and distal muscle weakness in the lower extremities. Findings from nerve conduction studies indicated axonal polyneuropathy. Upon detection of the <i>MME</i> gene mutation, the patient was diagnosed with autosomal-recessive Charcot–Marie–Tooth disease 2T (ARCMT2T). In this case, cyanosis of the lower extremities possibly was associated with ARCMT2T, and it was suggested to be due to neprilysin deletion linked with the <i>MME</i> mutation. This represents the first documented occurrence of cyanosis as a distinctive feature of CMT with <i>MME</i> mutation.</p>

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  • 髙嶋 博 .  間違いだらけの神経学 ―ヒステリー症候の終焉と新しい病態メカニズム― .  神経治療学40 ( 6 ) S199 - S199   2023間違いだらけの神経学 ―ヒステリー症候の終焉と新しい病態メカニズム―

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    DOI: 10.15082/jsnt.40.6_s199

  • M.D. Nagatomo Risa, M.D. Ph.D. Higuchi Yujiro, M.D. Takei Jun, M.D. Ph.D. Nakamura Tomonori, M.D. Ph.D. Hashiguchi Hiroaki, M.D. Ph.D. Takashima Hiroshi .  A case of myofibrillary myopathy due to <i>Bcl2-Associated Athanogene 3</i> (<i>BAG3</i>) mutation complicated by peripheral neuropathy .  Rinsho Shinkeigakuadvpub ( 0 )   2023A case of myofibrillary myopathy due to <i>Bcl2-Associated Athanogene 3</i> (<i>BAG3</i>) mutation complicated by peripheral neuropathy

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    <p>A 19-year-old female, normal at birth, grew up without neck movement when getting up. She needed a handrail to climb stairs since the age of 10 years old, and walked slowly since the age of 16 years old. Neurological examination revealed loss of deep tendon reflexes, decreased vibratory sensation, weakness of distal muscles of the lower extremities, and weakness of mainly cervical trunk muscles suspected to be due to myopathy. Nerve conduction studies suggested axonal polyneuropathy, and needle EMG showed short duration MUP, myotonic discharge, and rimmed vacuoles on muscle biopsy. Genetic analysis revealed a previously reported pathological mutation (p.P209L, heterozygous) in <i>Bcl2-Associated Athanogene 3</i> (<i>BAG3</i>), and a diagnosis of MFM6 was made. P209L is a poor prognosis myopathy that develops in childhood and is associated with cardiomyopathy. P209L is a solitary myopathy associated with axonal neuropathy and characterized by apex foot contracture and weak neck to trunk flexion. This disease is suspected in young-onset neuromyopathy.</p>

    DOI: 10.5692/clinicalneurol.cn-001915

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  • Ando M., Higuchi Y., Yuan J., Yoshimura A., Kojima F., Yamanishi Y., Aso Y., Izumi K., Imada M., Maki Y., Nakagawa H., Hobara T., Noguchi Y., Takei J., Hiramatsu Y., Nozuma S., Sakiyama Y., Hashiguchi A., Matsuura E., Okamoto Y., Takashima H. .  Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan .  Annals of Clinical and Translational Neurology   2023

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    Background and Objectives: The GAA repeat expansion within the fibroblast growth factor 14 (FGF14) gene has been found to be associated with late-onset cerebellar ataxia. This study aimed to investigate the genetic causes of cerebellar ataxia in patients in Japan. Methods: We collected a case series of 940 index patients who presented with chronic cerebellar ataxia and remained genetically undiagnosed after our preliminary genetic screening. To investigate the FGF14 repeat locus, we employed an integrated diagnostic strategy that involved fluorescence amplicon length analysis polymerase chain reaction (PCR), repeat-primed PCR, and long-read sequencing. Results: Pathogenic FGF14 GAA repeat expansions were detected in 12 patients from 11 unrelated families. The median size of the pathogenic GAA repeat was 309 repeats (range: 270–316 repeats). In these patients, the mean age of onset was 66.9 ± 9.6 years, with episodic symptoms observed in 56% of patients and parkinsonism in 30% of patients. We also detected FGF14 repeat expansions in a patient with a phenotype of multiple system atrophy, including cerebellar ataxia, parkinsonism, autonomic ataxia, and bilateral vocal cord paralysis. Brain magnetic resonance imaging (MRI) showed normal to mild cerebellar atrophy, and a follow-up study conducted after a mean period of 6 years did not reveal any significant progression. Discussion: This study highlights the importance of FGF14 GAA repeat analysis in patients with late-onset cerebellar ataxia, particularly when they exhibit episodic symptoms, or their brain MRI shows no apparent cerebellar atrophy. Our findings contribute to a better understanding of the clinical variability of GAA-FGF14-related diseases.

    DOI: 10.1002/acn3.51936

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  • Ando M., Higuchi Y., Yuan J., Yoshimura A., Kojima F., Yamanishi Y., Aso Y., Izumi K., Imada M., Maki Y., Nakagawa H., Hobara T., Noguchi Y., Takei J., Hiramatsu Y., Nozuma S., Sakiyama Y., Hashiguchi A., Matsuura E., Okamoto Y., Takashima H. .  Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan .  Annals of Clinical and Translational Neurology   2023

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    Background and Objectives: The GAA repeat expansion within the fibroblast growth factor 14 (FGF14) gene has been found to be associated with late-onset cerebellar ataxia. This study aimed to investigate the genetic causes of cerebellar ataxia in patients in Japan. Methods: We collected a case series of 940 index patients who presented with chronic cerebellar ataxia and remained genetically undiagnosed after our preliminary genetic screening. To investigate the FGF14 repeat locus, we employed an integrated diagnostic strategy that involved fluorescence amplicon length analysis polymerase chain reaction (PCR), repeat-primed PCR, and long-read sequencing. Results: Pathogenic FGF14 GAA repeat expansions were detected in 12 patients from 11 unrelated families. The median size of the pathogenic GAA repeat was 309 repeats (range: 270–316 repeats). In these patients, the mean age of onset was 66.9 ± 9.6 years, with episodic symptoms observed in 56% of patients and parkinsonism in 30% of patients. We also detected FGF14 repeat expansions in a patient with a phenotype of multiple system atrophy, including cerebellar ataxia, parkinsonism, autonomic ataxia, and bilateral vocal cord paralysis. Brain magnetic resonance imaging (MRI) showed normal to mild cerebellar atrophy, and a follow-up study conducted after a mean period of 6 years did not reveal any significant progression. Discussion: This study highlights the importance of FGF14 GAA repeat analysis in patients with late-onset cerebellar ataxia, particularly when they exhibit episodic symptoms, or their brain MRI shows no apparent cerebellar atrophy. Our findings contribute to a better understanding of the clinical variability of GAA-FGF14-related diseases.

    DOI: 10.1002/acn3.51936

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  • Yuan J.H., Higuchi Y., Hashiguchi A., Ando M., Yoshimura A., Nakamura T., Sakiyama Y., Takashima H. .  Genetic spectrum and founder effect of non-dystrophic myotonia: a Japanese case series study .  Journal of Neurology269 ( 12 ) 6406 - 6415   2022.12

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    Non-dystrophic myotonias (NDM) are rare skeletal muscle channelopathies, mainly linked to two voltage-gated ion channel genes, CLCN1 and SCN4A. The aim of this study is to identify the clinical and genetic features of patients with NDM in Japan. We collected a Japanese nationwide case series of patients with clinical diagnosis of NDM (1999–2021). Among 71 out of 88 pedigrees, using Sanger and next-generation sequencing targeting both CLCN1 and SCN4A genes, variants classified as pathogenic/likely pathogenic/unknown significance were detected from CLCN1 (31 probands), SCN4A (36 probands), or both genes (4 probands), and 11 of them were novel. Pedigrees carrying mono-allelic CLCN1 variants were more commonly seen than that with bi-allelic/double variants (24:7). Compared to patients with CLCN1 variants, patients harboring SCN4A variants showed younger onset age (5.64 ± 4.70 years vs. 9.23 ± 5.21 years), fewer warm-up phenomenon, but more paramyotonia, hyperCKemia, transient muscle weakness, and cold-induced myotonia. Haplotype analysis verified founder effects of the hot spot variants in both CLCN1 (p.T539A) and SCN4A (p.T1313M). This study reveals variants in CLCN1 and SCN4A from 80.7% of our case series, extending genetic spectrum of NDM, and would further our understanding of clinical similarity/diversity between CLCN1- and SCN4A-related NDM, as well as the genetic racial differences.

    DOI: 10.1007/s00415-022-11305-6

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  • Arimura Y, Sobue G, Hattori N, Takashima H, Harigai M, Nagata K, Makino H .  Intravenous immunoglobulin for chronic residual peripheral neuropathy in microscopic polyangiitis: A multicentre randomised double-blind trial. .  Modern rheumatology33 ( 6 ) 1125 - 1136   2022.11

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    Objectives: We conducted a Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of intravenous immunoglobulin (IVIg) in patients with glucocorticoid-refractory neuropathy associated with microscopic polyangiitis. Methods: Patients received immunoglobulin or placebo intravenously for 5 consecutive days at baseline and after 4 weeks. The IVIg and placebo groups received IVIg and placebo, respectively, after 8 weeks. The primary and major secondary end-points were the least squares mean of the change in the manual muscle test (MMT) sum score after 8 and 4 weeks, respectively. Results: A total of 37 patients were randomised into two groups (IVIg [19] and placebo [18]). The least squares mean for the change in the MMT sum score was 9.02 for IVIg and 6.71 for placebo (difference 2.32, 95% confidence interval −2.60 to 7.23, p = .345) after 8 weeks and 6.81 and 2.83 (difference 3.99, 95% confidence interval −1.22 to 9.19, p = .129), respectively, after 4 weeks. There were no new safety concerns for IVIg. Conclusions: MMT sum scores improved with IVIg compared with placebo after 8 weeks of dosing and two courses of treatment, but the differences were not statistically significant, and the results showed no clear efficacy of IVIg in this patient population. No new safety concerns were raised.

    DOI: 10.1093/mr/roac137

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  • 安藤 匡宏, 髙嶋 博 .  特集 RFC1遺伝子関連スペクトラム障害 RFC1遺伝子関連スペクトラム障害と小脳性運動失調 .  BRAIN and NERVE74 ( 11 ) 1273 - 1279   2022.11

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    Language:Japanese   Publisher:株式会社医学書院  

    DOI: 10.11477/mf.1416202227

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  • Muguruma Kazuki, Sugimoto Takamichi, Terada Yoshiko, Yuan Junhui, Nomura Eiichi, Takashima Hiroshi, Yamawaki Takemori, Kohriyama Tatsuo, Maruyama Hirofumi .  A case of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: Long-term treatment with repeated courses of immunotherapy(タイトル和訳中) .  Neurology and Clinical Neuroscience10 ( 6 ) 321 - 324   2022.11A case of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: Long-term treatment with repeated courses of immunotherapy(タイトル和訳中)

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    症例は48歳男性で、網膜症を発症し、8年後に運動障害と失語症を発症した。脳MRIにより左頭頂葉に腫瘍様病変が観察され、遺伝子検査の結果、three prime repair exonuclease 1(TREX1)遺伝子にヘテロ接合性バリアントc.703dup(p.V235Gfs*6)が検出された。これらの所見から、脳白質脳症および全身症状を伴った網膜血管症(RVCL-S)と診断され、メチルプレドニゾロンパルス療法と免疫グロブリン静注療法が施行された。治療後には髄液検査結果と臨床症状が改善されたが、3年後に新たな病変が出現し、免疫療法の治療効果が無効で、再発も反復して認められた。また、初回治療から6年間に及ぶ臨床検査と脳MRI検査結果を調べたところ、改善が得られていなかったことが明らかにされた。本例から、RVCL-Sに対する免疫療法の効果は限定的と考えられた。

  • Okada T., Yoshimoto T., Wada S., Yoshimura S., Chiba T., Egashira S., Kimura S., Shiozawa M., Inoue M., Ihara M., Toyoda K., Takashima H., Koga M. .  Intravenous Thrombolysis With Alteplase at 0.6 mg/kg in Patients With Ischemic Stroke Taking Direct Oral Anticoagulants .  Journal of the American Heart Association11 ( 19 ) e025809   2022.10

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    BACKGROUND: We elucidated the safety of treatment with alteplase at 0.6 mg/kg within 24 hours for patients on direct oral anticoagulants (DOACs) before ischemic stroke onset. METHODS AND RESULTS: Consecutive patients with acute ischemic stroke who underwent intravenous thrombolysis using alteplase at 0.6 mg/kg from 2011 to 2021 were enrolled from our single-center prospective stroke registry. We compared outcomes between patients taking DOACs and those not taking oral anticoagulants within 48 hours of stroke onset. The primary safety outcome was the rate of symptomatic intracranial hemorrhage with a ≥4-point increase on the National Institutes of Health Stroke Scale score from baseline. The efficacy outcome was defined as 3-month modified Rankin Scale score of 0 to 2 after stroke onset. Of 915 patients with acute ischemic stroke who received intravenous thrombolysis (358 women; median age, 76 years; median National Institutes of Health Stroke Scale score, 10), 40 patients took DOACs (6 took dabigatran, 8 took rivaroxaban, 16 took apixaban, and 10 took edoxaban) within 24 hours of onset and 753 patients did not take any oral anticoagulants. The rate of symptomatic intracranial hemorrhage was comparable between patients on DOACs and those not on oral anticoagulants (2.5% versus 2.4%, P=0.95). The rate of favorable outcomes was comparable between the 2 groups (59.4% versus 58.2%, P=0.46), although the admission National Institutes of Health Stroke Scale score was higher in patients on DOACs. No significant differences showed in any intracranial hemorrhage within 36 hours or mortality at 3 months. CONCLUSIONS: Intravenous thrombolysis would be safely performed for patients on DOACs following the recommendations of the Japanese guidelines. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02251665.

    DOI: 10.1161/JAHA.122.025809

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  • Nomura Emi, Tadokoro Koh, Sasaki Ryo, Nakata Yumi, Nakano Yumiko, Yunoki Taijun, Takemoto Mami, Morihara Ryuta, Ando Masahiro, Takashima Hiroshi, Yamashita Toru .  Japanese case of Charcot-Marie-Tooth disease type 2Z with severe retinitis pigmentosa(タイトル和訳中) .  Neurology and Clinical Neuroscience10 ( 5 ) 266 - 268   2022.9Japanese case of Charcot-Marie-Tooth disease type 2Z with severe retinitis pigmentosa(タイトル和訳中)

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    重度の網膜色素変性症を呈し、MORC2遺伝子に変異が検出されたCharcot-Marie-Tooth病2Z型(CMT2Z)の日本人症例について報告した。症例は48歳の日本人女性で、小児期から両下肢の筋力低下と歩行障害の進行が認められ、37歳時に歩行困難となった。また、42歳時には夜盲症と難聴を生じ、網膜色素変性症と診断され、視力は次第に低下し、48歳時に右目が失明したため入院となった。各種検査により、軽度の認知障害、感覚神経障害(感覚低下)、脳萎縮と脊髄萎縮が認められ、患者の21歳の長男にも患者同様に、小児期から続く両下肢の筋力低下と歩行障害の進行、感覚低下が認められていた。患者と長男から得たDNAを用いて、全エクソームシーケンシングを行ったところ、双方から、MORC2遺伝子変異c.754C>T(p.R252W)が同定された。これらの変異はSangerシーケンシングにより確認され、本例で得られた知見から、MORC2遺伝子変異が、光受容体の変性と網膜色素変性症の発症に関与していることが示唆された。

  • Matsuoka Chika, Taira Yuki, Sasaki Ryo, Matsumoto Namiko, Tadokoro Koh, Nomura Emi, Kawahara Yuko, Takemoto Mami, Morihara Ryuta, Hashiguchi Akihiro, Takashima Hiroshi, Takeuchi Hidemi, Araki Motoo, Abe Koji, Yamashita Toru .  A case of successful renal transplantation of Charcot-Marie-Tooth disease associated with FSGS due to mutation of the INF2 gene(タイトル和訳中) .  Neurology and Clinical Neuroscience10 ( 5 ) 252 - 254   2022.9A case of successful renal transplantation of Charcot-Marie-Tooth disease associated with FSGS due to mutation of the INF2 gene(タイトル和訳中)

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    INF2遺伝子にde novo変異をもつ、巣状分節性糸球体硬化症(FSGS)を伴ったCharcot-Marie-Tooth病(CMT)症例を報告した。症例は末期腎不全の35歳男性で、13歳時に歩行障害が認められ、20歳時にCMTと診断された。15歳時にはタンパク尿が出現し、腎生検でFSGSと診断され、28歳時に末期腎不全に対する血液透析が開始された。35歳時に母親をドナーとした生体腎移植とCMTの評価のため、当院に入院し、血清分析を行ったところ、クレアチニン値の上昇が認められた。また、DNA分析の結果からは、INF2遺伝子にヘテロ接合性の点突然変異c.206T>C(p.L69P)が検出され、これらの変異が両親からは未検出であったことから、de novo変異と判断された。母親をドナーとした生体腎移植は治療成功が得られ、術後経過も良好で、血清クレアチニン値も速やかに低下し、ベースラインレベルに維持されたが、CMTの神経学的所見に明らかな改善はみられなかった。本例ではINF2遺伝子変異の同定により、免疫抑制薬を減薬することが可能となり、これらの知見から、遺伝子検査の施行が、腎移植の治療計画の策定に有用であることが示唆された。

  • Ando M., Higuchi Y., Yuan J.H., Yoshimura A., Higashi S., Takeuchi M., Hobara T., Kojima F., Noguchi Y., Takei J., Hiramatsu Y., Nozuma S., Sakiyama Y., Hashiguchi A., Matsuura E., Okamoto Y., Nagai M., Takashima H. .  Genetic and clinical features of cerebellar ataxia with RFC1 biallelic repeat expansions in Japan .  Frontiers in Neurology13   952493   2022.8

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    The recessive intronic pentanucleotide repeat AAGGG expansion of replication factor complex subunit 1 (RFC1) is associated with cerebellar ataxia, sensory neuropathy, and vestibular areflexia syndrome. And the clinical spectrum has been continuously expanding. We conducted this study to demonstrate the clinical and genetic features of a large-scale case series of Japanese patients with cerebellar ataxia with RFC1 repeat expansions. We examined 1,289 Japanese patients with cerebellar ataxia and analyzed RFC1 repeat expansions in 840 patients, excluding those with genetic diagnoses or an autosomal dominant inheritance pattern. For individuals where no product was obtained by flanking polymerase chain reaction (PCR), repeat-primed PCR was performed using primers specific for the following four repeat motifs: AAAAG, AAAGG, AAGGG, and ACAGG. RFC1 analysis revealed multitype biallelic pathogenic repeat expansions in 15 patients, including (AAGGG)exp/(AAGGG)exp in seven patients, (ACAGG)exp/(ACAGG)exp in three patients, (AAGGG)exp/(ACAGG)exp in four patients, and (AAGGG)exp/(AAAGG)15(AAGGG)exp in one patient. Clinical analysis showed various combinations of cerebellar ataxia, vestibular dysfunction, neuropathy, cognitive decline, autonomic dysfunction, chronic cough, pyramidal tract disorder, parkinsonism, involuntary movement, and muscle fasciculation. Pathological RFC1 repeat expansions account for 1.8% (15/840) of undiagnosed patients with cerebellar ataxia and sporadic/recessive/unclassified inheritance. Screening of RFC1 repeat expansions should be considered in patients with cerebellar ataxia, irrespective of their subtype and onset age.

    DOI: 10.3389/fneur.2022.952493

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  • Ando M., Higuchi Y., Yuan J., Yoshimura A., Taniguchi T., Takei J., Takeuchi M., Hiramatsu Y., Shimizu F., Kubota M., Takeshima A., Ueda T., Koh K., Nagaoka U., Tokashiki T., Sawai S., Sakiyama Y., Hashiguchi A., Sato R., Kanda T., Okamoto Y., Takashima H. .  Novel heterozygous variants of SLC12A6 in Japanese families with Charcot–Marie–Tooth disease .  Annals of Clinical and Translational Neurology9 ( 7 ) 902 - 911   2022.7

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    Background: Recessive mutations in SLC12A6 have been linked to hereditary motor sensory neuropathy with agenesis of the corpus callosum. Patients with early-onset peripheral neuropathy associated with SLC12A6 heterozygous variants were reported in 2016. Only five families and three variants have been reported to date, and the spectrum is unclear. Here, we aim to describe the clinical and mutation spectra of SLC12A6-related Charcot–Marie–Tooth (CMT) disease in Japanese patients. Methods: We extracted SLC12A6 variants from our DNA microarray and targeted resequencing data obtained from 2598 patients with clinically suspected CMT who were referred to our genetic laboratory by neurological or neuropediatric departments across Japan. And we summarized the clinical and genetic features of these patients. Results: In seven unrelated families, we identified one previously reported and three novel likely pathogenic SLC12A6 heterozygous variants, as well as two variants of uncertain significance. The mean age of onset for these patients was 17.5 ± 16.1 years. Regarding electrophysiology, the median motor nerve conduction velocity was 39.6 ± 9.5 m/sec. For the first time, we observed intellectual disability in three patients. One patient developed epilepsy, and her brain MRI revealed frontal and temporal lobe atrophy without changes in white matter and corpus callosum. Conclusions: Screening for the SLC12A6 gene should be considered in patients with CMT, particularly those with central nervous system lesions, such as cognitive impairment and epilepsy, regardless of the CMT subtype.

    DOI: 10.1002/acn3.51603

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  • Ando Masahiro, Higuchi Yujiro, Okamoto Yuji, Yuan Junhui, Yoshimura Akiko, Takei Jun, Taniguchi Takaki, Hiramatsu Yu, Sakiyama Yusuke, Hashiguchi Akihiro, Matsuura Eiji, Nakagawa Hiroto, Sonoda Ken, Yamashita Toru, Tamura Akiko, Terasawa Hideo, Mitsui Jun, Ishiura Hiroyuki, Tsuji Shoji, Takashima Hiroshi .  An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families(タイトル和訳中) .  Journal of Human Genetics67 ( 7 ) 399 - 403   2022.7An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families(タイトル和訳中)

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    複数の日本人家系から、NEFH遺伝子に関連した臨床/遺伝学的スペクトラムが認められたため報告した。Charcot-Marie-Tooth(CMT)病および脊髄性筋萎縮症(SMA)を含む、日本全国の神経筋疾患患者から得た全エクソームシークエンシングデータを用いて、NEFH遺伝子の全てのバリアントを解析した。その結果、臨床的にCMTと診断された3家系(男性6例、女性1例、検査時年齢55歳~81歳)と、SMAと診断された1家系(男性1例、検査時年齢38歳)から、NEFH遺伝子にバリアントc.3017dup (p.Pro1007Alafs*56)が同定された。また、典型的な末梢神経障害を呈した患者に加え、CMT患者1例には錐体路兆候が、SMA患者には上腕三頭筋と大腿四頭筋に特徴的な、重度の筋力低下も認められた。さらに、これら4家系が全て鹿児島県在住の家系で、その後のハプロタイプ解析では、創始者効果が強く示唆された。本報はNEFH遺伝子の創始者変異に関する初報告例となり、得られた知見により、NEFH遺伝子関連疾患の表現型スペクトラムが拡大された。

  • Masahiro Ando, Yujiro Higuchi, Junhui Yuan, Akiko Yoshimura, Takaki Taniguchi, Fumikazu Kojima, Yutaka Noguchi, Takahiro Hobara, Mika Takeuchi, Jun Takei, Yu Hiramatsu, Yusuke Sakiyama, Akihiro Hashiguchi, Yuji Okamoto, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroshi Takashima .  Comprehensive Genetic Analyses of Inherited Peripheral Neuropathies in Japan: Making Early Diagnosis Possible. .  Biomedicines10 ( 7 )   2022.6International journal

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    Various genomic variants were linked to inherited peripheral neuropathies (IPNs), including large duplication/deletion and repeat expansion, making genetic diagnosis challenging. This large case series aimed to identify the genetic characteristics of Japanese patients with IPNs. We collected data on 2695 IPN cases throughout Japan, in which PMP22 copy number variation (CNV) was pre-excluded. Genetic analyses were performed using DNA microarrays, next-generation sequencing-based gene panel sequencing, whole-exome sequencing, CNV analysis, and RFC1 repeat expansion analysis. The overall diagnostic rate and the genetic spectrum of patients were summarized. We identified 909 cases with suspected IPNs, pathogenic or likely pathogenic variants. The most common causative genes were MFN2, GJB1, MPZ, and MME. MFN2 was the most common cause for early-onset patients, whereas GJB1 and MPZ were the leading causes of middle-onset and late-onset patients, respectively. Meanwhile, GJB1 and MFN2 were leading causes for demyelinating and axonal subtypes, respectively. Additionally, we identified CNVs in MPZ and GJB1 genes and RFC1 repeat expansions. Comprehensive genetic analyses explicitly demonstrated the genetic basis of our IPN case series. A further understanding of the clinical characteristics of IPN and genetic spectrum would assist in developing efficient genetic testing strategies and facilitate early diagnosis.

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  • Take Yoshito, Hiramatsu Yu, Yoshimoto Yusuke, Yoshida Takashi, Tanaka Sakie, Ueyama Misa, Iwata Hiroki, Imada Minako, Takahata Katsunori, Ando Masahiro, Tashiro Yuichi, Sakiyama Yusuke, Arata Hitoshi, Matsuura Eiji, Takashima Hiroshi .  A case of pneumococcal meningitis complicated by intervertebral discitis, spinal epidural abscess, and paravertebral abscess with splenic hypoplasia .  Journal of Japan Society of Neurological Emergencies & Critical Care34 ( 2 ) 21 - 25   2022.6

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    <p>Patients with splenic hypoplasia are more susceptible to infections with capsular bacteria such as <i>Streptococcus pneumoniae</i> and are more likely to develop severe infections, including bacterial meningitis. Here, we report the case of a 62-year-old male who was transferred to our hospital by emergency transport due to worsening headache and bilateral deafness. Based on the results of cerebrospinal fluid tests, the patient was diagnosed with pneumococcal meningitis and was started on antibiotic treatment. Computed tomography showed hypoplastic spleen and low levels of IgM and IgG, suggesting that hyposplenism was involved in the patient’s pneumococcal infection. Despite the administration of appropriate antibiotics, the patient developed recurrent fever and back pain; subsequent magnetic resonance imaging scans showed intervertebral discitis, spinal epidural abscess, and paravertebral abscess. After administration of intravenous immunoglobulin and subsequent vancomycin (6 weeks), and oral amoxicillin (3 weeks), symptoms and imaging findings improved and the patient was discharged on day 66. There are several reports in the literature of splenic hypoplasia associated with aggravation of pneumococcal infection and abscess formation. In cases of splenic hypoplasia, active treatment and periodic abscess search are key factors, as is a vaccination to prevent infections.</p>

    DOI: 10.11170/jjsnecc.34.2_21

  • Kimura Yasuyoshi, Nishikawa Akira, Hashiguchi Akihiro, Etoh Masaki, Yoshimura Akiko, Asai Kanako, Miyashita Noriko, Takashima Hiroshi, Sumi Hisae, Naka Takashi .  視神経萎縮、神経因性膀胱機能障害、横隔膜筋力低下を認めるMFN2関連Charcot-Marie-Tooth病患者の1例(An MFN2-related Charcot-Marie-Tooth Disease Patient with Optic Nerve Atrophy, Neurogenic Bladder Dysfunction, and Diaphragmatic Weakness) .  Internal Medicine61 ( 11 ) 1743 - 1747   2022.6視神経萎縮、神経因性膀胱機能障害、横隔膜筋力低下を認めるMFN2関連Charcot-Marie-Tooth病患者の1例(An MFN2-related Charcot-Marie-Tooth Disease Patient with Optic Nerve Atrophy, Neurogenic Bladder Dysfunction, and Diaphragmatic Weakness)

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    症例は64歳女性で、緩徐進行型筋力低下、脊柱側彎症、視神経萎縮、神経因性膀胱による尿失禁、便秘、横隔膜弛緩症を伴う拘束性肺機能障害を認めた。47歳時に神経学的検査、眼科検査、聴覚検査、複合筋活動電位と知覚神経活動電位(SNAP)の評価、筋電図検査、脳MRIを行い、臨床的にCharcot-Marie-Tooth病(CMT)と診断した。62歳時に呼吸困難が出現し、CMTの横隔神経浸潤によると思われる拘束性肺機能障害と診断した。63歳時に遺伝子検査を行い、MFN2エクソン8の新規ヘテロ接合一塩基多型(c.740 G>C)が特定され、MFN2 GTPaseドメインのミスセンス変異(p.R247P)をきたしていることが判明した。64歳時の追跡検査では、徒手筋力検査に47歳時からの大きな低下は認められず、神経伝導検査では正中神経のSNAPのみが惹起された。超音波検査では、残尿量が約120mLであることが判明した。頸部・胸部・腰部MRIで、神経因性膀胱の明らかな原因となる中枢神経病変は認めなかった。肺活量は31%に低下し、無呼吸低呼吸指数は上昇していた。

  • Shirakawa Shunichi, Murakami Tatsufumi, Hashiguchi Akihiro, Takashima Hiroshi, Hasegawa Hiroshi, Ichida Kimiyoshi, Sunada Yoshihide .  日本人CMTX5患者における新規PRPS1変異(A Novel PRPS1 Mutation in a Japanese Patient with CMTX5) .  Internal Medicine61 ( 11 ) 1749 - 1751   2022.6日本人CMTX5患者における新規PRPS1変異(A Novel PRPS1 Mutation in a Japanese Patient with CMTX5)

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    症例は33歳男性で、先天性両側聴力障害を有し、3歳まで歩行の遅延が認められ、11歳時に視力低下が判明した。高校生までは短下肢装具で歩行できたが、その後は車椅子使用となった。30歳まではパソコンや携帯電話を使用できたが、視力が徐々に低下し、両側視神経萎縮が判明したため、確定診断のために入院した。神経学的検査により、両側視神経萎縮と聴力障害が明らかとなった。猿手と鷲手、凹足変形、四肢の遠位筋萎縮を認め、徒手筋力検査では遠位筋の筋力低下が示された。下肢遠位に感覚鈍麻があり、足関節の振動覚がなく、爪先の位置覚が障害されていた。四肢の腱反射は低下していた。血清クレアチンキナーゼ値が1118U/Lに上昇していた。神経伝導検査により、重度の運動感覚性ニューロパチーが判明した。Charcot-Marie-Tooth病についての遺伝子検査を行い、PRPS1遺伝子の新規半接合変異c82 G>C(p.G28R)が特定された。赤血球ホスホリボシルピロリン酸合成酵素1の酵素活性が著明に低下していた。

  • Taniguchi Takaki, Ando Masahiro, Okamoto Yuji, Yoshimura Akiko, Higuchi Yujiro, Hashiguchi Akihiro, Matsuda Nozomu, Yamamoto Mamoru, Dohi Eisuke, Takahashi Makoto, Yoshino Masanao, Nomura Taichi, Matsushima Masaaki, Yabe Ichiro, Sanpei Yui, Ishiura Hiroyuki, Mitsui Jun, Nakagawa Masanori, Tsuji Shoji, Takashima Hiroshi .  Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments(タイトル和訳中) .  Journal of Human Genetics67 ( 6 ) 353 - 362   2022.6Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments(タイトル和訳中)

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    遺伝性トランスサイレチン(ATTRv)アミロイドーシス患者では、発症時にCharcot-Marie-Tooth病(CMT)と誤診される症例が一定数存在することから、CMT疑い患者に対し効率的な治療を行うには、トランスサイレチン(TTR)遺伝子検査が不可欠か検討した。2007年4月~2019年6月までの期間内に、CMT疑診例2133例を対象とした横断研究を行い、遺伝子検査でATTRvアミロイドーシスが確認された患者10例と、CMT患者489例の臨床所見、髄液所見ならびに電気生理学所見を比較した。その結果、神経症状の発症年齢中央値はATTRvアミロイドーシ患者が69歳、CMT患者が12歳で、初期症状として感覚障害を呈した患者の割合は、ATTRvアミロイドーシス患者では70%、CMT患者では7.1%であった。また、慢性炎症性脱髄性多発根神経炎(CIDP)疑いの既往歴を有する患者の割合はATTRvアミロイドーシス患者では50%、CMT患者では8.7%で、遺伝子検査後に進行が認められたATTRvアミロイドーシス患者6例のうち、薬物治療や遺伝子治療を受けた5例は、いずれも生存例であることも確認された。以上より、発症時の神経症状や初期の感覚障害、CIDP疑い既往歴を有するCMT疑診例の高齢患者に効果的な治療を行うには、TTR遺伝子検査が不可欠と結論付けられた。

  • Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Ruriko Kitao, Takehiko Morimoto, Takaki Taniguchi, Mika Takeuchi, Jun Takei, Yu Hiramatsu, Yusuke Sakiyama, Akihiro Hashiguchi, Yuji Okamoto, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroshi Takashima .  Novel de novo POLR3B mutations responsible for demyelinating Charcot-Marie-Tooth disease in Japan. .  Annals of clinical and translational neurology9 ( 5 ) 747 - 755   2022.5International journal

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    BACKGROUND: Biallelic POLR3B mutations cause a rare hypomyelinating leukodystrophy. De novo POLR3B heterozygous mutations were recently associated with afferent ataxia, spasticity, variable intellectual disability, and epilepsy, and predominantly demyelinating sensorimotor peripheral neuropathy. METHODS: We performed whole-exome sequencing (WES) of DNA samples from 804 Charcot-Marie-Tooth (CMT) cases that could not be genetically diagnosed by DNA-targeted resequencing microarray using next-generation sequencers. Using WES data, we analyzed the POLR3B mutations and confirmed their clinical features. RESULTS: We identified de novo POLR3B heterozygous missense mutations in two patients. These patients presented with early-onset demyelinating sensorimotor neuropathy without ataxia, spasticity, or cognitive impairment. Patient 1 showed mild cerebellar atrophy and spinal cord atrophy on magnetic resonance imaging and eventually died of respiratory failure in her 50s. We classified these mutations as pathogenic based on segregation studies, comparison with control database, and in silico analysis. CONCLUSION: Our study is the third report on patients with demyelinating CMT harboring heterozygous POLR3B mutations and verifies the pathogenicity of POLR3B mutations in CMT. Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT-related gene panel for comprehensive genetic screening, particularly for patients with early-onset demyelinating CMT.

    DOI: 10.1002/acn3.51555

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  • 濱田 拓人, 中澤 祐則, 寺崎 寛人, 谷口 雄大, 髙嶋 博, 坂本 泰二 .  臨床報告 両眼に重篤な眼所見を呈し視力予後が不良であった猫ひっかき病の1例 .  臨床眼科76 ( 4 ) 449 - 456   2022.4

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    DOI: 10.11477/mf.1410214347

  • Hamada Yuki, Shigehisa Ayano, Kanda Yoshiki, Ikeda Mei, Takaguchi Go, Matsuoka Hideki, Takashima Hiroshi .  Enhancement of the Ivy Sign During an Ischemic Event in Moyamoya Disease: A Case Report .  Internal Medicineadvpub ( 0 ) 617 - 621   2022

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    Language:English   Publisher:The Japanese Society of Internal Medicine  

    <p>We herein report a case of increased and expanded ipsilateral ivy sign paralleling the expansion of cerebral infarction in a patient with moyamoya disease. A 67-year-old woman visited our hospital with symptoms of left hemiplegia, left homonymous hemianopia, and left unilateral spatial neglect. Magnetic resonance imaging of the head showed cerebral infarction in the right parietal lobe. In addition, ivy signs were evident on fluid-attenuated inversion recovery imaging. These findings were enhanced by the expansion of cerebral infarction and disappeared once the ischemia resolved, implying hemodynamic changes. As a result of continuing medical treatment without antithrombotic therapy, the patient obtained a good outcome. Treatment for moyamoya disease in the acute phase is considered to require complex knowledge of multiple factors, such as the anatomical background of the individual patient and the progression grade of ischemia. </p>

    DOI: 10.2169/internalmedicine.9326-22

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  • 髙嶋 博 .  脊髄性筋萎縮症の遺伝子治療の実際とその未来 .  神経治療学39 ( 4 ) 540 - 540   2022脊髄性筋萎縮症の遺伝子治療の実際とその未来

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    Language:Japanese   Publisher:日本神経治療学会  

    DOI: 10.15082/jsnt.39.4_540

  • Higuchi Yujiro, Takashima Hiroshi .  Review/Advances in Neurological Therapeutics (2021). Spinocerebellar degeneration .  Neurological Therapeutics39 ( 5 ) 773 - 777   2022Review/Advances in Neurological Therapeutics (2021). Spinocerebellar degeneration

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    <p>We would like to review the recent therapeutic advances of spinocerebellar degeneration (SCD) that were published in 2021. Currently, SCD treatment is limited only to symptomatic mitigation, and no therapy is available to stop or delay the disease progression. Various pre–clinical and clinical trials were carried out in 2021. Some interesting trials have been reported, and further developments are expected. This article introduces the outline of therapies with rovatirelin, riluzole/troriluzole, leriglitazone, sodium valproate, CRISPR/Cas9 gene editing, antisense oligonucleotides (ASOs), mesenchymal stem cells (MSCs), and cerebello–spinal transcranial direct current stimulation (tDCS). We expect that these treatments will benefit the patients with SCD.</p>

    DOI: 10.15082/jsnt.39.5_773

  • Takashima Hiroshi .  How to deal with unexplained events in neurology .  Neurological Therapeutics39 ( 1 ) 3 - 6   2022

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    Language:Japanese   Publisher:Japanese Society of Neurological Therapeutics  

    <p>Medical scientists are asked to make various judgments when new diseases emerge, such as COVID–19, but even for these experts, their judgments are often incorrect. Experts always attempt to convince the public using a term “science–based evidence” but, in many cases, without real solid evidence. There are massive of unexplained diseases and pathogenicity in neurology. In order to discover and elucidate new diseases and their pathophysiological conditions, it is important to carefully examine and investigate each patient, followed by a persistent tracing sincerely and deeply. Medicine is still developing, and to make the neurology more practical and useful for the world, I would like to expect flexibility, innovation, and conscience from doctors with neurological expertise.</p>

    DOI: 10.15082/jsnt.39.1_3

  • Jun-Hui Yuan, Yujiro Higuchi, Masahiro Ando, Eiji Matsuura, Akihiro Hashiguchi, Akiko Yoshimura, Tomonori Nakamura, Yusuke Sakiyama, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroshi Takashima .  Multi-type RFC1 repeat expansions as the most common cause of hereditary sensory and autonomic neuropathy. .  Frontiers in neurology13   986504 - 986504   2022International journal

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    Non-coding repeat expansions within RFC1 and NOTCH2NLC genes have lately been linked to multisystem neurodegenerative diseases, which also shed light on yet undiagnosed patients with inherited peripheral neuropathies. The aim of this study was to identify the genetic basis of patients with hereditary sensory and autonomic neuropathy (HSAN). We collected 79 unrelated DNA samples clinically suspected with HSAN from multiple regions of Japan. Mutation screening was first performed using gene panel sequencing and whole-exome sequencing. Pathogenic/likely pathogenic variants were identified from genes of WNK1/HSN2 (6 cases), SCN9A (3 cases), NTRK1 (3 cases), and DNMT1 (2 cases). Subsequently, long-range flanking PCR and repeat-primed PCR were applied to analyze repeat expansions in RFC1 and NOTCH2NLC. Bi-allelic RFC1 repeat expansions were detected from 20 adult-onset HSAN patients, consisting of [(AAGGG)exp/(AAGGG)exp] (8 cases), [(ACAGG)exp/(ACAGG)exp] (8 cases), and [(AAGGG)exp/(ACAGG)exp] (4 cases). GGC repeat expansion in NOTCH2NLC was found in 1 case. Single-nucleotide variant-based haplotype analysis of patients harboring disease-associated repeat expansions in RFC1 revealed distinguishable haplotypes among subgroups with different repeat genotypes. These findings substantially redefine the genetic spectrum of HSAN, where multi-type RFC1 repeat expansions account for 25.3% of all patients, highlighting the necessity of genetic screening, particularly for adult-onset patients.

    DOI: 10.3389/fneur.2022.986504

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  • Ito Ken, Higurashi Norimichi, Kogawa Kentaro, Hashiguchi Akihiro, Takashima Hiroshi, Kikuchi Kenjiro .  The brothers of X-linked Charcot-Marie-Tooth disease affected MERS type-2 .  NO TO HATTATSU54 ( 1 ) 56 - 60   2022Reviewed

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    Language:Japanese   Publisher:The Japanese Society of Child Neurology  

    <p>  Transient cerebral manifestations resembling mild encephalopathy with a reversible splenial lesion (MERS) type-2 have been reported in patients with X-linked Charcot-Marie-Tooth disease type-1 (CMTX1). Here, we report the case of two brothers with MERS type-2, who was later diagnosed with CMTX1. The 12-year-old younger brother developed an altered state of consciousness, quadriplesia, and dysarthria after an acute phase of mycoplasma pneumonia. We diagnosed MERS type-2 after diffusion-weighted magnetic resonance imaging revealed transient symmetric hyperintensity lesions in the splenium of the corpus callosum and cerebral white matter. We suspected CMTX1 because his older brother had previously suffered from MERS type-2 and further examination of the lower limbs revealed a persistent absence of deep tendon reflexes, high-arched feet, and “inverted champagne bottle” legs in both mother and brothers. Presence of the <i>GJB1</i> missense mutation—NM_000166.6 (GJB1) : c. 77C>T (p. Ser26Leu) —was later confirmed in the younger brother. In cases of MERS type-2 with cerebral focal sign and without seizure, CMTX1 is considered as an underlying condition, but motor symptoms may be unnoticeable in childhood. Therefore, it is crucial to examine carefully lower limbs signs which can appear as early symptoms, not only in probands but also in their family.</p>

    DOI: 10.11251/ojjscn.54.56

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  • Satoshi Nozuma, Matsuura E, Tashiro Y, Nagata R, Ando M, Hiramatsu Y, Higuchi Y, Sakiyama Y, Hashiguchi A, Michizono K, Higashi K, Matsuzaki T, Kodama D, Tanaka M, Yamano Y, Moritoyo T, Kubota R, Takashima H .  Efficacy of l-Arginine treatment in patients with HTLV-1-associated neurological disease. .  Annals of clinical and translational neurology10 ( 2 ) 237 - 245   2022Reviewed

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    <h4>Objective</h4>HTLV-1 infection causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), resulting in loss of motor function. In this Phase 2 trial, we assessed the efficacy and safety of l-arginine in patients with HAM/TSP.<h4>Methods</h4>This open-label, single-arm, Phase 2 study enrolled patients diagnosed with HAM/TSP. Patients received l-arginine at a dose of 20 g orally for 1 week and were followed-up for 3 weeks. The primary endpoint was change in walking speed in the 10-m walk test (10MWT). The main secondary endpoints were change in Timed Up and Go Test (TUGT) time, improvement in inflammatory markers in cerebrospinal fluid (CSF), safety, and tolerability.<h4>Results</h4>The study enrolled 20 patients (13 [65%] female) with a mean age of 67.8 years (95% CI 62.3 to 73.3). Although the primary endpoint, the changes in 10MWT time between baseline (Day 0) and Day 7, did not reach statistical significance (mean percent change in time -3.5%, 95% CI -10.8% to 3.7%; P = 0.32), a significant improvement was detected between baseline and Day 14 (-9.4%, 95% CI -16.6% to -2.2%; P = 0.01). Significant improvements were also observed in selected secondary endpoints, including in TUGT time (-9.1%, 95% CI -15.5% to -2.7%; P < 0.01), and in neopterin concentration in CSF (-2.1 pmol/mL, 95% CI -3.8 to -0.5; P = 0.01). Adverse events were infrequent, mild, and resolved rapidly.<h4>Interpretation</h4>l-arginine therapy improved motor function and decreased CSF inflammatory markers. l-arginine thus represents a promising therapeutic option for patients with HAM/TSP.<h4>Trial registration number</h4>UMIN000023854.

    DOI: 10.1002/acn3.51715

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  • 安藤 匡宏, 吉村 明子, 谷口 雄大, 武井 潤, 平松 有, 樋口 雄二郎, 田代 雄一, 崎山 佑介, 橋口 昭大, 岡本 裕嗣, 高嶋 博 .  Charcot-Marie-Tooth病におけるcopy number variation解析 .  臨床神経学61 ( Suppl. ) S308 - S308   2021.9Charcot-Marie-Tooth病におけるcopy number variation解析

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  • 藤崎 なつみ, 諏訪園 秀吾, 末原 雅人, 中地 亮, 城戸 美和子, 藤原 善寿, 妹尾 洋, 渡嘉敷 崇, 高嶋 博 .  沖縄型神経原性筋萎縮症(HMSN-P)患者の呼吸機能の経過について .  臨床神経学61 ( Suppl. ) S321 - S321   2021.9沖縄型神経原性筋萎縮症(HMSN-P)患者の呼吸機能の経過について

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  • Kodama D., Tanaka M., Matsuzaki T., Nozuma S., Matsuura E., Takashima H., Izumo S., Kubota R. .  Anti-human T-cell Leukemia virus type 1 (HTLV-1) antibody assays in cerebrospinal fluid for the diagnosis of HTLV-1 associated myelopathy/tropical spastic paraparesis .  Journal of Clinical Microbiology59 ( 5 )   2021.5

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    The anti-human T-cell leukemia virus type 1 (HTLV-1) antibody assay in common use has changed from the particle agglutination (PA) method to chemiluminescent immunoassay (CLIA) and chemiluminescent enzyme immunoassay (CLEIA). These assays were validated in serum but not in cerebrospinal fluid (CSF). However, anti-HTLV-1 antibody positivity in CSF is a requisite for diagnosing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We qualitatively compared the assays in CSF from 47 HAM/TSP patients diagnosed using PA, 15 HTLV-1 carriers (HCs), and 18 negative controls. In determining the positivity or negativity of CSF anti-HTLV-1 antibodies, we used serum cutoff points for CLIA and CLEIA because CSF cutoff points had not been decided. Truth table analysis revealed that the performance of CLIA was closer to that of PA and that CLEIA had low sensitivity. CSF antibodies from HAM/TSP patients were all positive by PA and CLIA but 83.0% positive by CLEIA. CSF antibodies from HCs were positive in 73.3%, 80.0%, and 6.7% by PA, CLIA, and CLEIA, respectively. Receiver operator characteristic curve analysis for CSF revealed that with the default cutoff point used for serum, CLIA and PA had comparable performances and CLEIA was less sensitive. The best performances of CLIA and CLEIA with adjusted cutoff points were 94.8% sensitivity and 95.5% specificity and 89.7% sensitivity and 95.5% specificity, respectively. We conclude that low-sensitivity CLEIA can underdiagnose HAM/TSP and that CLIA is a better alternative to PA in anti-HTLV-1 antibody assay for CSF with the current cutoff points.

    DOI: 10.1128/JCM.03230-20

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  • Daisuke Kodama, Masakazu Tanaka, Toshio Matsuzaki, Satoshi Nozuma, Eiji Matsuura, Hiroshi Takashima, Shuji Izumo, Ryuji Kubota .  Anti-Human T-Cell Leukemia Virus Type 1 (HTLV-1) Antibody Assays in Cerebrospinal Fluid for the Diagnosis of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis .  JOURNAL OF CLINICAL MICROBIOLOGY59 ( 5 )   2021.5Anti-Human T-Cell Leukemia Virus Type 1 (HTLV-1) Antibody Assays in Cerebrospinal Fluid for the Diagnosis of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMER SOC MICROBIOLOGY  

    The anti-human T-cell leukemia virus type 1 (HTLV-1) antibody assay in common use has changed from the particle agglutination (PA) method to chemiluminescent immunoassay (CLIA) and chemiluminescent enzyme immunoassay (CLEIA). These assays were validated in serum but not in cerebrospinal fluid (CSF). However, anti-HTLV-1 antibody positivity in CSF is a requisite for diagnosing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We qualitatively compared the assays in CSF from 47 HAM/TSP patients diagnosed using PA, 15 HTLV-1 carriers (HCs), and 18 negative controls. In determining the positivity or negativity of CSF anti-HTLV-1 antibodies, we used serum cutoff points for CLIA and CLEIA because CSF cutoff points had not been decided. Truth table analysis revealed that the performance of CLIA was closer to that of PA and that CLEIA had low sensitivity. CSF antibodies from HAM/TSP patients were all positive by PA and CLIA but 83.0% positive by CLEIA. CSF antibodies from HCs were positive in 73.3%, 80.0%, and 6.7% by PA, CLIA, and CLEIA, respectively. Receiver operator characteristic curve analysis for CSF revealed that with the default cutoff point used for serum, CLIA and PA had comparable performances and CLEIA was less sensitive. The best performances of CLIA and CLEIA with adjusted cutoff points were 94.8% sensitivity and 95.5% specificity and 89.7% sensitivity and 95.5% specificity, respectively. We conclude that low-sensitivity CLEIA can underdiagnose HAM/TSP and that CLIA is a better alternative to PA in anti-HTLV-1 antibody assay for CSF with the current cutoff points.

    DOI: 10.1128/JCM.03230-20

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  • Daisuke Kodama, Masakazu Tanaka, Toshio Matsuzaki, Satoshi Nozuma, Eiji Matsuura, Hiroshi Takashima, Shuji Izumo, Ryuji Kubota .  Anti-human T-cell Leukemia virus type 1 (HTLV-1) antibody assays in cerebrospinal fluid for the diagnosis of HTLV-1 associated myelopathy/tropical spastic paraparesis .  Journal of Clinical Microbiology59 ( 5 )   2021.5Anti-human T-cell Leukemia virus type 1 (HTLV-1) antibody assays in cerebrospinal fluid for the diagnosis of HTLV-1 associated myelopathy/tropical spastic paraparesis

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    The anti-human T-cell leukemia virus type 1 (HTLV-1) antibody assay in common use has changed from the particle agglutination (PA) method to chemiluminescent immunoassay (CLIA) and chemiluminescent enzyme immunoassay (CLEIA). These assays were validated in serum but not in cerebrospinal fluid (CSF). However, anti-HTLV-1 antibody positivity in CSF is a requisite for diagnosing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We qualitatively compared the assays in CSF from 47 HAM/TSP patients diagnosed using PA, 15 HTLV-1 carriers (HCs), and 18 negative controls. In determining the positivity or negativity of CSF anti-HTLV-1 antibodies, we used serum cutoff points for CLIA and CLEIA because CSF cutoff points had not been decided. Truth table analysis revealed that the performance of CLIA was closer to that of PA and that CLEIA had low sensitivity. CSF antibodies from HAM/TSP patients were all positive by PA and CLIA but 83.0% positive by CLEIA. CSF antibodies from HCs were positive in 73.3%, 80.0%, and 6.7% by PA, CLIA, and CLEIA, respectively. Receiver operator characteristic curve analysis for CSF revealed that with the default cutoff point used for serum, CLIA and PA had comparable performances and CLEIA was less sensitive. The best performances of CLIA and CLEIA with adjusted cutoff points were 94.8% sensitivity and 95.5% specificity and 89.7% sensitivity and 95.5% specificity, respectively. We conclude that low-sensitivity CLEIA can underdiagnose HAM/TSP and that CLIA is a better alternative to PA in anti-HTLV-1 antibody assay for CSF with the current cutoff points.

    DOI: 10.1128/JCM.03230-20

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  • Kodama D, Tanaka M, Matsuzaki T, Nozuma S, Matsuura E, Takashima H, Izumo S, Kubota R .  Anti-Human T-Cell Leukemia Virus Type 1 (HTLV-1) Antibody Assays in Cerebrospinal Fluid for the Diagnosis of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis. .  Journal of clinical microbiology59 ( 5 )   2021.4Anti-Human T-Cell Leukemia Virus Type 1 (HTLV-1) Antibody Assays in Cerebrospinal Fluid for the Diagnosis of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

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    DOI: 10.1128/JCM.03230-20

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  • Dozono Mika, Shigehisa Ayano, Taniguchi Takaki, Nozuma Satoshi, Tashiro Yuichi, Nakamura Tomonori, Hashiguchi Akihiro, Okubo Ryuichi, Takashima Hiroshi .  A Case of Acute Edematous Dermatomyositis Elevated CK 170,000 U/<i>l</i> .  Nihon Naika Gakkai Zasshi110 ( 3 ) 598 - 604   2021.3

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    Language:Japanese   Publisher:The Japanese Society of Internal Medicine  

    DOI: 10.2169/naika.110.598

  • 関島 良樹, 髙嶋 博 .  チャレンジ! 遺伝性末梢神経疾患治療 司会の言葉 .  神経治療学38 ( 3 ) 369 - 369   2021

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    DOI: 10.15082/jsnt.38.3_369

  • 樋口 雄二郎, 髙嶋 博 .  増大特集 難病研究の進歩 Ⅰ.神経・筋 シャルコー・マリー・トゥース病 .  生体の科学71 ( 5 ) 394 - 395   2020.10増大特集 難病研究の進歩 Ⅰ.神経・筋 シャルコー・マリー・トゥース病

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    DOI: 10.11477/mf.2425201205

  • Sakiyama Yusuke, Matsuura Eiji, Shigehisa Ayano, Hamada Yuki, Dozono Mika, Nozuma Satoshi, Nakamura Tomonori, Higashi Keiko, Hashiguchi Akihiro, Takahashi Yukitoshi, Takashima Hiroshi .  Cryptococcus Meningitis Can Co-occur with Anti-NMDA Receptor Encephalitis .  Internal Medicine59 ( 18 ) 2301 - 2306   2020.9

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    <p>We herein report a 50-year-old man with alcoholic cirrhosis who developed loss of consciousness and tremor of the upper limbs. Magnetic resonance imaging findings were suggestive of limbic encephalitis with bilateral hippocampal damage, and a cerebrospinal fluid (CSF) examination confirmed anti-N-methyl-D-aspartate (NMDA) and anti-glutamate receptor antibodies. Despite initial corticosteroid therapy, meningeal irritation symptoms appeared, owing to the development of cryptococcal meningitis (CM), diagnosed by the detection of cryptococcal capsular polysaccharide antigen in the follow-up CSF analysis. Cerebral infarction with reversible stenosis of major cerebral arteries during the clinical course was also observed. Following administration of antifungals and corticosteroids, the number of cells in the CSF gradually declined, and NMDA receptor antibodies disappeared. Our study demonstrates the unique coexistence of CM with anti-NMDA receptor encephalitis in adults. </p>

    DOI: 10.2169/internalmedicine.4629-20

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  • 野崎章仁, 森未央子, 熊田知浩, 橋口昭大, 高嶋 博, 村山 圭, 藤井達哉 .  SUCLA2関連ミトコンドリアDNA枯渇症候群の1例 .  脳と発達52 ( 5 ) 318 - 322   2020.9SUCLA2関連ミトコンドリアDNA枯渇症候群の1例

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  • Hidaka Masaoki, Higashi Eiji, Uwatoko Takeshi, Uwatoko Kiku, Urashima Mayumi, Takashima Hiroshi, Watanabe Yoriko, Kitazono Takanari, Sugimori Hiroshi .  Late-onset ornithine transcarbamylase deficiency: a rare cause of recurrent abnormal behavior in adults(和訳中) .  Acute Medicine & Surgery7 ( 1 ) 1 of 4 - 4 of 4   2020.9Late-onset ornithine transcarbamylase deficiency: a rare cause of recurrent abnormal behavior in adults(和訳中)

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    症例は34歳男性で、異常行動と嗜眠が突然出現し、入院となった。高アンモニア血症(108μmol/L)を認めた。臨床所見から焦点性てんかんと診断し、レベチラセタム治療を開始したところ、2日目に霧視を除いて症状は改善し、血清アンモニア濃度は正常化した。31日目に異常行動、嗜眠、高アンモニア血症(122μmol/L)が再び出現したため、再入院となった。鶏肉に対する不耐症と早世の家族歴から尿素サイクル異常症を疑い、33日目よりタンパク質制限食およびアルギニン治療を開始した。その結果、翌日に霧視を含めて症状は消失し、血清アンモニア濃度は正常化した。34日目よりフェニル酪酸ナトリウム治療を追加した。血清アミノ酸プロファイルから遅発型のオルニチントランスカルバミラーゼ(OTC)欠損症が示唆された。44日目に退院に至り、その後は再発を認めていない。OTC遺伝子にR40H(c.119G>A)変異が同定された。

  • Daisuke Kodama, Masakazu Tanaka, Toshio Matsuzaki, Kimiko Izumo, Nobuaki Nakano, Eiji Matsuura, Mineki Saito, Masahiro Nagai, Masahisa Horiuchi, Atae Utsunomiya, Hiroshi Takashima, Ryuji Kubota, Shuji Izumo .  Inhibition of abl1 tyrosine kinase reduces htlv-1 proviral loads in peripheral blood mononuclear cells from patients with htlv-1-associated myelopathy/tropical spastic paraparesis .  PLoS Neglected Tropical Diseases14 ( 7 ) 1 - 21   2020.7Inhibition of abl1 tyrosine kinase reduces htlv-1 proviral loads in peripheral blood mononuclear cells from patients with htlv-1-associated myelopathy/tropical spastic paraparesis

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    Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that the ABL1 is an important gene in HAM/TSP. ABL1 is a known survival factor for T-and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whether ABL1 is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, ABL1 siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhib-iting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP.

    DOI: 10.1371/journal.pntd.0008361

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  • Daisuke Kodama, Masakazu Tanaka, Toshio Matsuzaki, Kimiko Izumo, Nobuaki Nakano, Eiji Matsuura, Mineki Saito, Masahiro Nagai, Masahisa Horiuchi, Atae Utsunomiya, Hiroshi Takashima, Ryuji Kubota, Shuji Izumo .  Inhibition of abl1 tyrosine kinase reduces htlv-1 proviral loads in peripheral blood mononuclear cells from patients with htlv-1-associated myelopathy/tropical spastic paraparesis .  PLoS Neglected Tropical Diseases14 ( 7 ) 1 - 21   2020.7Inhibition of abl1 tyrosine kinase reduces htlv-1 proviral loads in peripheral blood mononuclear cells from patients with htlv-1-associated myelopathy/tropical spastic paraparesis

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    Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that the ABL1 is an important gene in HAM/TSP. ABL1 is a known survival factor for T-and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whether ABL1 is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, ABL1 siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhib-iting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP.

    DOI: 10.1371/journal.pntd.0008361

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  • Daisuke Kodama, Masakazu Tanaka, Toshio Matsuzaki, Kimiko Izumo, Nobuaki Nakano, Eiji Matsuura, Mineki Saito, Masahiro Nagai, Masahisa Horiuchi, Atae Utsunomiya, Hiroshi Takashima, Ryuji Kubota, Shuji Izumo .  Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis .  PLOS NEGLECTED TROPICAL DISEASES14 ( 7 )   2020.7Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis

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    Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that theABL1is an important gene in HAM/TSP.ABL1is a known survival factor for T- and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whetherABL1is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore,ABL1siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting thatABL1is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP.Author summary Human T-cell leukemia virus type 1 (HTLV-1) is integrated as a provirus in the genomic DNA mainly of CD4+ T cell population in the infected people. HTLV-1-infected CD4+ T cells are transmitted via breast milk, semen, and blood transfusions. HTLV-1 is endemic in Japan, the Middle East, Africa, Caribbean islands, and Central and South America. A small proportion of infected people develop adult T-cell leukemia, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and other diseases. HAM/TSP, a chronic neuroinflammatory disorder, is characterized by spastic paraparesis and urinary disturbance. HTLV-1-infected CD4+ T cells infiltrate the spinal cord and cause inflammation, which results in such neurological symptoms. We have identified the tyrosine kinase geneABL1as a gene frequently found in the signal transduction pathways in HTLV-1-infected CD4+ T cells. Therefore,ABL1appears to be important in the pathogenesis of HAM/TSP. Inhibiting ABL1 with tyrosine kinase inhibitors (TKIs), which is used for chronic myelogenous leukemia (CML), reduced the proviral load (PVL)in vitro. We found a rare case of a patient with HAM/TSP and CML by our clinical records, who showed a decrease in PVL after TKI treatment for CML. Hence, TKIs are potential therapeutic agents for HAM/TSP.

    DOI: 10.1371/journal.pntd.0008361

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  • Daisuke Kodama, Masakazu Tanaka, Toshio Matsuzaki, Kimiko Izumo, Nobuaki Nakano, Eiji Matsuura, Mineki Saito, Masahiro Nagai, Masahisa Horiuchi, Atae Utsunomiya, Hiroshi Takashima, Ryuji Kubota, Shuji Izumo .  Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. .  PLoS neglected tropical diseases14 ( 7 ) e0008361   2020.7Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis.International journal

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    Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that the ABL1 is an important gene in HAM/TSP. ABL1 is a known survival factor for T- and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whether ABL1 is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, ABL1 siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP.

    DOI: 10.1371/journal.pntd.0008361

    PubMed

  • Kodama D, Tanaka M, Matsuzaki T, Izumo K, Nakano N, Matsuura E, Saito M, Nagai M, Horiuchi M, Utsunomiya A, Takashima H, Kubota R, Izumo S .  Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. .  PLoS neglected tropical diseases14 ( 7 ) e0008361   2020.7Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis.

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    DOI: 10.1371/journal.pntd.0008361

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  • 橋口昭大, 吉村明子, 安藤匡宏, 樋口雄二郎, 中村友紀, 岡本裕嗣, 松浦英治, 高嶋 博 .  GARS変異による遺伝性末梢神経障害7例の臨床的特徴 .  末梢神経31 ( 1 ) 98 - 104   2020.6GARS変異による遺伝性末梢神経障害7例の臨床的特徴

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  • 菊池 晃, 岡本 裕嗣, 橋口 裕, 吉重 幸一, 谷口 雄大, 出口 尚寿, 高嶋 博, 西尾 善彦 .  認知機能低下を契機に発見されたミトコンドリア糖尿病の1例 .  糖尿病63 ( 5 ) 344 - 349   2020.5認知機能低下を契機に発見されたミトコンドリア糖尿病の1例

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    DOI: https://doi.org/10.11213/tonyobyo.63.344

  • Ishihara S, Okamoto Y, Tanabe H, Yoshimura A, Higuchi Y, Yuan JH, Hashiguchi A, Ishiura H, Mitsui J, Suwazono S, Oya Y, Sasaki M, Nakagawa M, Tsuji S, Ohya Y, Takashima H. .  Clinical Features of Inherited Neuropathy With BSCL2 Mutations in Japan .  J Peripher Nerv Syst.   2020.2Clinical Features of Inherited Neuropathy With BSCL2 Mutations in Japan Reviewed

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    DOI: doi.org/10.1111/jns.12369

  • Hosokawa S, Kubo Y, Arakawa R, Takashima H, Saito K. .  Analysis of Spinal Muscular Atrophy-Like Patients by Targeted Resequencing .  Brain Dev. 42 ( 2 ) 148 - 156   2020.2Analysis of Spinal Muscular Atrophy-Like Patients by Targeted Resequencing Reviewed

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    DOI: doi.org/10.1016/j.braindev.2019.10.008

  • Hosokawa Shinichi, Kubo Yuji, Arakawa Reiko, Takashima Hiroshi, Saito Kayoko .  脊髄性筋萎縮症によく似た所見を呈する患者を対象としたターゲットリシケーンシング法による解析(Analysis of spinal muscular atrophy-like patients by targeted resequencing) .  Brain & Development42 ( 2 ) 148 - 156   2020.2脊髄性筋萎縮症によく似た所見を呈する患者を対象としたターゲットリシケーンシング法による解析(Analysis of spinal muscular atrophy-like patients by targeted resequencing)

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    下位運動ニューロン症状がみられ、当初は脊髄性筋萎縮症が疑われたが診断がつかなかった患者を分子診断するため、次世代シーケンス解析(NGS)と従来式のシーケンス解析を適用した。2005〜2016年に当施設を受診した上記患者のうち、最終的に8家系に属する12名を対象に、NGSを利用したターゲットリシケーンシング解析を施行した。検出された遺伝子変異体を文献検索とデータベースに基づいて選別し、病原性変異体の候補となったものについてはSanger法によるシーケンス解析にて検証した。その結果、2家系に属する患者3名から新規変異体を発見した。患者1と2は共に6歳の男児で双生児であり、TTN遺伝子の2種の変異体を有する複合ヘテロ接合体(c.6621delG, p.W2207Cfs*28およびc.23718T>A, p.F7906L)であった。患者3はKIF1A遺伝子変異体の複合ヘテロ接合体(c.3871C>T, p.R1291Cおよびc.3898G>A,p.V1300M)であった。このように未診断患者3名において新規原因遺伝子の発見に成功したことから、本アプローチは有効であることが示された。

  • Hosokawa S. .  Analysis of spinal muscular atrophy-like patients by targeted resequencing .  Brain and Development42 ( 2 ) 148 - 156   2020.2Reviewed International journal

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    DOI: 10.1016/j.braindev.2019.10.008

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  • Hidaka M, Higashi E, Uwatoko T, Uwatoko K, Urashima M, Takashima H, Watanabe Y, Kitazono T, Sugimori H .  Late-onset ornithine transcarbamylase deficiency: a rare cause of recurrent abnormal behavior in adults. .  Acute medicine & surgery7 ( 1 ) e565   2020.1Late-onset ornithine transcarbamylase deficiency: a rare cause of recurrent abnormal behavior in adults.

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  • Sawada Jun, Katayama Takayuki, Tokashiki Takashi, Kikuchi Shiori, Kano Kohei, Takahashi Kae, Saito Tsukasa, Adachi Yoshiki, Okamoto Yuji, Yoshimura Akiko, Takashima Hiroshi, Hasebe Naoyuki .  一卵性双生児における脊髄小脳失調症8型の初の症例(The First Case of Spinocerebellar Ataxia Type 8 in Monozygotic Twins) .  Internal Medicine59 ( 2 ) 277 - 283   2020.1一卵性双生児における脊髄小脳失調症8型の初の症例(The First Case of Spinocerebellar Ataxia Type 8 in Monozygotic Twins)

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    症例1は女性で、26歳時によろめき歩行、発話および嚥下障害が出現して徐々に悪化し、32歳時に来院した。症例2は症例1の一卵性双生児の姉。25歳時によろめき歩行が出現し、31歳時に来院した。両症例ともに眼振、構語障害、四肢および体幹の運動失調を認め、脳MRIで小脳萎縮が判明した。母方の祖父と叔父、症例2の次男でも眼振が認められた。遺伝子検査では、両症例ともにアタキシン8逆鎖(ATXN8OS)CTA/CTG反復が25/97であり、脊髄小脳失調症8型と診断した。タルチレリン水和物による治療を行ったが、失調症は徐々に悪化した。本症例は、ATXN8OS遺伝子反復伸長を認めた一卵性双生児についての初の報告であった。

  • Aoki Reika, Komagamine Tomoko, Kokubun Norito, Hashiguchi Akihiro, Takashima Hiroshi, Hirata Koichi .  A patient with X-linked Charcot–Marie–Tooth disease type 1 who responded to intravenous immunoglobulin therapy .  Japanese Journal of Clinical Neurophysiology48 ( 1 ) 8 - 14   2020Reviewed

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    <p>Previous reports showed that some patients with X-linked Charcot–Marie–Tooth disease type 1 (CMTX1) showed favorable response after intravenous immunoglobulin therapy (IVIg). Immunological vulnerability of the myelin is hypothesized to underlie mechanism of such groups. Here, we report a patient with CMTX1 who responded to IVIg. A 51-year-old male became to be easy to stumble from about 46 years old, and developed subacute progression of gait disturbance three months before admission. Examination revealed hammer toes, muscle weakness in the distal four extremities, diminished tendon reflexes, and sensory ataxia. Nerve conduction study showed demyelinating features, fulfilled the criteria for CIDP. IVIg showed favorable effect. However, his symptom gradually worsened several months after IVIg. His mother also had peripheral neuropathy predominantly in the lower limbs. CMT was suspected and genetic test revealed P70S mutation in <i>GJB1</i>. The diagnosis of CMTX1 was made. His symptom improved again after second IVIg, and then, repeated IVIg maintained his symptoms.</p>

    DOI: 10.11422/jscn.48.8

  • Furuzono Mai, Takashima Hiroshi, Matsumoto Riku, Mayumi Hanako, Tashiro Yuichi, Arata Hitoshi, Yamano Yoshihisa, Tanaka Masakazu, Kubota Ryuji, Matsuura Eiji .  The initial symptom as a clinical parameter for rapid progression of HAM/TSP .  NEUROINFECTION25 ( 1 ) 146   2020

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    <p>Background : While Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive neurological disease, the progression of the disease varies from person to person. While some blood or cerebrospinal fluid biomarkers for rapid progression of HAM/TSP have been reported, no clinical parameter associated with rapid progression of HAM/TSP has been identified except for older age. Purpose : We tried to find the initial symptom associated with rapid progression of the disease using registry data on patients ( n=527 ) enrolled in the Japanese HAM/TSP patient registry "HAM-net." We determined the periods from the onset of HAM/TSP to the age of wheelchair use in daily life of all the patients and compared the periods by their initial symptom. Result : Urinary disturbance as an initial symptom was significantly associated with slowly progression of HAM/TSP. Sensory disturbance as an initial symptom was significantly associated with rapid progression. Conclusion : The result showed that Initial symptoms could suggest the disease course of the patients with HAM/TSP.</p>

    DOI: 10.34397/jsnd.25.1_146

  • Nozaki Fumihito, Mori Mioko, Kumada Tomohiro, Hashiguchi Akihiro, Takashima Hiroshi, Murayama Kei, Fujii Tatsuya .  A rare case of <i>SUCLA2</i>-related mitochondrial DNA depletion syndrome .  NO TO HATTATSU52 ( 5 ) 318 - 322   2020Reviewed

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    <p>  <i>SUCLA2</i>-related mitochondrial DNA depletion syndrome is known as Leigh syndrome with methylmalonic aciduria. The patient was a 12-year-old girl with non-consanguineous parents. The clinical features included psychomotor retardation, hypotonia, sensorineural hearing impairment, feeding difficulty, growth retardation, muscular atrophy, external ophthalmoplegia, blepharoptosis, gastroesophageal reflux, recurrent vomiting, sagittal craniosynostosis, peripheral axonal neuropathy, restrictive respiratory failure and kyphoscoliosis. Lactate levels in blood and cerebrospinal fluid were elevated at 8 months of age, and brain MRI showed cerebral atrophy. The MRI at 2 years of age revealed hyperintense areas in the bilateral basal ganglia on T2-weighted imaging. Therefore, the patient was diagnosed with Leigh syndrome. Although the serum acylcarnitine profile revealed slightly elevated propionylcarnitine, urine organic acid analysis was decided as normal. At 9 years of age, exome sequencing for the research of peripheral neuropathy revealed novel compound heterozygous variants, NM_003850.2 (SUCLA2) : c.1300del (p.Asp434Metfs<sup>*</sup>8) +c.664-1G>A. Her parents were heterozygous of each variant. A second analysis of urine organic acid showed mildly elevated methylmalonic acid. Muscle biopsy revealed that the activities of complexes Ⅰ and Ⅳ were at the lower limit of the normal range. Thus, the patient was diagnosed with <i>SUCLA2</i>-related mitochondrial DNA depletion syndrome. It is important to pay attention to elevated serum propionylcarnitine and mildly elevated urinary methylmalonic acid levels in patients with mitochondrial diseases.</p>

    DOI: 10.11251/ojjscn.52.318

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  • M.D. Ph.D. Maruta Kyoko, M.D. Ph.D. Ando Masahiro, M.D. Ph.D. Otomo Takanobu, M.D. Ph.D. Takashima Hiroshi .  A case of spastic paraplegia 48 with a novel mutation in the <i>AP5Z1</i> gene .  Rinsho Shinkeigaku60 ( 8 ) 543 - 548   2020Reviewed

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    <p>We describe an additional patient with spastic paraplegia 48 (SPG48). A 52-year-old woman with gradually increasing gait disturbance was admitted to our hospital. When she was 47 years old, acquaintances noted a shuffling gait. Gait worsening was evident at 48 years. Spastic gait was apparent at 50, and she required a walking stick at 54. Her elder brother had similar gait disturbance. No consanguinity was known. Neurologic examination at 52 disclosed spasticity and moderate weakness in the lower limbs. Spasticity and brisk reflexes in all limbs. Laboratory studies including HTLV-1 titer detected no abnormalities. MRI demonstrated mild corpus callosum narrowing and prominent anterior periventricular hyperintensities in fluid attenuation inversion recovery images. In limb muscles, electromyography (EMG) showed a chronic neurogenic pattern including reduced interference. Gene analysis identified compound homozygosity in exon 7 of adaptor-related protein complex 5 subunit zeta 1 (<i>AP5Z1</i>), including a novel frameshift mutation, c.1662_1672del;p.Glu554Hfs*15 in the patient, and a heterozygous missense mutation in asymptomatic family members, including her mother, two siblings, and a daughter. The frameshift mutation is considered a pathogenic variant according to American College of Medical Genetics and Genomics standards and guidelines. Based on clinical features, imaging findings and genetic abnormalities, we diagnosed this patient with SPG48. Mutations in <i>AP5Z1</i>, which encodes the ζ subunit of AP-5, underlie SPG48. The AP-5 adaptor protein complex, which is mutated in SPG48, binds to both spastizin and spatacsin. While hereditary spastic paraplegias generally are clinically and genetically heterogenous, SPG48, SPG11, and SPG15 are clinically similar.</p>

    DOI: 10.5692/clinicalneurol.60.cn-001419

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  • M.D. Ph.D. Nakane Shunya, M.D. Ph.D. Kimura Kazumi, M.D. Ph.D. Suzuki Masahiko, M.D. Ph.D. Takashima Hiroshi, M.D. Ph.D. Terayama Yasuo, M.D. Ph.D. Nishiyama Kazutoshi, M.D. Ph.D. Furuya Hirokazu, M.D. Ph.D. Matsubara Etsuro, M.D. Ph.D. Muramatsu Shin-Ichi, M.D. Ph.D. Yamamura Osamu, M.D. Ph.D. Takeda Atsushi, M.D. Ph.D. Mizoguchi Kouichi, M.D. Ph.D. Ito Hidefumi, Committee for Measures Against Disaster Japanese Society of Neurology, M.D. Ph.D. Abe Koji, M.D. Ph.D. Atsuta Naoki, M.D. Ph.D. Iguchi Yasuyuki, M.D. Ph.D. Ikeda Yoshio, M.D. Ph.D. Kaji Ryuji, M.D. Ph.D. Kamei Satoshi, M.D. Ph.D. Kitagawa Kazuo .  Role of the liaison officer in disaster countermeasures implemented by the Japanese Society of Neurology: Hope for the best and prepare for the worst .  Rinsho Shinkeigaku60 ( 10 ) 643 - 652   2020Reviewed

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    <p>Disaster countermeasures have been implemented by the Japanese Society of Neurology based on the experience of support to the areas affected by the Great East Japan Earthquake on March 11, 2011. The countermeasures activity began at the end of 2011. We, the Committee for Measures Against Disaster, officially started work in 2014. We developed a support network to urgently deal with patients with intractable neurological disease at the time of disaster and strengthen disaster measures, including effective disaster countermeasure training. During the 2016 Kumamoto earthquake, we realized the need to prepare for natural disasters, leading to a state of emergency, at normal times. A list of vulnerable people should be prepared and the individual support plan for disaster should be confirmed during normal times. Furthermore, during disaster, livelihood support is required for patients with intractable neurological disease living in evacuation centers in affected areas. Therefore, we compiled and published the book, titled "The manual of disaster countermeasures," in 2017. The Committee for Measures Against Disaster in the Japanese Society of Neurology has appointed a liaison officer for patients with intractable neurological disease in each prefecture. The liaison's role of is gathering and disseminating information on the disaster-hit areas, arranging medical support, and coordinating health activities, when natural disasters occur. It is hoped that the liaison officer will play an active role both at normal times and during disaster, even unforeseen ones. Although we hope for the best, we aim to be prepared for the worst.</p>

    DOI: 10.5692/clinicalneurol.cn-001493

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  • M.D. Ph.D. Kitao Ruriko, M.D. Ph.D. Honma Yutaka, M.D. Ph.D. Hashiguchi Akihiro, M.D. Ph.D. Mizoguchi Kouichi, M.D. Ph.D. Takashima Hiroshi, M.D. Ph.D. Komori Tetsuo .  A case of motor and sensory polyneuropathy and respiratory failure with novel heterozygous mutation of the senataxin gene .  Rinsho Shinkeigaku60 ( 7 ) 466 - 472   2020Reviewed

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    <p>The patient was a 29-year-old male. He took his first steps at two-and-a-half years old, but his physical strength deteriorated and he became non-ambulatory at 12 years old. He had respiratory failure at the age of 20, and finally underwent tracheostomy with invasive positive-pressure ventilation (TPPV). He showed distal dominant muscle weakness and atrophy, including the face. Spinal scoliosis was recognized. He had peripheral predominance of sensory disorders. Nerve conduction studies showed a decrease of compound muscle action potential and a reduction of motor nerve conduction velocity. Sensory nerve action potential was not evoked. In genetic analysis, c.23 C> T (p. T8M) heterozygous mutation was found in the senataxin gene (<i>SETX</i>). Although <i>SETX</i> is a causative gene of familial amyotrophic lateral sclerosis type 4 (ALS4), this case suggests that <i>SETX</i> mutation can also cause motor and sensory polyneuropathy.</p>

    DOI: 10.5692/clinicalneurol.60.cn-001415

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  • Kikuchi Akira, Okamoto Yuji, Hashiguchi Hiroshi, Yoshishige Koichi, Taniguchi Takaki, Deguchi Takahisa, Takashima Hiroshi, Nishio Yoshihiko .  A Case of Mitochondrial Diabetes Mellitus Diagnosed by Development of Cognitive Decline .  Journal of the Japan Diabetes Society63 ( 5 ) 344 - 349   2020Reviewed

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    <p>The patient was a 64-year-old woman with a family history of diabetes mellitus who was diagnosed with focal glomerulosclerosis and diabetes mellitus at 40 and 53 years of age, respectively. Five years previously, the patient had switched from oral hypoglycemic drugs to intensive insulin therapy due to poor glycemic control. Three years later, the patient was diagnosed with progressive memory loss that was thought to be the reason for the deterioration in glycemic control. A neurological examination revealed impairment of the higher brain functions and coordination of arm movements. Bilateral white matter lesions with cerebral, brain stem, and cerebellar atrophy were observed on brain MRI. In addition, a left biceps muscle biopsy revealed myopathy accompanied by ragged red fiber, a characteristic finding of mitochondrial diabetes. The re-examination of the renal biopsy specimen that was obtained at 57 years of age was also suggestive of a mitochondrial-related lesion. Surprisingly, the patient's older sister was also diagnosed with mitochondrial diabetes. There are no previous reports of cases in which mitochondrial diabetes was discovered due to poor control as a result of associated cognitive decline. We describe the present case with consideration of the relevant literature.</p>

    DOI: 10.11213/tonyobyo.63.344

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  • 髙嶋 博, 山村 隆 .  自己免疫性脳炎の診療の進歩 update 司会の言葉 .  神経治療学37 ( 4 ) 634 - 634   2020

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    DOI: 10.15082/jsnt.37.4_634

  • Sakiyama Yusuke, Takashima Hiroshi .  Review/Advances in Neurological Therapeutics (2019). Spinocerebellar degeneration .  Neurological Therapeutics37 ( 5 ) 732 - 735   2020

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    <p>We reviewed the recent advances in therapeutics of spinocerebellar degeneration (SCD) that were published in 2019. Ion channel modulation may contribute to recover for Purkinje neuron dysfunction and motor impairment in a variety of cerebellar ataxias. The role of RNA–binding proteins as RNA chaperones may lead to the development of new treatments for SCA31. Aminopyridines and acetyl–DL–leucine will provide new therapeutic strategies of cerebellar disorders. We expect that these treatments will contribute to patients with cerebellar motor dysfunction and ataxia.</p>

    DOI: 10.15082/jsnt.37.5_732

  • Yamashita S, Kimura E, Zhang Z, Tawara N, Hara K, Yoshimura A, Takashima H, Ando Y .  Muscle pathology of hereditary motor and sensory neuropathy with proximal dominant involvement with TFG mutation. .  Muscle & nerve60 ( 6 ) 739 - 744   2019.12Reviewed International journal

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    BACKGROUND: Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is characterized by adult onset, a slowly progressive course and autosomal dominant inheritance. It remains unclear whether myopathic changes occur histopathologically. METHODS: We encountered 2 patients in a family with a heterozygous p.P285L mutation in TRK-fused gene (TFG), which is known to cause HMSN-P. The affected individuals developed proximal-dominant muscle weakness in their 40s, which slowly progressed to a motor neuron disease-like phenotype. RESULTS: Muscle biopsy showed myopathic pathology including fiber size variability, increased internal nuclei, fiber splitting, and core-like structures, associated with neurogenic changes: large groups of atrophic fibers and fiber type-grouping. Immunohistochemistry revealed sarcoplasmic aggregates of TFG, TDP-43, and p62 without congophilic material. CONCLUSIONS: The present study demonstrates myopathic changes in HMSN-P. Although the mechanisms underlying the skeletal muscle involvement remain to be elucidated, immunohistochemistry suggests that abnormal protein aggregation may be involved in the myopathic pathology.

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  •  Shojima Yuri, Nishioka Kenya, Watanabe Masao, Jo Takayuki, Tanaka Keiko, Takashima Hiroshi, Noda Kazuyuki, Okuma Yasuyuki, Urabe Takao, Yokoyama Kazumasa, Hattori Nobutaka .  Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case Series .  Internal Medicine 58 ( 23 ) 3369 - 3378   2019.12Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case SeriesReviewed

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    DOI: doi.org/10.2169/internalmedicine.3029-19

  • Shojima Yuri, Nishioka Kenya, Watanabe Masao, Jo Takayuki, Tanaka Keiko, Takashima Hiroshi, Noda Kazuyuki, Okuma Yasuyuki, Urabe Takao, Yokoyama Kazumasa, Hattori Nobutaka .  確定した自己免疫性辺縁系脳炎の臨床特性 30症例のケースシリーズ(Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case Series) .  Internal Medicine58 ( 23 ) 3369 - 3378   2019.12確定した自己免疫性辺縁系脳炎の臨床特性 30症例のケースシリーズ(Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case Series)

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    確定した自己免疫性辺縁系脳炎(LE)患者の臨床特性を後向きに評価した。日本3施設でLEと診断された患者16759例の医療記録を評価し、臨床的に確定した自己免疫性LE患者30例を特定した(有病率0.2%)。8例が抗N-メチル-D-アスパラギン酸受容体(NMDAR)抗体陽性、2例が抗電位依存性カリウムチャネル(VGKC)複合抗体陽性、2例が腫瘍随伴症候群関連抗体陽性で、18例は抗体陰性であった。NMDAR陽性群では典型的症状が認められた。脳MRI所見では、退院後1年間の追跡時に有意な内側側頭葉の萎縮が認められた。合併症としての認知機能障害の有病率は64%(9/14例)であった。一次免疫療法の成績は良好で、修正Rankin尺度スコアは4.0±1.1から1.1±1.1に著明に改善した。NMDAR陽性群、VGKC陽性群、抗体陰性群のいずれにおいても治療成績は良好であったことから、早期臨床診断と早期治療開始の重要性が示唆された。

  • Mizokami T, Uwatoko T, Matsumoto K, Ooya Y, Hashimoto G, Koguchi M, Iwashita H, Uwatoko K, Takashima H, Sugimori H, Sakata S .  Aspiration Catheter Reach to Thrombus (ART) Sign in Combined Technique for Mechanical Thrombectomy: Impact for First-Pass Complete Reperfusion. .  Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association28 ( 10 ) 104301   2019.10Aspiration Catheter Reach to Thrombus (ART) Sign in Combined Technique for Mechanical Thrombectomy: Impact for First-Pass Complete Reperfusion.

  • Ukon Shinichiro, Watanabe Shohei, Tatsumi Yoshiki, Hashiguchi Akihiro, Takashima Hiroshi, Yoshikawa Hiroo .  Mitofusin 2 S245Rを発現するCharcort-Marie-Tooth病2A型モデルのトランスジェニックマウスにおける、視神経でのミトコンドリア形態異常(Mitochondria! Malformation in the Optic Nerve of a Transgenic Mouse Model of Charcot-Marie-Tooth Type 2A Expressing Mitofusin 2 S245R) .  兵庫医科大学医学会雑誌44 ( 1 ) 59 - 67   2019.9Mitofusin 2 S245Rを発現するCharcort-Marie-Tooth病2A型モデルのトランスジェニックマウスにおける、視神経でのミトコンドリア形態異常(Mitochondria! Malformation in the Optic Nerve of a Transgenic Mouse Model of Charcot-Marie-Tooth Type 2A Expressing Mitofusin 2 S245R)

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    異常な視覚誘発性電位を呈したCharcort-Marie-Tooth病2A型(CMT2A)の日本人家系にヘテロ接合MFN2遺伝子変異(c.733A>C: p.Ser245Arg)を検出した。そこで、ニューロンにmitofusin 2(MFN2) S245Rを特異的に発現するトランスジェニック(TG)マウスを作成し、その生態病理について検討した。その結果、このTGマウスは対照マウスに比べて坐骨神経内のg-ratioが有意に大きかった。次にTGマウスの視神経を検討すると、横断面と縦断面のいずれでもミトコンドリアのサイズが対照マウスに比べて有意に小さく、これはミトコンドリアの融合障害に起因すると推測された。以上より、変異MFN2はミトコンドリア融合に影響を及ぼし、視神経症を引き起こすと考えられた。

  • Takashima Hiroshi .  Progress of Medical Treatment of Neuropathy .  Nihon Naika Gakkai Zasshi108 ( 8 ) 1515 - 1516   2019.8

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    DOI: 10.2169/naika.108.1515

  • Sone J, Mitsuhashi S, Fujita A, Mizuguchi T, Hamanaka K, Mori K, Koike H, Hashiguchi A, Takashima H, Sugiyama H, Kohno Y, Takiyama Y, Maeda K, Doi H, Koyano S, Takeuchi H, Kawamoto M, Kohara N, Ando T, Ieda T, Kita Y, Kokubun N, Tsuboi Y, Katoh K, Kino Y, Katsuno M, Iwasaki Y, Yoshida M, Tanaka F, Suzuki IK, Frith MC, Matsumoto N, Sobue G .  Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. .  Nature genetics51 ( 8 ) 1215 - 1221   2019.8Reviewed International journal

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    Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult1-8, but skin biopsy enables its ante-mortem diagnosis9-12. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.

    DOI: 10.1038/s41588-019-0459-y

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  • Tomari S. .  Effect of direct oral anticoagulant for acute major cerebral artery occlusion in cardioembolic stroke/transient ischemic attack patients with non-valvular atrial fibrillation .  Journal of the Neurological Sciences402   162 - 166   2019.7Reviewed International journal

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    DOI: 10.1016/j.jns.2019.05.023

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  • Togawa Jumpei, Ohi Takekazu, Yuan Jun-Hui, Takashima Hiroshi, Furuya Hirokazu, Takechi Shinji, Fujitake Junko, Hayashi Saki, Ishiura Hiroyuki, Naruse Hiroya, Mitsui Jun, Tsuji Shoji .  緩徐進行性の下肢優勢晩期発症筋力低下および萎縮を伴う非定型家族性筋萎縮性側索硬化症(Atypical Familial Amyotrophic Lateral Sclerosis with Slowly Progressing Lower Extremities-predominant Late-onset Muscular Weakness and Atrophy) .  Internal Medicine58 ( 13 ) 1851 - 1858   2019.7緩徐進行性の下肢優勢晩期発症筋力低下および萎縮を伴う非定型家族性筋萎縮性側索硬化症(Atypical Familial Amyotrophic Lateral Sclerosis with Slowly Progressing Lower Extremities-predominant Late-onset Muscular Weakness and Atrophy)

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    家族性筋萎縮性側索硬化症(fALS)の同胞6例を対象に、臨床的インタビューと臨床検査を行ってfALSの非定型表現型について報告し、末梢血標本の遺伝子解析を行った。罹患同胞は5例(男性3例、女性2例)、健康同胞は1例(女性)であった。fALSの臨床特性は、緩徐進行性(平均罹病期間19.6±3.9年)、下肢優勢晩期発症筋力低下(筋力低下の平均発症時年齢52.8±2.6歳)であった。遺伝子解析により、すべての罹患同胞においてPLEC遺伝子のヘテロ接合型ミスセンス変異(OMIM 601282,c.2668C>T,p.R890C)、ST3GAL6遺伝子のヘテロ接合型ミスセンス変異(OMIM 607156,c.421G>C,p.V141L)が検出された。臨床経過が比較的良好な新規の非定型fALS家族について報告し、この表現型に関連する二つの候補遺伝子変異を特定した。

  • Kawarai T, Yamazaki H, Miyamoto R, Takamatsu N, Mori A, Osaki Y, Orlacchio A, Nodera H, Hashiguchi A, Higuchi Y, Yoshimura A, Takashima H, Kaji R .  PMP22-related disease: A novel splice site acceptor variant and intrafamilial phenotype variability. .  Neuromuscular disorders : NMD29 ( 6 ) 422 - 426   2019.6Reviewed International journal

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    PMP22 is the most frequent mutated gene in Charcot-Marie-Tooth disease (CMT) type 1A. Another phenotype, hereditary neuropathy with pressure palsies (HNPP), could be caused by PMP22 mutations. PMP22 encodes a peripheral myelin protein with molecular weight 22-kDa. Various pathomechanisms have been postulated in PMP22-related disease, including dysfunction due to missense mutations, and alteration of a gene dose due to duplication/deletion mutations. We identified a novel PMP22 splice site acceptor variant, c.179-1G>A, in a patient with adult-onset chronic generalized polyneuropathy and two asymptomatic family members. Pathophysiological features of the members mainly overlapped with those reported in HNPP, but broad intrafamilial clinical variations were observed. PMP22 transcripts lacking of exon 4 were produced by the variant, presumably leading to in-frame deletion of 47 amino acids. The variant was also shown to exert effect on dosage of PMP22 mRNA. The complex molecular pathology would lead to the unique clinical and pathophysiological conditions.

    DOI: 10.1016/j.nmd.2019.03.010

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  • Jialin Li, Kojiro Suda, Ibuki Ueoka, Ryo Tanaka, Hideki Yoshida, Yasushi Okada, Yuji Okamoto, Yu Hiramatsu, Hiroshi Takashima, Masamitsu Yamaguchi .  Neuron-specific knockdown of Drosophila HADHB induces a shortened lifespan, deficient locomotive ability, abnormal motor neuron terminal morphology and learning disability. .  Experimental cell research379 ( 2 ) 150 - 158   2019.6Reviewed International journal

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    Mutations in the HADHB gene induce dysfunctions in the beta-oxidation of fatty acids and result in a MTP deficiency, which is characterized by clinical heterogeneity, such as cardiomyopathy and recurrent Leigh-like encephalopathy. In contrast, milder forms of HADHB mutations cause the later onset of progressive axonal peripheral neuropathy (approximately 50-80%) and myopathy with or without episodic myoglobinuria. The mechanisms linking neuronal defects in these diseases to the loss of HADHB function currently remain unclear. Drosophila has the CG4581 (dHADHB) gene as a single human HADHB homologue. We herein established pan-neuron-specific dHADHB knockdown flies and examined their phenotypes. The knockdown of dHADHB shortened the lifespan of flies, reduced locomotor ability and also limited learning abilities. These phenotypes were accompanied by an abnormal synapse morphology at neuromuscular junctions (NMJ) and reduction in both ATP and ROS levels in central nervous system (CNS). The Drosophila NMJ synapses are glutamatergic that is similar to those in the vertebrate CNS. The present results reveal a critical role for dHADHB in the morphogenesis and function of glutamatergic neurons including peripheral neurons. The dHADHB knockdown flies established herein provide a useful model for investigating the pathological mechanisms underlying neuropathies caused by a HADHB deficiency.

    DOI: 10.1016/j.yexcr.2019.03.040

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  • Miyaue N. .  Phenotypic diversity of hereditary sensory and autonomic neuropathy type IE: A case series and review of the literature .  Neurology Asia24 ( 1 ) 15 - 20   2019.3Reviewed International journal

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  • Takuya Miyabayashi, Tatsuhiro Ochiai, Naoki Suzuki, Masashi Aoki, Takehiko Inui, Yukimune Okubo, Ryo Sato, Noriko Togashi, Hiroshi Takashima, Hiroyuki Ishiura, Shoji Tsuji, Kishin Koh, Yoshihisa Takiyama, Kazuhiro Haginoya .  A novel homozygous mutation of the TFG gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy. .  Journal of human genetics64 ( 2 ) 171 - 176   2019.2Reviewed International journal

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    The tropomyosin-receptor kinase fused gene (TFG) has recently been implicated in several distinct hereditary disorders, including the autosomal-recessive form of complicated hereditary spastic paraplegia called SPG57. Previously, three homozygous variants of the TFG gene were reported in five families with SPG57, in which early onset spastic paraplegia, optic atrophy, and peripheral neuropathy were variably identified. Here, we present the first Japanese patient with SPG57, and have added a homozygous p.Ile66Thr variant as the fourth SPG57 genotype.

    DOI: 10.1038/s10038-018-0538-4

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  • Nishikura N, Yamagata T, Morimune T, Matsui J, Sokoda T, Sawai C, Sakaue Y, Higuchi Y, Hashiguchi A, Takashima H, Takeuchi Y, Maruo Y .  X-linked Charcot-Marie-Tooth disease type 5 with recurrent weakness after febrile illness. .  Brain & development41 ( 2 ) 201 - 204   2019.2Reviewed International journal

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    DOI: 10.1016/j.braindev.2018.08.006

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  • Nishikura Noriko, Yamagata Takanori, Morimune Takao, Matsui Jun, Sokoda Tatsuyuki, Sawai Chihiro, Sakaue Yuko, Higuchi Yujiro, Hashiguchi Akihiro, Takashima Hiroshi, Takeuchi Yoshihiro, Maruo Yoshihiro .  発熱後に再発する虚脱感を呈した5型X連鎖Charcot-Marie-Tooth病(X-linked Charcot-Marie-Tooth disease type 5 with recurrent weakness after febrile illness) .  Brain & Development41 ( 2 ) 201 - 204   2019.2発熱後に再発する虚脱感を呈した5型X連鎖Charcot-Marie-Tooth病(X-linked Charcot-Marie-Tooth disease type 5 with recurrent weakness after febrile illness)

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    症例1は13歳男児で、出生時から言語習得前難聴が認められた。8歳から11歳にかけて、呼吸器感染症に罹患した後に突然発症の筋力低下を計3回にわたり繰り返していた。12歳時に行った神経伝導検査では、遠位下肢における複合筋活動電位(CMAP)の低下がみられ、13歳時、歩行障害、反射低下および難聴を認めた。症例2は症例1の弟。生後1年目に言語習得前難聴がみられ、2歳ごろから発熱後の歩行困難を呈していた。8歳時に受診となり、神経学的検査で膝関節と足関節の反射低下、重度の近位筋力低下を認めた。頭部・脊椎・筋MRIでは異常所見なく、髄液検査でも異常はなかった。神経伝導検査でCMAPの低下、脛骨神経と総合腓骨神経の一時的分散がみられた。ニューロパシー関連遺伝子72個のSangerシークエンス解析を行ったところ、PRSP1遺伝子内に新規c.319A>C半接合ミスセンス変異が検出された。発端者は半接合変異、母親はヘテロ接合変異を有することが判明し、5型X連鎖Charcot-Marie-Tooth病との確定診断を得た。

  • Miyabayashi Takuya, Ochiai Tatsuhiro, Suzuki Naoki, Aoki Masashi, Inui Takehiko, Okubo Yukimune, Sato Ryo, Togashi Noriko, Takashima Hiroshi, Ishiura Hiroyuki, Tsuji Shoji, Koh Kishin, Takiyama Yoshihisa, Haginoya Kazuhiro .  早発性痙性対麻痺および晩発性感覚運動性ポリニューロパチー患者におけるTFG遺伝子の新規ホモ接合性変異(A novel homozygous mutation of the TFG gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy) .  Journal of Human Genetics64 ( 2 ) 171 - 176   2019.2早発性痙性対麻痺および晩発性感覚運動性ポリニューロパチー患者におけるTFG遺伝子の新規ホモ接合性変異(A novel homozygous mutation of the TFG gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy)

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    本報では日本人初の常染色体劣性遺伝性痙性対麻痺(SPG57)患者を報告し、4番目のSPG57遺伝子型の新規変異体について報告した。症例は43歳女性で、いとこ婚による健常両親の第3子として出生し、長兄も同様の病歴を有し、次兄は原因不明の軽度知覚障害を伴っていた。本例は3〜4歳で自立歩行となり、三輪車にも乗れたが、5歳で歩行困難を来し、脳性麻痺と診断された。10歳時には自立歩行困難になったが、知能は正常で、専門学校を卒業後は事務員として勤務していた。30歳で緑内障を発症し、39歳で腰痛のため来院した際に、痙性両麻痺および遠位優性末梢性感覚運動障害を指摘された。全エクソーム解析等の遺伝学的解析により、病原性変異として、tropomyosin-receptor kinase fused gene(TFG)のエクソン3にホモ接合性ミスセンス変異体c.197T>C:p.Ile66Thrが同定され、SPG57と確定診断された。

  • Jumpei Togawa, Takekazu Ohi, Jun-Hui Yuan, Hiroshi Takashima, Hirokazu Furuya, Shinji Takechi, Junko Fujitake, Saki Hayashi, Hiroyuki Ishiura, Hiroya Naruse, Jun Mitsui, Shoji Tsuji .  Atypical Familial Amyotrophic Lateral Sclerosis with Slowly Progressing Lower Extremities-predominant Late-onset Muscular Weakness and Atrophy. .  Internal medicine (Tokyo, Japan)58 ( 13 ) 1851 - 1858   2019Reviewed International journal

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    Objective Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the progressive loss of the upper and lower motor neurons that progresses to paralysis of almost all skeletal muscles of the extremities, bulbar, and respiratory system. Although most ALS cases are sporadic, about 10% are dominantly inherited. We herein report an atypical phenotype of familial ALS (fALS). To elucidate the phenotype-genotype correlation of this atypical phenotype of fALS, clinical and genetic investigations were performed. Methods and Patients Five sibling patients (three men, two women) from a Japanese family and one healthy sibling (a woman) were clinically interviewed and examined. Genetic analyses, including genome-wide linkage analyses and whole-exome sequencing, were performed using genomic DNA extracted from the peripheral blood samples of these siblings. Results The clinical features of fALS are characterized by slow progression (mean duration of the disease±standard deviation [SD]: 19.6±3.9 years) and lower extremities-predominant late-onset muscular weakness (mean onset of muscular weakness±SD: 52.8±2.6 years). Genetic analyses revealed novel heterozygous missense mutations of c.2668C>T, p.R890C in the PLEC gene and c.421G>C, p.V141L in the ST3GAL6 gene in all affected siblings. Conclusion A new atypical fALS family with a benign clinical course is herein reported. We identified two candidate gene mutations of PLEC and ST3GAL6 linked to this phenotype.

    DOI: 10.2169/internalmedicine.2222-18

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  • Komatsu K. .  Various associations of aging and long-term HIV infection with different neurocognitive functions: detailed analysis of a Japanese nationwide multicenter study .  Journal of NeuroVirology   2019

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    Publisher:Journal of NeuroVirology  

    DOI: 10.1007/s13365-018-0704-7

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  • 髙嶋 博 .  自己免疫性脳症の臨床症候と治療の実際―ヒステリーとの鑑別― .  神経治療学36 ( 6 ) S154 - S154   2019

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    Language:Japanese   Publisher:日本神経治療学会  

    DOI: 10.15082/jsnt.36.6_S154

  • Shojima Yuri, Nishioka Kenya, Watanabe Masao, Jo Takayuki, Tanaka Keiko, Takashima Hiroshi, Noda Kazuyuki, Okuma Yasuyuki, Urabe Takao, Yokoyama Kazumasa, Hattori Nobutaka .  Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case Series .  Internal Medicine58 ( 23 ) 3369 - 3378   2019Invited International journal

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    <p><b>Objective </b>Limbic encephalitis (LE) is an inflammatory condition of the limbic system that has an acute or subacute onset. Several types of antibodies are related to the onset of LE, including anti-N-methyl D-aspartate receptor (NMDAR) antibodies and voltage-gated potassium channel (VGKC)-complex antibodies. However, the characteristics and prevalence of LE remain unclear, especially in Asian cohorts, due to the rarity. We aimed to survey their characteristics. </p><p><b>Materials and Methods </b>Data of 30 cases clinically defined as "definite autoimmune LE" (based on the standard criteria) were retrospectively collected. These patients were categorized into four subtypes: NMDAR (+) (n=8), VGKC (+) (n=2), antibodies related to paraneoplastic syndrome (n=2), and an antibody-negative group (uncategorized) (n=18). </p><p><b>Results </b>LE is rare in Japan, and affected only 30 of 16,759 hospital patients (0.2%) over a ten-year period. The NMDAR (+) group showed distinctive symptoms, while the other three groups had similar indications. Brain MRI indicated significant medial temporal lobe atrophy at one year follow up after discharge. The prevalence of cognitive dysfunction as a complication was 64% (9/14). First-line immunotherapy resulted in a good outcome. A drastic improvement was seen from 4.0±1.1 to 1.1+ on the modified Rankin Scale. A good treatment outcome was observed in all groups (NMDAR, VGKC, and uncategorized), suggesting the importance of an early clinical diagnosis and the early initiation of treatment. Furthermore, we reviewed 26 cases that were clinically diagnosed as definitive autoimmune LE in previous case reports. </p><p><b>Conclusion </b>Our findings show that the establishment of a clinical diagnosis based on the clinical criteria of definitive autoimmune LE is important for the initiation of immunotherapy. </p>

    DOI: 10.2169/internalmedicine.3029-19

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  • Sakiyama Yusuke, Takashima Hiroshi .  Review/Advances in Neurological Therapeutics (2018). Spinocerebellar degeneration .  Neurological Therapeutics36 ( 5 ) 580 - 583   2019Reviewed

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    Authorship:Last author   Language:Japanese   Publisher:Japanese Society of Neurological Therapeutics  

    <p>We reviewed the recent advances in therapeutics of spinocerebellar degeneration (SCD) that were published in 2018. This article introduces the outline of therapies with mesenchymal stem cells, cerebello–spinal tDCS, betamethasone, and cyclodextrin. We expect that these treatments will contribute to patients with cerebellar motor dysfunction and ataxia.</p>

    DOI: 10.15082/jsnt.36.5_580

  • Yamagishi Y, Samukawa M, Kuwahara M, Takada K, Saigoh K, Mitsui Y, Oka N, Hashiguchi A, Takashima H, Kusunoki S. .  Charcot-Marie-Tooth disease with a mutation in FBLN5 accompanying with the small vasculitis and widespread onion-bulb formations. .  J Neurol Sci410   116623   2019Charcot-Marie-Tooth disease with a mutation in FBLN5 accompanying with the small vasculitis and widespread onion-bulb formations.Reviewed

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  • Sugahara Y, Ono N, Morishita E, Takashima H .  [A case of recurrent cerebral vein thrombosis with protein C gene mutation identified]. .  Rinsho shinkeigaku = Clinical neurology58 ( 12 ) 764 - 766   2018.12[A case of recurrent cerebral vein thrombosis with protein C gene mutation identified].

  • Shima T, Yamamoto Y, Kanazawa N, Murata KY, Ito H, Kondo T, Yuan J, Hashiguchi A, Takashima H, Furukawa F .  Repeated hyperhidrosis and chilblain-like swelling with ulceration of the fingers and toes in hereditary sensory and autonomic neuropathy type II. .  The Journal of dermatology45 ( 11 ) 308 - 309   2018.11Reviewed

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    DOI: 10.1111/1346-8138.14336

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  • Takanashi M, Funayama M, Matsuura E, Yoshino H, Li Y, Tsuyama S, Takashima H, Nishioka K, Hattori N .  Isolated nigral degeneration without pathological protein aggregation in autopsied brains with LRRK2 p.R1441H homozygous and heterozygous mutations. .  Acta neuropathologica communications6 ( 1 ) 105 - 105   2018.10Reviewed International journal

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    Leucine-rich repeat kinase 2 (LRRK2) is the most common causative gene for autosomal dominant Parkinson's disease (PD) and is also known to be a susceptibility gene for sporadic PD. Although clinical symptoms with LRRK2 mutations are similar to those in sporadic PD, their pathologies are heterogeneous and include nigral degeneration with abnormal inclusions containing alpha-synuclein, tau, TAR DNA-binding protein 43, and ubiquitin, or pure nigral degeneration with no protein aggregation pathologies. We discovered two families harboring heterozygous and homozygous c.4332 G > A; p.R1441H in LRRK2 with consanguinity, sharing a common founder. They lived in the city of Makurazaki, located in a rural area of the southern region, the Kagoshima prefecture, in Kyushu, Japan. All patients presented late-onset parkinsonism without apparent cognitive decline and demonstrated a good response to levodopa. We obtained three autopsied cases that all presented with isolated nigral degeneration with no alpha-synuclein or other protein inclusions. This is the first report of neuropathological findings in patients with LRRK2 p.R1441H mutations that includes both homozygous and heterozygous mutations. Our findings in this study suggest that isolated nigral degeneration is the primary pathology in patients with LRRK2 p.R1441H mutations, and that protein aggregation of alpha-synuclein or tau might be secondary changes.

    DOI: 10.1186/s40478-018-0617-y

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  • Shimizu Y, Tonooka K, Yoshida Y, Furuse M, Takashima H .  Growth and superconductivity of niobium titanium alloy thin films on strontium titanate (001) single-crystal substrates for superconducting joints. .  Scientific reports8 ( 1 ) 15135   2018.10Growth and superconductivity of niobium titanium alloy thin films on strontium titanate (001) single-crystal substrates for superconducting joints.

  • Sakiyama Y, Matsuura E, Maki Y, Yoshimura A, Ando M, Nomura M, Shinohara K, Saigo R, Nakamura T, Hashiguchi A, Takashima H .  Peripheral neuropathy in a case with CADASIL: a case report. .  BMC neurology18 ( 1 ) 134 - 134   2018.8Reviewed International journal

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    DOI: 10.1186/s12883-018-1131-3

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  • Mizokami Taichiro, Uwatoko Takeshi, Furukawa Takashi, Higashi Eiji, Sakaki Yusuke, Suetsugi Natsuki, Takamatsu Yuichiro, Matsumoto Kenichi, Takashima Hiroshi, Sugimori Hiroshi, Sakata Shuji .  経橈骨動脈アプローチによる後方循環の急性期再開通療法(Transradial Approach for Mechanical Thrombectomy of Posterior Circulation Stroke) .  JNET: Journal of Neuroendovascular Therapy12 ( 6 ) 314 - 319   2018.6経橈骨動脈アプローチによる後方循環の急性期再開通療法(Transradial Approach for Mechanical Thrombectomy of Posterior Circulation Stroke)

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    Publisher:(NPO)日本脳神経血管内治療学会  

    目的)治療時間短縮のために、初回のアプローチルートとして橈骨動脈アプローチ(Transradial Approach:TRA)を選択した後方循環の急性期再開通療法について報告する。症例)2015年11月から2017年3月の期間に、4例の後方循環主幹動脈閉塞症に対してTRAを用いて急性期再開通療法をおこなった。TRAは術前のMRIで右側の椎骨動脈(Vertebral Artery:VA)が優位である症例において初回のアプローチルートとして用いた。全例でアプローチルートの変更なく手技を完遂でき、TICI2b以上の再開通を全例の100%に、TICI3の再開通を3例の75.0%で得られた。橈骨動脈穿刺から初回の頭蓋内造影までの時間は7.3±1.5分で、有効再開通までの治療時間は28.8±6.2分であった。穿刺部合併症は認めなかった。結論)橈骨動脈アプローチを初回から行った後方循環の急性期再開通療法では、迅速で確実な再開通が得られた。右VAにアプローチ可能な症例では第一選択として利用できる可能性が示唆された。(著者抄録)

  • Vuu My Dung, Dang Ngoc Anh Suong, Yuji Okamaoto, Yu Hiramatsu, Dang Thi Phuong Thao, Hideki Yoshida, Hiroshi Takashima, Masamitsu Yamaguchi .  Neuron-specific knockdown of Drosophila PDHB induces reduction of lifespan, deficient locomotive ability, abnormal morphology of motor neuron terminals and photoreceptor axon targeting .  Experimental Cell Research366 ( 2 ) 92 - 102   2018.5Reviewed International journal

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    Pyruvate dehydrogenase complex deficiency (PDCD) is a common primary cause of defects in mitochondrial function and also can lead to peripheral neuropathy. Pyruvate dehydrogenase E1 component subunit beta (PDHB) is a subunit of pyruvate dehydrogenase E1, which is a well-known component of PDC. In Drosophila melanogaster, the CG11876 (dPDHB) gene is a homolog of human PDHB. In this study, we established a Drosophila model with neuron-specific knockdown of dPDHB to investigate its role in neuropathy pathogenesis. Knockdown of dPDHB in pan-neurons induced locomotor defects in both larval and adult stages, which were consistent with abnormal morphology of the motor neuron terminals at neuromuscular junctions and mitochondrial fragmentation in brains. Moreover, neuron-specific knockdown of dPDHB also shortened the lifespan of adult flies. In addition, flies with knockdown of dPDHB manifested a rough eye phenotype and aberrant photoreceptor axon targeting. These results with the Drosophila model suggest the involvement of PDHB in peripheral neuropathy.

    DOI: 10.1016/j.yexcr.2018.02.035

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  • Yuan JH, Hashiguchi A, Okamoto Y, Yoshimura A, Ando M, Shiomi K, Saito K, Takahashi M, Ichinose K, Ohmichi T, Ichikawa K, Tadashi A, Takigawa H, Shibayama H, Takashima H. .  Clinical and mutational spectrum of Japanese patients with recessive variants in SH3TC2. .  J Hum Genet   2018.3Clinical and mutational spectrum of Japanese patients with recessive variants in SH3TC2.Reviewed

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  • Dung VM, Suong DNA, Okamaoto Y, Hiramatsu Y, Thao DTP, Yoshida H, Takashima H, Yamaguchi M. .  Neuron-specific knockdown of Drosophila PDHB induces reduction of lifespan, deficient locomotive ability, abnormal morphology of motor neuron terminals and photoreceptor axon targeting. .  Exp Cell Res   2018.2Neuron-specific knockdown of Drosophila PDHB induces reduction of lifespan, deficient locomotive ability, abnormal morphology of motor neuron terminals and photoreceptor axon targeting.Reviewed

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  • Fujisaki N, Suwazono S, Suehara M, Nakachi R, Kido M, Fujiwara Y, Oshiro S, Tokashiki T, Takashima H, Nakagawa M.  .  The natural history of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) in 97 Japanese patients. .  Intractable Rare Dis Res   2018.2The natural history of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) in 97 Japanese patients.Reviewed

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  • Azusa Ikeda, Sumimasa Yamashita, Yu Tsuyusaki, Mio Tanaka, Yukichi Tanaka, Akihiro Hashiguchi, Hiroshi Takashima, Tomohide Goto .  Peripheral nerve pathology at fixed stage in spinal muscular atrophy with respiratory distress type 1. .  Brain & development40 ( 2 ) 155 - 158   2018.2Reviewed International journal

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    Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is characterized by severe respiratory failure due to diaphragmatic paralysis and distal muscular weakness in early infancy. After an initial decline in respiratory state and motor function until 1-2years of age, residual capabilities reach a plateau. We report the peripheral neuropathological findings of a patient with SMARD1 at 1year and 1month of age, when his muscle strength and respiratory symptoms had deteriorated and then stabilized for several months. Peripheral nerve biopsy revealed severely progressed axonal degeneration. This finding suggests the rapid progression of peripheral axonal neuropathy in SMARD1 that leads to its characteristic clinical course of respiratory failure and paralysis in the early infantile period.

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  • Fujisaki Natsumi, Suwazono Shugo, Suehara Masahito, Nakachi Ryo, Kido Miwako, Fujiwara Yoshihisa, Oshiro Saki, Tokashiki Takashi, Takashima Hiroshi, Nakagawa Masanori .  日本人患者97例における近位筋優位遺伝性運動感覚ニューロパチー(HMSN-P)の自然歴(The natural history of hereditary motor and sensory neuropathy with proximal dominant involvement(HMSN-P) in 97 Japanese patients) .  IRDR: Intractable & Rare Diseases Research7 ( 1 ) 7 - 12   2018.2日本人患者97例における近位筋優位遺伝性運動感覚ニューロパチー(HMSN-P)の自然歴(The natural history of hereditary motor and sensory neuropathy with proximal dominant involvement(HMSN-P) in 97 Japanese patients)

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    Publisher:IACMHR.Co.,Ltd.  

    1980年以降の30年間に当院で検査を受けた近位筋優位遺伝性運動感覚ニューロパチー(HMSN-P)患者130例のうち、詳細な診療録を確認できた97例(男性55例、女性42例、初診時年齢中央値48.5歳)の臨床経過を評価した。評価項目として、初診時の年齢、疼痛性筋痙攣の発症年齢、上/下肢筋力、知覚、起立、歩行、嚥下、呼吸、死亡年齢、初診時のCK値、TRK-fused gene(TFG)の変異型などを調べた。さらに疾患進行期の嚥下障害、呼吸不全、気管切開術、死亡年齢、死亡時の状況などを確認した。97例中79例でTFG変異を検査し、その全例でp.Pro285 Leu変異であることが確認された。発症には20〜30年の個人差があり、進行にも大きな個人差があった。

  • Minami Kazushi, Takahashi Shinichi, Nihei Yoshihiro, Oki Koichi, Suzuki Shigeaki, Ito Daisuke, Takashima Hiroshi, Suzuki Norihiro .  BSCL2 N88S変異を有するseipinopathyの初の日本人症例報告(The First Report of a Japanese Case of Seipinopathy with a BSCL2 N88S Mutation) .  Internal Medicine57 ( 4 ) 613 - 615   2018.2BSCL2 N88S変異を有するseipinopathyの初の日本人症例報告(The First Report of a Japanese Case of Seipinopathy with a BSCL2 N88S Mutation)Reviewed International journal

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    症例は63歳女性で、小学生の頃はランニングなどの運動が得意ではなく、30歳時に次第に歩行が困難になった。60歳時に両手、63歳時に両足の脱力と筋萎縮を自覚した。身体検査で二頭筋、三頭筋、腕橈骨筋、膝の両側反射亢進、凹足、両手・両足の遠位優位の筋萎縮・脱力が明らかになった。バビンスキー反射およびチャドック反射は陰性であったが、左トレムナー反射は陽性であった。針筋電図で両側第一背側骨間筋および前脛骨筋に慢性神経因性変化が認められ、遺伝子解析ではBSCL2遺伝子のp.N88Sにヘテロ変異が明らかになった。BSCL2遺伝子変異は小胞体ストレスを介して運動ニューロン変性を引き起こすことが知られている。筋萎縮性側索硬化症に類似した症状を呈する患者では、Seipinopathyを考慮すべきであることが示唆された。

  • Ikeda Azusa, Yamashita Sumimasa, Tsuyusaki Yu, Tanaka Mio, Tanaka Yukichi, Hashiguchi Akihiro, Takashima Hiroshi, Goto Tomohide .  呼吸窮迫を伴う脊髄性筋萎縮症1型のfixed stageにおける末梢神経病態(Peripheral nerve pathology at fixed stage in spinal muscular atrophy with respiratory distress type 1) .  Brain & Development40 ( 2 ) 155 - 158   2018.2呼吸窮迫を伴う脊髄性筋萎縮症1型のfixed stageにおける末梢神経病態(Peripheral nerve pathology at fixed stage in spinal muscular atrophy with respiratory distress type 1)Reviewed International journal

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    症例は男児で、妊娠36週で子宮内胎児発育遅延が明らかになり、妊娠39週で出生した。出生時より筋緊張低下、弱い泣き声、内反尖足が認められた。生後4ヵ月でも頭部を持ち上げることができず、その後、呼吸器感染症による急性呼吸不全のため入院となった。呼吸窮迫がみられ、身体検査では下肢の反射消失、軽度凹足があり、上肢の深部腱反射が弱かった。脳MRIでは白質量の減少が認められ、生後5ヵ月時の神経伝導検査では上肢の複合筋活動電位と運動伝道速度の減少が示された。筋電図検査では下肢に神経原性パターンが明らかになった。生後8ヵ月で気管開口術を施行し、在宅人工呼吸療法を継続したところ、呼吸状態と筋力が安定した。1歳1ヵ月時に腓腹神経生検を施行し、神経原性筋萎縮症が認められた。患児と両親の遺伝性末梢神経障害に対する遺伝子検査を実施した。IGHMBP2遺伝子の複合ヘテロ接合性変異(c826C>T、p.Gln276*とc.1702C>T、p.Gln568*)が検出された。1歳4ヵ月時には様々な顔面表情がみられ、名前の呼びかけに反応した。

  • Ryota Hikiami, Hirofumi Yamashita, Natsuko Koita, Naoto Jingami, Nobukatsu Sawamoto, Kaoru Furukawa, Hiromichi Kawai, Tomoya Terashima, Nobuyuki Oka, Akihiro Hashiguchi, Hiroshi Takashima, Makoto Urushitani, Ryosuke Takahashi .  Charcot-Marie-Tooth disease type 2A with an autosomal-recessive inheritance: The first report of an adult-onset disease .  Journal of Human Genetics63 ( 1 ) 89 - 92   2018.1Reviewed International journal

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    Axonal Charcot-Marie-Tooth disease (CMT) is most frequently caused by mutations in the MFN2 gene (CMT2A) that can lead to various clinical phenotypes. The age at disease onset varies, but most cases occur before adolescence. We report two Japanese sisters who presented with middle-age-onset peripheral neuropathy with distinct clinical features. In the affected sisters, a homozygous missense mutation, c.1894C&gt
    T, p.R632W, corresponding to the transmembrane domain of MFN2 was identified
    this mutation was heterozygous in another non-affected sibling, demonstrating co-segregation of the genotype and phenotype. The patients developed adult-onset slowly progressive muscle weakness that was predominant in the calf muscles and sensory disturbance. Magnetic resonance imaging revealed diffuse atrophy of the spinal cord, especially in the thoracic segment, and mild atrophy of the parietal lobe and the cerebellum in both patients. Electron microscopy of the sural nerve revealed clusters of round and swollen mitochondria. This is the first case report of adult-onset CMT2A with an autosomal-recessive inheritance pattern. The phenotype caused by the MFN2 mutation in these cases is very mild, considering that the mutation causes middle-aged-onset Charcot-Marie-Tooth even in the homozygous state. The mechanism of MFN2 mutation-induced toxicity is an interesting theme that awaits further investigations.

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  • Hikiami R, Yamashita H, Koita N, Jingami N, Sawamoto N, Furukawa K, Kawai H, Terashima T, Oka N, Hashiguchi A, Takashima H, Urushitani M, Takahashi R. .  Charcot-Marie-Tooth disease type 2A with an autosomal-recessive inheritance: the first report of an adult-onset disease. .  J Hum Genet63 ( 1 ) 89 - 92   2018.1Charcot-Marie-Tooth disease type 2A with an autosomal-recessive inheritance: the first report of an adult-onset disease.Reviewed

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  • Hikiami Ryota, Yamashita Hirofumi, Koita Natsuko, Jingami Naoto, Sawamoto Nobukatsu, Furukawa Kaoru, Kawai Hiromichi, Terashima Tomoya, Oka Nobuyuki, Hashiguchi Akihiro, Takashima Hiroshi, Urushitani Makoto, Takahashi Ryosuke .  常染色体劣性遺伝を伴うCharcot-Marie-Tooth病2A型 成人発症による初報告(Charcot-Marie-Tooth disease type 2A with an autosomal-recessive inheritance: the first report of an adult-onset disease) .  Journal of Human Genetics63 ( 1 ) 89 - 92   2018.1常染色体劣性遺伝を伴うCharcot-Marie-Tooth病2A型 成人発症による初報告(Charcot-Marie-Tooth disease type 2A with an autosomal-recessive inheritance: the first report of an adult-onset disease)Reviewed International journal

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    中年期になってCharcot-Marie-Tooth病2A型(CMT2A)を発症した、日本人姉妹2例を報告した。症例1は3人姉妹の三女で、41歳時に両足裏に感覚麻痺を呈し、つま先歩きが困難になった。症状は徐々に悪化し、5年以内に杖歩行となり、52歳時の神経学的検査により、遠位下肢筋力低下と萎縮および反射消失が認められた。症例2は姉妹の長女で、42歳時に緩徐進行性の歩行困難を来たし、その後、両足裏の感覚麻痺が認められた。65歳時に車椅子生活となり、神経学的検査により、遠位下肢筋力低下、反射消失および感覚消失が認められた。なお、姉妹の次女に関しては、62歳時の神経学的検査では異常はみられなかったが、症例1および2では、MFN2遺伝子の膜貫通ドメインに対応するホモ接合性ミスセンス変異c.1894C>T、p.T632Wが同定された。一方、神経学的検査で正常であった次女では、これら変異はヘテロ接合性であったことから、遺伝子型と表現型の共分離が示唆された。MRIにより、症例1と2には脊髄、特に胸髄おける萎縮と、頭頂葉および小脳の軽度な萎縮が認められ、腓腹神経の電子顕微鏡観察により、円形および膨潤したミトコンドリアのクラスターの存在が明らかにされた。

  • Kazushi Minami, Shinichi Takahashi, Yoshihiro Nihei, Koichi Oki, Shigeaki Suzuki, Daisuke Ito, Hiroshi Takashima, Norihiro Suzuki .  The first report of a japanese case of seipinopathy with a BSCL2 N88S mutation .  Internal Medicine57 ( 4 ) 613 - 615   2018Reviewed International journal

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    Seipinopathy is an autosomal dominant neurodegenerative disease caused by mutations of the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) gene. We report the first Japanese case of seipinopathy with a heterozygous mutation of p.N88S in the BSCL2 gene. The patient showed bilateral hyperreflexia of the biceps, triceps, brachioradialis, and knee, as well as the pes cavus and distal dominant weakness and atrophy of both arms and legs, suggesting the involvement of both upper and lower motor neurons. Mutations of the BSCL2 gene have been known to cause motor neuron degeneration through endoplasmic reticulum stress. Seipinopathy should be considered in patients with symptoms mimicking amyotrophic lateral sclerosis.

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  • Yamaguchi M, Takashima H .  Drosophila Charcot-Marie-Tooth Disease Models. .  Advances in experimental medicine and biology1076   97 - 117   2018Reviewed International journal

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    DOI: 10.1007/978-981-13-0529-0_7

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  • Shimizu Chisato, Kasahara Hiroo, Furuta Natsumi, Shibata Makoto, Nagashima Kazuaki, Hashiguchi Akihiro, Takashima Hiroshi, Ikeda Yoshio .  Charcot-Marie-Tooth disease showing transient central nervous system lesions after a large amount of alcohol intake: A case report .  Rinsho Shinkeigaku58 ( 8 ) 479 - 484   2018Reviewed

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    <p>A 23-year-old man experienced numbness in the perioral region and right arm, and right leg weakness on the second day after drinking a large amount of alcohol during foreign travel. His symptoms disappeared but then reappeared repetitively. Cerebral MRI performed on the third day after onset showed multiple white matter lesions; however, these lesions disappeared 26 days after onset. Neurological examination and nerve conduction studies revealed demyelinating polyneuropathy. Genetic testing for Charcot-Marie-Tooth disease, X-linked dominant 1 (CMTX1) due to <i>GJB1</i> mutation was conducted based on the symptoms of transient central nervous system lesions and polyneuropathy exhibited by the patient and his mother. As a result, a c.530T>C (p.V177A) substitution in exon 2 of <i>GJB1</i> was identified. CMTX1 patients should be advised to avoid excessive drinking because this could induce central nervous system lesions.</p>

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  • Takemaru Makoto, Shimoe Yutaka, Sato Kota, Hashiguchi Akihiro, Takashima Hiroshi, Kuriyama Masaru .  Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with heterozygote mutation of <i>GJB1</i> gene: case report of a female patient .  Rinsho Shinkeigaku58 ( 5 ) 302 - 307   2018Reviewed

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    <p>A 32-year-old woman showed transient central type facial nerve palsy and bulbar symptoms. Brain MRI revealed high intensity signals in the cerebral white matter, splenium of corpus callosum, and posterior limb of internal capsule. Two elder brothers of the patient had distal dominant peripheral neuropathies in four limbs. In this family, the point mutation of GJB1 gene, encoding connexin 32, was revealed and X-linked Charcot-Marie-Tooth disease (CMTX1) was diagnosed. The presented case was a heterozygote of this mutation. She showed severe transient central nervous system (CNS) symptoms and subclinical demyelinating peripheral neuropathy. The CNS symptoms and alterations of brain images were very similar among three siblings. There are many reports on male patients with CMTX1 who show associated CN symptoms, but female patients are very rare. There has been no previous report of a CMTX1 patient similar to the patient presented here. The trigger factors have been recognized at the onset of transient CN symptoms in these cases. The prevention of these factors is important for the management of such patients.</p>

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  • 髙嶋 博 .  自己免疫性脳症の臨床症候と治療の実際 ―ヒステリーとの鑑別― .  神経治療学35 ( 6 ) S105 - S105   2018

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    DOI: 10.15082/jsnt.35.6_S105

  • Kodama Kento, Takashima Hiroshi, Sakiyama Yusuke, Kozako Takuya, Takei Ran, Nakamura Tomonori, Hashiguchi Akihiro, Michizono Kumiko, Matsuura Eiji, Nakane Shunya .  A case of systemic anhidrosis with anti-ganglionic acetylcholine receptor antibody .  Nihon Naika Gakkai Zasshi107 ( 1 ) 95 - 102   2018Reviewed

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    DOI: 10.2169/naika.107.95

  • Hamada Kyosuke, Takei Ran, Sakiyama Yusuke, Moriyama Hiroto, Hashiguchi Akihiro, Takashima Hiroshi .  A case of chronic progressive neuro-Behçet disease with extensive cerebral atrophy and elevated CSF IL-6 activity treated with infliximab .  Rinsho Shinkeigaku58 ( 1 ) 30 - 34   2018Reviewed

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    <p>A 43-year-old man without a previous episode of uveitis presented with slowly progressive neurological symptoms that appeared within the past year such as dysarthria, ataxic gait, and behavioral changes. Brain MRI findings showed atrophic lesions in the brainstem and cerebellum. Because these clinical symptoms and abnormal MRI findings indicated spinocerebellar degeneration as the initial diagnosis, he was admitted to our hospital. On admission, we noticed that he had non-neurological manifestations of Behçet disease, such as stomatitis, genital ulcers, and folliculitis. HLA-B51 was positive. He also showed pleocytosis (29 cells/mm<sup>3</sup>, predominantly mononuclear cells) and elevated cerebrospinal fluid (CSF) IL-6 levels (213 pg/m<i>l</i>), hence he was diagnosed with chronic progressive neuro-Behçet disease (CPNBD). The therapeutic effect of a high-dose intravenous methylprednisolone pulse (1,000 mg/day for 3 days) and methotrexate (maximum dosage, 16 mg/week) was poor against both neurological symptoms and CSF findings. Intravenous infliximab therapy (5 mg/kg, 2 weeks) dramatically decreased CSF IL-6 levels (13 pg/m<i>l</i>) but clinical symptoms remained unchanged. MRI findings of extensive cerebral atrophy and increased CSF IL-6 levels at the pretreatment time point reflected irreversible neurological involvement in CPNBD. For cases with progressive psychiatric symptoms and cerebellar ataxia in the early stage of the disease, skin manifestations should be examined immediately, CSF IL-6 levels measured, and immunosuppressive therapy initiated before CPNBD progresses to brainstem atrophy.</p>

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  • Sakiyama Yusuke, Takashima Hiroshi .  Review/Advances in Neurological Therapeutics (2017). Spinocerebellar degeneration .  Neurological Therapeutics35 ( 5 ) 605 - 608   2018Reviewed

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    <p>We reviewed the recent advances in therapeutics of spinocerebellar degeneration (SCD) that were published in 2017. This article introduces the outline of therapies with antisense oligonucleotide, docosahexaenoic acid, mesenchymal stem cells, acetyl–DL–leucine, and rehabilitation using wearable devices and virtual reality. We expect that these treatments will contribute to patients with SCD.</p>

    DOI: 10.15082/jsnt.35.5_605

  • Mineki Saito, Hiroe Sejima, Tadasuke Naito, Hiroshi Ushirogawa, Toshio Matsuzaki, Eiji Matsuura, Yuetsu Tanaka, Tatsufumi Nakamura, Hiroshi Takashima .  The CC chemokine ligand (CCL) 1, upregulated by the viral transactivator Tax, can be downregulated by minocycline: possible implications for long-term treatment of HTLV-1-associated myelopathy/tropical spastic paraparesis .  VIROLOGY JOURNAL14 ( 1 ) 234   2017.12Reviewed International journal

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    Background: Chemokine (C-C motif) ligand 1 (CCL1) is produced by activated monocytes/macrophages and T-lymphocytes, and acts as a potent attractant for Th2 cells and a subset of T-regulatory (Treg) cells. Previous reports have indicated that CCL1 is overexpressed in adult T-cell leukemia cells, mediating an autocrine anti-apoptotic loop. Because CCL1 is also known as a potent chemoattractant that plays a major role in inflammatory processes, we investigated the role of CCL1 in the pathogenesis of human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP).
    Results: The results showed that: (1) CCL1 was preferentially expressed in HAM/TSP-derived HTLV-1-infected T-cell lines, (2) CCL1 expression was induced along with Tax expression in the Tax-inducible T-cell line JPX9, (3) transient Tax expression in an HTLV-1-negative T-cell line activated the CCL1 gene promoter, (4) plasma levels of CCL1 were significantly higher in patients with HAM/TSP than in HTLV-1-seronegative patients with multiple sclerosis and HTLV-1-infected asymptomatic healthy carriers, and (5) minocycline inhibited the production of CCL1 in HTLV-1-infected T-cell lines.
    Conclusions: The present results suggest that elevated CCL1 levels may be associated with the pathogenesis of HAM/TSP. Although further studies are required to determine the in vivo significance, minocycline may be considered as a potential candidate for the long-term treatment of HAM/TSP via its anti-inflammatory effects, which includes the inhibition of CCL1 expression.

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  • Yuko Yamagishi, Hidekazu Suzuki, Masahiro Sonoo, Satoshi Kuwabara, Takanori Yokota, Kyoichi Nomura, Atsuro Chiba, Ryuji Kaji, Takashi Kanda, Kenichi Kaida, Shu-ichi Ikeda, Tatsuro Mutoh, Ryo Yamasaki, Hiroshi Takashima, Makoto Matsui, Kazutoshi Nishiyama, Gen Sobue, Susumu Kusunoki .  Markers for Guillain-Barre syndrome with poor prognosis: a multi-center study .  JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM22 ( 4 ) 433 - 439   2017.12Reviewed International journal

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    Guillain-Barre syndrome (GBS) is an acute monophasic neuropathy. Prognostic tools include the modified Erasmus GBS outcome score (mEGOS), Erasmus GBS respiratory insufficiency score (EGRIS), and the increase in serum IgG levels (IgG) 2 weeks after intravenous immunoglobulin (IVIg) treatment. Given that proportions of GBS subtypes differ between Western countries and Japan, the usefulness of these tools in Japan or other countries remains unknown. We enrolled 177 Japanese patients with GBS from 15 university hospitals and retrospectively obtained mEGOS and EGRIS for all and IgG status for 79 of them. High mEGOS scores on admission or on day 7 were significantly associated with poorer outcomes (unable to walk independently at 6 months). High EGRIS scores (5 points) were associated with an increased risk for mechanical ventilation. Patients with IgG &lt;1,108 mg/dl had significantly poorer outcomes. We suggest that mEGOS, EGRIS, and IgG in GBS are clinically relevant in Japan.

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  • Tashiro Y, Takashima H .  [Motor Symptoms of Autoimmune Encephalopathies]. .  Brain and nerve = Shinkei kenkyu no shinpo69 ( 12 ) 1387 - 1399   2017.12[Motor Symptoms of Autoimmune Encephalopathies].

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  • Noriyuki Miyaue, Satoshi Tada, Rina Ando, Hirotaka Iwaki, Hayato Yabe, Noriko Nishikawa, Masahiro Nagai, Hiroshi Takashima, Masahiro Nomoto .  DAT SPECT may have diagnostic value in prodromal SCA2 patients with parkinsonism .  PARKINSONISM & RELATED DISORDERS44   137 - 141   2017.11

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    Introduction: Although spinocerebellar ataxia type 2 (SCA2) is classified as hereditary spinocerebellar degeneration, some patients present with parkinsonism before developing cerebellar ataxia.
    Methods: I-123-metaiodobenzyl guanidine (I-123-MIBG) myocardial scintigraphy and/or dopamine transporter single photon emission computed tomography (DAT SPECT) using I-123-iofiupane (I-123-FP-CIT) were performed for the six patients from three SCA2 families.
    Results: I-123-MIBG myocardial scintigraphy showed reduced cardiac uptake in four of five patients and an association with Lewy body disease was suggested. DAT SPECT showed decreased uptake in the striatum in all four patients who were scanned, including one patient without parkinsonism. When patterns of uptake were compared to those with Parkinson's disease, most of the patients had minimal reduction uptake in the putamen.
    Conclusion: DAT SPECT is expected to be useful in differentiating SCA2 from Parkinson's disease, making an early diagnosis, and allowing early therapeutic intervention. (C) 2017 Published by Elsevier Ltd.

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  • Yasuo Shiohama, Tadasuke Naito, Toshio Matsuzaki, Reiko Tanaka, Takeaki Tomoyose, Hiroshi Takashima, Takuya Fukushima, Yuetsu Tanaka, Mineki Saito .  Prevalence of plasma autoantibody against cancer testis antigen NY-ESO-1 in HTLV-1 infected individuals with different clinical status .  VIROLOGY JOURNAL14 ( 1 ) 130 - 130   2017.7Reviewed International journal

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    Background: Detection of specific immune responses against cancer/testis antigen NY-ESO-1 was recently reported in patients with adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-infected asymptomatic carriers (ACs). However, the relationship of the responses with the HTLV-1 proviral load (PVL) and the levels of viral gene expression remain unclear.
    Findings: We measured plasma levels of autoantibodies to NY-ESO-1 immunogenic tumor antigen in HTLV-1-infected individuals with different clinical status, and in healthy controls. Data were compared to tax and HBZ mRNA levels, and PVL. Plasma anti-NY-ESO-1 antibody was detectable in 13.7% (7/51) of ACs, 29.2% (38/130) of patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), and 18.9% (10/53) of patients with ATL. Anti-NY-ESO-1 plasma levels were significantly higher in patients with HAM/TSP than in patients with ATL or ACs. Anti-NY-ESO-1 levels were not associated with PVL or the expression levels of tax and HBZ mRNA among HTLV-1-infected individuals, regardless of clinical status.
    Conclusions: The present results indicate the strong humoral immune response against NY-ESO-1 in natural HTLV-1 infection, irrespective of the clinical status. The higher immunoreactivity against NY-ESO-1 is not simply associated with the levels of both HTLV-1 gene expression and the number of infected cells in vivo. Rather, it might reflect chronic and generalized immune activation in infected individuals.

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  • Kimitoshi Hirayanagi, Yuji Okamoto, Eriko Takai, Kunihiko Ishizawa, Kouki Makioka, Yukio Fujita, Yuka Kaneko, Makoto Tanaka, Hiroshi Takashima, Yoshio Ikeda .  Bilateral striatal necrosis caused by a founder mitochondrial 14459G &gt; A mutation in two independent Japanese families .  JOURNAL OF THE NEUROLOGICAL SCIENCES378   177 - 181   2017.7Reviewed International journal

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    Bilateral striatal necrosis (BSN) has many causes and is characterized by unique clinical and neuroradiological features. Herein, we report a clinical and genetic analysis of three BSN cases from two independent Japanese families harboring a mitochondrial DNA (mtDNA) 14459G &gt; A mutation located in a coding region of the NADH dehydrogenase subunit 6 gene. In the first family, two male siblings from non-consanguineous parents exhibited similar phenotypes, with infantile-onset generalized dystonia. A third sporadic case involved a male patient with a comparatively milder phenotype characterized by juvenile-onset mild truncal ataxia and parkinsonism. Cerebral magnetic resonance imaging of these cases revealed abnormal signal intensities along the bilateral putaminal area and enlarged lateral ventricle anterior horns caused by caudate nuclear atrophy, particularly in the sibling pair. The sibling-pair cases shared a homoplasmic 14459G &gt; A mutation, and the sporadic case showed heteroplasmy of the same mutation. Additionally, all three cases harbored the 14605A &gt; G single nucleotide polymorphism, which was previously reported as a rare synonymous variation (4.3%) in a Japanese population. Plasmid sequencing revealed a genetic linkage of these two DNA substitutions, suggesting that the three patients shared a genetic founder. Although our mtDNA analysis was only accessible using leukocytes, clinical severity might be associated with homoplasmy or heteroplasmy. In summary, it is important to evaluate potential mtDNA defects in BSN cases, regardless of familial occurrence. (C) 2017 Elsevier B.V. All rights reserved.

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  • Aya Nakamura, Ryo Tanaka, Kazushige Morishita, Hideki Yoshida, Yujiro Higuchi, Hiroshi Takashima, Masamitsu Yamaguchi .  Neuron-specific knockdown of the Drosophila fat induces reduction of life span, deficient locomotive ability, shortening of motoneuron terminal branches and defects in axonal targeting .  GENES TO CELLS22 ( 7 ) 662 - 669   2017.7Reviewed International journal

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    Mutations in FAT4 gene, one of the human FAT family genes, have been identified in Van Maldergem syndrome (VMS) and Hennekam lymphangiectasia-lymphedema syndrome (HS). The FAT4 gene encodes a large protein with extracellular cadherin repeats, EGF-like domains and Laminin G-like domains. FAT4 plays a role in tumor suppression and planar cell polarity. Drosophila contains a human FAT4 homologue, fat. Drosophila fat has been mainly studied with Drosophila eye and wing systems. Here, we specially knocked down Drosophila fat in nerve system. Neuron-specific knockdown of fat shortened the life span and induced the defect in locomotive abilities of adult flies. In consistent with these phenotypes, defects in synapse structure at neuromuscular junction were observed in neuron-specific fat-knockdown flies. In addition, aberrations in axonal targeting of photoreceptor neuron in third-instar larvae were also observed, suggesting that fat involves in axonal targeting. Taken together, the results indicate that Drosophila fat plays an essential role in formation and/or maintenance of neuron. Both VMS and HS show mental retardation and neuronal defects. We therefore consider that these two rare human diseases could possibly be caused by the defect in FAT4 function in neuronal cells.

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  • 田畑 健太郎, 佐野 輝, 石塚 貴周, 斉之平 一隆, 横塚 紗永子, 新井 薫, 塩川 奈理, 春日井 基文, 中村 雅之, 荒田 仁, 高嶋 博, 吉水 宗裕 .  ドパミン調節異常症候群が考えられ、修正型電気けいれん療法が著効した若年性パーキンソン病の一例 .  精神神経学雑誌 ( 2017特別号 ) S635 - S635   2017.6ドパミン調節異常症候群が考えられ、修正型電気けいれん療法が著効した若年性パーキンソン病の一例Reviewed

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  • Satoshi Nozuma, Eiji Matsuura, Daisuke Kodama, Yuichi Tashiro, Toshio Matsuzaki, Ryuji Kubota, Shuji Izumo, Hiroshi Takashima .  Effects of host restriction factors and the HTLV-1 subtype on susceptibility to HTLV-1-associated myelopathy/tropical spastic paraparesis .  RETROVIROLOGY14 ( 1 ) 26   2017.4Reviewed International journal

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    Background: Although human T-lymphotropic virus type 1 (HTLV-1) infection is a prerequisite for the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), specific provirus mutations in HAM/TSP have not yet been reported. In this study, we examined whether HAM/TSP patients had the disease-specific genomic variants of HTLV-1 by analyzing entire sequences of HTLV-1 proviruses in these patients, including familial cases. In addition, we investigated the genetic variants of host restriction factors conferring antiretroviral activity to determine which mutations may be related to resistance or susceptibility to HAM/TSP.
    Results: The subjects included 30 patients with familial HAM/TSP (f-HAM/TSP), 92 patients with sporadic HAM/TSP (s-HAM/TSP), and 89 asymptomatic HTLV-1 carriers (ACs). In all 211 samples, 37 samples (18%) were classified into transcontinental subtype and 174 samples (82%) were classified as Japanese subtype. Among three groups, the percentage of transcontinental subtype in f-HAM/TSP, s-HAM/TSP and ACs was 33, 23 and 7%, respectively. The frequency of transcontinental subtype was significantly higher in both f-HAM/TSP (p &lt; 0.001) and s-HAM/TSP (p &lt; 0.001) than in ACs. Fifty mutations in HTLV-1 sequences were significantly more frequent in HAM/TSP patients than in ACs, however, they were common only in transcontinental subtype. Among these mutations, ten common mutations causing amino acid changes in the HTLV-1 sequences were specific to the transcontinental subtype. We examined host restriction factors, and detected a rare variant in TRIM5 alpha in HAM/TSP patients. The patients with TRIM5 alpha 136Q showed lower proviral loads (PVLs) than those with 136R (354 vs. 654 copies/10(4) PBMC, p = 0.003). The patients with the 304L variant of TRIM5 alpha had significantly higher PVLs than those with 304H (1669 vs. 595 copies/10(4) PBMC, p = 0.025). We could not find any HAM/TSP-specific mutations of host restriction factors.
    Conclusions: Transcontinental subtype is susceptible to HAM/TSP, especially in familial cases. Ten common mutations causing amino acid changes in the HTLV-1 gene were specific to the transcontinental subtype. TRIM5 alpha polymorphisms were associated with PVLs, indicating that TRIM5 alpha could be implicated in HTLV-1 replication.

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  • Matsuura E, Enose-Akahata Y, Yao K, Oh U, Tanaka Y, Takashima H, Jacobson S. .  Dynamic acquisition of HTLV-1 tax protein by mononuclear phagocytes: Role in neurologic disease. .  Journal of Neuroimmunology304   43 - 50   2017.3Dynamic acquisition of HTLV-1 tax protein by mononuclear phagocytes: Role in neurologic disease.Reviewed

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    DOI: 10.1016/j.jneuroim

  • Eiji Matsuura, Yoshimi Enose-Akahata, Karen Yao, Unsong Oh, Yuetsu Tanaka, Hiroshi Takashima, Steven Jacobson .  Dynamic acquisition of HTLV-1 tax protein by mononuclear phagocytes: Role in neurologic disease .  JOURNAL OF NEUROIMMUNOLOGY304   43 - 50   2017.3Reviewed International journal

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    Pathology of HTLV-1 associated myelopathy/Tropical spastic paraparesis (HAM/rsp) is believed to be the result of "bystander damage" involving effector CD8 (+) T lymphocytes (CTLs) killing of virus infected cells. But the specific cellular events leading up to tissue injury are still unclear. Here, we developed the Microscopy Imaging of Cytotoxic T lymphocyte assay with Fluorescence emission (MI-CaFe), an optimized visualization analysis to explore the interactions between CTLs and virus infected or viral antigen presenting target cells. Various cell-to -cell formations can be observed and our results demonstrate elevated frequencies of CTL-target cell conjugates in HAM/TSP patient PBMCs compared to control PBMCs. Furthermore, HTLV-1 Tax protein expression can be localized at the cell -cell junctions and also tracked moving from an infected cell to a CD14 (+) mononuclear phagocyte (MP). Activation of CD14 (+) MPs in HAM/TSP patient PBMCs and antigenic presentation of HTLV-1 Tax by MPs can be inferred by their spontaneous cytotoxicity after 18 h of in vitro culture. Given that CD4 (+) T lymphocytes are the primary reservoirs of HTLV-1 and MPs are scavenger cells responsible for pathogen clearance, spontaneous cytotoxicity against MPs in HAM/TSP PBMCs suggests a mechanism of chronic inflammation, secondary to low level of persistent virus infection within the central nervous system. Published by Elsevier B.V.

    DOI: 10.1016/j.jneuroim.2016.09.014

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  • Yu Hiramatsu, Michiyoshi Yoshimura, Ryuji Saigo, Hitoshi Arata, Yuji Okamoto, Eiji Matsuura, Haruhiko Maruyama, Hiroshi Takashima .  Toxocara canis myelitis involving the lumbosacral region: a case report .  JOURNAL OF SPINAL CORD MEDICINE40 ( 2 ) 241 - 245   2017.3Reviewed International journal

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    Context: Toxocara canis is a parasite known to cause visceral larva migrans. The infection rarely affects the central nervous system but there have been several reports of myelitis caused by visceral larva migrans due to Toxocara canis. In previous reported cases, the lesions were located in the thoracic or cervical spinal cord. To the best of our knowledge, this is the first report of a lesion involving the lumbosacral region.
    Findings: A 60-year-old man developed weakness and dysesthesia in the lower limbs. The symptoms resolved spontaneously, but recurred after five months. One month later, the patient developed pollakiuria and constipation. He was a dog owner and frequently ate raw chicken meat and beef liver. Sagittal T2-weighted image (T2WI) showed swelling and hyperintensity in the spinal cord from T10 to the lumbosacral region and focal nodular enhancement on the posterior segment of the lumbar spinal cord. Blood cell counts showed slight eosinophilia and elevated serum immunoglobulin E level. Cerebrospinal fluid examination showed slight pleocytosis with eosinophilia. Enzyme-linked immunosorbent assay showed high levels of anti-Toxocara antibodies in the serum and cerebrospinal fluid. In addition, confirmatory test by Western blot was positive. The patient was initially treated with intravenous methylprednisolone with slight improvement in muscle weakness. Albendazole was added with a second course of intravenous methylprednisolone. The muscle weakness in the lower limbs improved considerably, and swelling and hyperintensity on T2WI almost disappeared.
    Conclusion: Our results suggest that Toxocara canis myelitis cannot be discounted even if the myelitis involves the lumbosacral region.

    DOI: 10.1080/10790268.2015.1114230

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  • Yoshimura A, Yuan JH, Hashiguchi A, Hiramatsu Y, Ando M, Higuchi Y, Nakamura T, Okamoto Y, Matsumura K, Hamano T, Sawaura N, Shimatani Y, Kumada S, Okumura Y, Miyahara J, Yamaguchi Y, Kitamura S, Haginoya K, Mitsui J, Ishiura H, Tsuji S, Takashima H. .  Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants. .  Clinical Genetics   2017.2Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants.Reviewed

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    DOI: 10.1111/cge.13002.

  • Yuan JH, Hashiguchi A, Yoshimura A, Yaguchi H, Tsuzaki K, Ikeda A, Wada-Isoe K, Ando M, Nakamura T, Higuchi Y, Hiramatsu Y, Okamoto Y, Takashima H. .  Clinical diversity caused by novel IGHMBP2 variants. .  Journal of Human Genetics   2017.2Clinical diversity caused by novel IGHMBP2 variants.Reviewed

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    DOI: Clinical diversity caused by novel IGHMBP2 variants.

  • Emi Motokura, Toru Yamashita, Yoshiaki Takahashi, Keiichiro Tsunoda, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Akihiro Hashiguchi, Hiroshi Takashima, Koji Abe .  An AOA2 patient with a novel compound heterozygous SETX frame shift mutations .  JOURNAL OF THE NEUROLOGICAL SCIENCES372   294 - 296   2017.1Reviewed

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    DOI: 10.1016/j.jns.2016.11.074

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  • Arata Hitoshi, Takashima Hiroshi .  I. Neurological Findings to Identify Autoimmune Encephalopathy .  Nihon Naika Gakkai Zasshi106 ( 8 ) 1542 - 1549   2017

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    DOI: 10.2169/naika.106.1542

  • Fujisawa Miwako, Sano Yasuteru, Omoto Masatoshi, Ogasawara Jyun-ichi, Koga Michiaki, Takashima Hiroshi, Kanda Takashi .  Charcot-Marie-Tooth disease type 2 caused by homozygous <i>MME</i> gene mutation superimposed by chronic inflammatory demyelinating polyneuropathy .  Rinsho Shinkeigaku57 ( 9 ) 515 - 520   2017Reviewed

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    <p>We report a 59-year-old Japanese male who developed gradually worsening weakness and numbness of distal four extremities since age 50. His parents were first cousins, and blood and cerebral spinal examinations were unremarkable. Homozygous mutation of <i>MME</i> gene was detected and thus he was diagnosed as autosomal-recessive Charcot-Marie-Tooth disease 2T (AR-CMT2T); however, electrophysiological examinations revealed scattered demyelinative changes including elongated terminal latency in several peripheral nerve trunks. Sural nerve biopsy showed endoneurial edema and a lot of thinly myelinated nerve fibers with uneven distribution of remnant myelinated fibers within and between fascicles. Immunoglobulin treatment was initiated considering the possibility of superimposed inflammation and demyelination, and immediate clinical as well as electrophysiological improvements were noted. Our findings indicate that AR-CMT2T caused by <i>MME</i> mutation predisposes to a superimposed inflammatory demyelinating neuropathy. This is the first report which documented the co-existence of CMT2 and chronic inflammatory demyelinating polyneuropathy (CIDP); however, in the peripheral nervous system, neprilysin, a product of <i>MME</i> gene, is more abundant in myelin sheath than in axonal component. The fragility of myelin sheath due to mutated neprilysin may trigger the detrimental immune response against peripheral myelin in this patient.</p>

    DOI: 10.5692/clinicalneurol.cn-001036

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  • Yamamoto Yuki, Matsui Naoko, Hiramatsu Yu, Miyazaki Yoshimichi, Nodera Hiroyuki, Izumi Yuishin, Takashima Hiroshi, Kaji Ryuji .  Mitochondrial trifunctional protein deficiency: an adult patient with similar progress to Charcot-Marie-Tooth disease .  Rinsho Shinkeigaku57 ( 2 ) 82 - 87   2017Reviewed

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    <p>A 45-year-old man presented to us due to slowly progressive muscle weakness and sensory disturbances in his lower limbs since his 40's. He reported multiple episodes of exercise-induced severe muscle fatigue and brown urine in his childhood, which disappeared by age 20. A nerve conduction study showed peripheral axonal neuropathy and then Charcot-Marie-Tooth disease (CMT) was considered as the most likely diagnosis; however, exome sequencing failed to identify a mutation in the known genes of CMTs. Since age 55, he recurrently developed severe rhabdomyolysis that required hospitalization. On suspicion of lipid metabolism disorders, we performed serum acylcarnitine analysis, and which revealed mildly elevated long-chain fatty acids. We re-examined variants obtained via exome sequencing and found a mutation in <i>HADHB</i>. Mitochondrial trifunctional protein (MTP) deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid beta-oxidation caused by <i>HADHA</i> or <i>HADHB</i> mutation. It can be a life-threatening multiorgan disorder with early infantile onset, but it can also present in childhood or adolescence with peripheral neuropathy and recurrent rhabdomyolysis. This case of adult-diagnosed MTP deficiency was characterized by slowly progressive peripheral neuropathy masquerading CMT in addition to muscular symptoms. MTP deficiency should be considered in patients with the combination of peripheral neuropathy and recurrent rhabdomyolysis.</p>

    DOI: 10.5692/clinicalneurol.cn-000976

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  • Taniguchi Takaki, Hokezu Youichi, Okada Takashi, Ishibashi Masato, Hashiguchi Akihiro, Matsuura Eiji, Takashima Hiroshi .  A amyotrophic lateral sclerosis (ALS) 4 family misdiagnosed as hereditary spastic paraplegia―a case report― .  Rinsho Shinkeigaku57 ( 11 ) 685 - 690   2017Reviewed

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    <p>We report a 44 years old man with slowly progressive muscular atrophy of the extremities for over 30 years. He experienced difficulty in walking in his 10's and was diagnosed as hereditary spastic paraplegia (HSP) in his 20's. And then, muscle atrophy of the extremities slowly progressed especially in his distal muscles. Sensory axonal neuropathy was detected with sural nerve biopsy. His father and uncle have been diagnosed as HSP in their early days. His father noticed weakness of his leg in his 20's. He lost motor function of the leg in his 60's. In addition, marked disturbance of thermal sensation, vibration, and sense of position were found by physical examination. Our genetic study detected senataxin (<i>SETX</i>) gene mutation (c.8C>T,p.T3I) in the blood of those two patients, and they had been identified as family cases of amyotrophic lateral sclerosis (ALS) 4. As clinical symptoms of ALS4 would be similar to those of HSP at the onset, we suggest considering ALS4 in seeing patients with HSP without gene diagnosis.</p>

    DOI: 10.5692/clinicalneurol.cn-000996

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  • Matsuura E, Nozuma S, Tashiro Y, Kubota R, Izumo S, Takashima H. .  HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP): A comparative study to identify factors that influence disease progression. .  Journal of Neurological Sciences 371   112 - 116   2016.12HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP): A comparative study to identify factors that influence disease progression.Reviewed

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    DOI: 10.1016/j.jns.2016.10.030.

  • hirano M, Oka N, Hashiguchi A, Ueno S, Sakamoto H, Takashima H, Higuchi Y, Kusunoki S, Nakamura Y. .  Histopathological features of a patient with Charcot-Marie-Tooth disease type 2U/AD-CMTax-MARS. .  Journal of Peripheral Nervous System21 ( 4 ) 370 - 374   2016.12Histopathological features of a patient with Charcot-Marie-Tooth disease type 2U/AD-CMTax-MARS.Reviewed

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    DOI: 10.1111/jns.12193

  • Sone J, Mori K, Inagaki T, Katsumata R, Takagi S, Yokoi S, Araki K, Kato T, Nakamura T, Koike H, Takashima H, Hashiguchi A, Kohno Y, Kurashige T, Kuriyama M, Takiyama Y, Tsuchiya M, Kitagawa N, Kawamoto M, Yoshimura H, Suto Y, Nakayasu H, Uehara N, Sugiyama H, Takahashi M, Kokubun N, Konno T, Katsuno M, Tanaka F, Iwasaki Y, Yoshida M, Sobue G. .  Clinicopathological features of adult-onset neuronal intranuclear inclusion disease. .  Brain139   3170 - 3186   2016.12Clinicopathological features of adult-onset neuronal intranuclear inclusion disease.Reviewed

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  • Kawarai T, Yamasaki K, Mori A, Takamatsu N, Osaki Y, Banzrai C, Miyamoto R, Oki R, Pedace L, Orlacchio A, Nodera H, Hashiguchi A, Higuchi Y, Takashima H, Nishida Y, Izumi Y, Kaji R. .  MFN2 transcripts escaping from nonsense-mediated mRNA decay pathway cause Charcot-Marie-Tooth disease type 2A2. .  Journal of Neurology, Neurosurgery and Psychiatry87 ( 11 ) 1263 - 1265   2016.11MFN2 transcripts escaping from nonsense-mediated mRNA decay pathway cause Charcot-Marie-Tooth disease type 2A2.

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    DOI: 10.1136/jnnp-2015-312646

  • Ichikawa K, Numasawa K, Takeshita S, Hashiguchi A, Takashima H. .  Novel mutations in SH3TC2 in a young Japanese girl with Charcot-Marie-Tooth disease type 4C. .  Pediatrics International58 ( 11 ) 1252 - 1254   2016.11Novel mutations in SH3TC2 in a young Japanese girl with Charcot-Marie-Tooth disease type 4C.Reviewed

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    DOI: 10.1111/ped.13152

  • Misawa S, Sato Y, Katayama K, Nagashima K, Aoyagi R, Sekiguchi Y, Sobue G, Koike H, Yabe I, Sasaki H, Watanabe O, Takashima H, Nishizawa M, Kawachi I, Kusunoki S, Mitsui Y, Kikuchi S, Nakashima I, Ikeda S, Kohara N, Kanda T, Kira J, Hanaoka H, Kuwabara S; Japanese POEMS Syndrome for Thalidomide (J-POST) Trial Study Group. .  Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial. Misawa S, Sato Y, Katayama K, Nagashima K, Aoyagi R, Sekiguchi Y, Sobue G, Koike H, Yabe I, Sasaki H, Watanabe O, Takashima H, Nishizawa M, Kawachi I, Kusunoki S, Mitsui Y, Kikuchi S, Nakashima I, Ikeda S, Kohara N, Kanda T, Kira J, Hanaoka H, Kuwabara S; Japanese POEMS Syndrome for Thalidomide (J-POST) Trial Study Group. .  The Lancet, Neurology15 ( 11 ) 1129 - 1137   2016.11Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial. Misawa S, Sato Y, Katayama K, Nagashima K, Aoyagi R, Sekiguchi Y, Sobue G, Koike H, Yabe I, Sasaki H, Watanabe O, Takashima H, Nishizawa M, Kawachi I, Kusunoki S, Mitsui Y, Kikuchi S, Nakashima I, Ikeda S, Kohara N, Kanda T, Kira J, Hanaoka H, Kuwabara S; Japanese POEMS Syndrome for Thalidomide (J-POST) Trial Study Group.Reviewed

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    DOI: 10.1016/S1474-4422(16)30157-0.

  • Maruyama K, Ogaya S, Kurahashi N, Umemura A, Yamada K, Hashiguchi A, Takashima H, Torres RJ, Aso K. .  Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report. .  Brain and Development38 ( 10 ) 954 - 958   2016.11 Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report.Reviewed

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    DOI: 10.1016/j.braindev.2016.05.003

  • Yamada K, Yuan J, Mano T, Takashima H, Shibata M. .  Arthropathy-related pain in a patient with congenital impairment of pain sensation due to hereditary sensory and autonomic neuropathy type II with a rare mutation in the WNK1/HSN2 gene: a case report. .  BMC Neurology16 ( 1 ) 201 - 201   2016.10Arthropathy-related pain in a patient with congenital impairment of pain sensation due to hereditary sensory and autonomic neuropathy type II with a rare mutation in the WNK1/HSN2 gene: a case report.Reviewed

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  • Maki Y, Takashima H .  [Clinical Features and Treatment of Hashimoto Encephalopathy .  Brain and Nerve68 ( 9 ) 1025 - 1033   2016.9[Clinical Features and Treatment of Hashimoto Encephalopathy

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  • Shiohama Y, Naito T, Matsuzaki T, Tanaka R, Tomoyose T Takashima H, Fukushima T, Tanaka Y, Saito M7. .  Absolute quantification of HTLV-1 basic leucine zipper factor (HBZ) protein and its plasma antibody in HTLV-1 infected individuals with different clinical status. .  Retrovirology13 ( 29 )   2016.4Absolute quantification of HTLV-1 basic leucine zipper factor (HBZ) protein and its plasma antibody in HTLV-1 infected individuals with different clinical status.Reviewed

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    DOI: 10.1186/s12977-016-0263-z.

  • Koge J, Hayashi S, Murai H, Yokoyama J, Mizuno Y, Uehara T, Ueda N, Watanabe O, Takashima H, Kira J. .  Morvan's syndrome and myasthenia gravis related to familial Mediterranean fever gene mutations. .  Journal of Neuroinflammation13 ( 1 ) 68 - 68   2016.3Morvan's syndrome and myasthenia gravis related to familial Mediterranean fever gene mutations.Reviewed

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  • Higuchi Y, Hashiguchi A, Yuan J, Yoshimura A, Mitsui J, Ishiura H, Tanaka M, Ishihara S, Tanabe H, Nozuma S, Okamoto Y, Matsuura E, Ohkubo R, Inamizu S, Shiraishi W, Yamasaki R, Ohyagi Y, Kira J, Oya Y, Yabe H, Nishikawa N, Tobisawa S, Matsuda N, Masuda M, Kugimoto C, Fukushima K, Yano S, Yoshimura J, Doi K, Nakagawa M, Morishita S, Tsuji S, Takashima H. .  Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2. .  Annals of Neurology79 ( 4 ) 659 - 672   2016.3Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2.Reviewed

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  • Adachi H, Ishihara K, Tachibana H, Oka N, Higuchi Y, Takashima H, Yoneda Y, Kageyama Y. .  Adult-onset Krabbe disease presenting with an isolated form of peripheral neuropathy. .  Muscle and Nerve   2016.2Adult-onset Krabbe disease presenting with an isolated form of peripheral neuropathy.Reviewed

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  • Nakazato Y, Mochizuki H, Ishii N, Ohkubo R, Hirano R, Takashima H, Shiomi K, Nakazato M. .  Spinocerebellar ataxia 36 accompanied by cervical dystonia. .  Journal of Neurological Science357 ( 1-2 ) 304 - 306   2015.10Spinocerebellar ataxia 36 accompanied by cervical dystonia.Reviewed

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  • Sakiyama Y, Kanda N, Higuchi Y, Yoshimura M, Wakaguri H, Takata Y, Watanabe O, Yuan J, Tashiro Y, Saigo R, Nozuma S, Yoshimura A, Arishima S, Ikeda K, Shinohara K, Arata H, Michizono K, Higashi K, Hashiguchi A, Okamoto Y, Hirano R, Shiraishi T, Matsuura E, Okubo R, Higuchi I, Goto M, Hirano H, Sano A, Iwasaki T, Matsuda F, Izumo S, Takashima H. .  New type of encephalomyelitis responsive to trimethoprim/sulfamethoxazole treatment in Japan. .  Neurology Neuroimmunology and Neuroinflammation2 ( 5 ) e143   2015.8New type of encephalomyelitis responsive to trimethoprim/sulfamethoxazole treatment in Japan.Reviewed

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  • Yoshinaga H, Sakoda S, Shibata T, Akiyama T, Oka M, Yuan JH, Takashima H, Takahashi MP, Kitamura T, Murakami N, Kobayashi K. .  Phenotypic variability in childhood of skeletal muscle sodium channelopathies. .  Pediatric Neurology52 ( 5 ) 504 - 508   2015.5Phenotypic variability in childhood of skeletal muscle sodium channelopathies.Reviewed

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  • Mitsui J, Matsukawa T, Sasaki H, Yabe I, Matsushima M, Dürr A, Brice A, Takashima H, Kikuchi A, Aoki M, Ishiura H, Yasuda T, Date H, Ahsan B, Iwata A, Goto J, Ichikawa Y, Nakahara Y, Momose Y, Takahashi Y, Hara K, Kakita A, Yamada M, Takahashi H, Onodera O, Nishizawa M, Watanabe H, Ito M, Sobue G, Ishikawa K, Mizusawa H, Kanai K, Hattori T, Kuwabara S, Arai K, Koyano S, Kuroiwa Y, Hasegawa K, Yuasa T, Yasui K, Nakashima K, Ito H, Izumi Y, Kaji R, Kato T, Kusunoki S, Osaki Y, Horiuchi M, Kondo T, Murayama S, Hattori N, Yamamoto M, Murata M, Satake W, Toda T, Filla A, Klockgether T, Wüllner U, Nicholson G, Gilman S, Tanner CM, Kukull WA, Stern MB, Lee VM, Trojanowski JQ, Masliah E, Low PA, Sandroni P, Ozelius LJ, Foroud T, Tsuji S. .  Variants associated with Gaucher disease in multiple system atrophy. .  Annals of Clinical and Translational Neurology2 ( 4 ) 417 - 426   2015.4Variants associated with Gaucher disease in multiple system atrophy.Reviewed

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  • Matsuura E, Yoshimura A, Nozuma S, Higuchi I, Kubota R, Takashima H. .  Clinical presentation of axial myopathy in two siblings with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). .  BMC Neurology28 ( 15 ) 18 - 18   2015.2Clinical presentation of axial myopathy in two siblings with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP).Reviewed

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  • Yuan J, Ando M, Higuchi I, Sakiyama Y, Matsuura E, Michizono K, Watanabe O, Nagano S, Inamori Y, Hashiguchi A, Higuchi Y, Yoshimura A, Takashima H. .  Partial deficiency of emerin caused by a splice site mutation in EMD. .  Intern Med. 53 ( 14 ) 1563 - 1568   2014.7Partial deficiency of emerin caused by a splice site mutation in EMD.Reviewed

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  • Furukawa Y, Hashiguchi T, Minami R, Yamamoto M, Takashima H. .  Exacerbation of microcytic anemia associated with cessation of anti-retroviral therapy in an HIV-1-infected patient with beta thalassemia. .  J Infect Chemother. 20 ( 6 ) 387 - 389   2014.6Exacerbation of microcytic anemia associated with cessation of anti-retroviral therapy in an HIV-1-infected patient with beta thalassemia.Reviewed

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  • Hiramatsu Y, Wakita M, Matsuoka H, Kasuya J, Hamada R, Takashima H. .  Cerebral infarction associated with accessory middle cerebral arteries: two case reports. .  Intern Med. 53 ( 12 ) 1381 - 1384   2014.6Cerebral infarction associated with accessory middle cerebral arteries: two case reports.Reviewed

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  • Nozuma S, Matsuura E, Matsuzaki T, Watanabe O, Kubota R, Izumo S, Takashima H. .  Familial clusters of HTLV-1-associated myelopathy/tropical spastic paraparesis. .  PLoS One. 9 ( 5 ) e86144 - e86144   2014.5Familial clusters of HTLV-1-associated myelopathy/tropical spastic paraparesis.Reviewed

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  • 荒田仁、大窪隆一、渡邊修、髙嶋博、橋口照人 .  神経疾患ノバイオマーカーの新展開 .  日本内科学会雑誌102 ( 12 ) 3174 - 3182   2013.12神経疾患ノバイオマーカーの新展開Reviewed

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  • 平野隆城、樋口雄二郎、西郷隆二、大窪隆一、髙嶋博 .  南九州地域の遺伝性脊髄小脳変性症 -疾患の特徴と遺伝子診断- .  神経内科78 ( 3 ) 257 - 264   2013.3南九州地域の遺伝性脊髄小脳変性症 -疾患の特徴と遺伝子診断-Reviewed

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  • 出口尚寿、有村愛子、髙嶋博、西尾善彦 .  糖尿病性筋委縮症:病態と治療 .  糖尿病合併症27 ( 2 ) 173 - 177   2013.2糖尿病性筋委縮症:病態と治療Reviewed

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  • Inamori Y, Higuchi I, Inoue T, Sakiyama Y, Hashiguchi A, Higashi K, Shiraishi T, Okubo R, Arimura K, Mitsuyama Y, Takashima H .  Inclusion body myositis coexisting with hypertrophic cardiomyopathy: An autopsy study. .  Neuromuscul Disord22 ( 8 ) 747 - 754   2012.9 Inclusion body myositis coexisting with hypertrophic cardiomyopathy: An autopsy study.Reviewed

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  • Saiga T, Tateishi T, Torii T, Kawamura N, Nagara Y, Shigeto H, Hashiguchi A, Takashima H, Honda H, Ohyagi Y, Kira J. .  Inflammatory radiculoneuropathy in an ALS4 patient with a novel SETX mutation. .  J Neurol Neurosurg Psychiatry17 ( 2 ) 763 - 764   2012.7Inflammatory radiculoneuropathy in an ALS4 patient with a novel SETX mutation.Reviewed

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  • Zhao Z, Hashiguchi A, Hu J, Sakiyama Y, Okamoto Y, Tokunaga S, Zhu L, Shen H, Takashima H .  Alanyl-tRNA synthetase mutation in a family with dominant distal hereditary motor neuropathy. .  Neurology78 ( 21 ) 1644 - 1649   2012.5Alanyl-tRNA synthetase mutation in a family with dominant distal hereditary motor neuropathy. Reviewed

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  • Tomonori Nakamura, Akihiro Hashiguchi, Shinsuke Suzuki, Kimiharu Uozumi, Shoko Tokunaga, Hiroshi Takashima .  Vincristine exacerbates asymptomatic Charcot-Marie-Toothdisease with a novel EGR2 mutation. .  Neurogenetics13 ( 1 ) 77 - 82   2012.2Vincristine exacerbates asymptomatic Charcot-Marie-Toothdisease with a novel EGR2 mutation.Reviewed

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  • Kensuke Shiga, Yuichi Noto, Ikuko Mizuta, Akihiro Hashiguchi, Hiroshi Takashima, Masanori Nakagawa .  A novel EGR2 mutation within a family with a mild demyelinating form of Charcot-Marie-Tooth disease. .  Journal of the Peripheral Nervous System17 ( 2 ) 206 - 209   2012.2A novel EGR2 mutation within a family with a mild demyelinating form of Charcot-Marie-Tooth disease. Reviewed

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  • Aiko Arimura , Takahisa Deguchi, Kazuhiro Sugimoto, Tadashi Uto T, Tomonori Nakamura, Yumiko Arimura, Kimiyoshi Arimura, Soroku Yagihashi, Yoshihiko Nishio, Hiroshi Takashima .  Intraepidermal nerve fiber density and nerve conduction study parameters correlate with clinical staging of diabetic polyneuropathy. .  Diabetes Research and Clinical Practice99 ( 1 ) 24 - 29   2012.1Intraepidermal nerve fiber density and nerve conduction study parameters correlate with clinical staging of diabetic polyneuropathy. Reviewed

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  • Hiroyuki Yamashita, Kazuo Kubota, Yuko Takahashi, Ryogo Minaminoto, Miyako Morooka, Kimiteru Ito, Toshikazu Kano, Hiroshi Kaneko, Hiroshi Takashima and Akio Mimoiri .  Whole-body fluorodeoxyglucose positron emission tomography/computed tomography in patients with active polymyalgia rheumatica: evidence for distinctive bursitis and large-vessel vasculitis. .  Mod Rheumatol.Online First #UTM#UR - December , 2011   2011.12Whole-body fluorodeoxyglucose positron emission tomography/computed tomography in patients with active polymyalgia rheumatica: evidence for distinctive bursitis and large-vessel vasculitis.Reviewed

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  • Okamoto Yuji, Higuchi Itsuro, Sakiyama Yusuke, Tokunaga Shohko, Watanabe Osamu, Arimura Kimiyoshi, Nakagawa Masanori, Takashima Hiroshi. .  A new mitochondria-related disease showing myopathy with episodic hyper-creatine kinase-emia. .  Annals of Neurology70 ( 3 ) 486 - 492   2011.9A new mitochondria-related disease showing myopathy with episodic hyper-creatine kinase-emia.Reviewed

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  • Sakiyama Y, Okamoto Y, Higuchi I, Inamori Y, Sangatsuda Y, Michizono K, Watanabe O, Hatakeyama H, Goto YI, Arimura K, Takashima H. .  A new phenotype of mitochondrial disease characterized by familial late-onset predominant axial myopathy and encephalopathy. .  Acta Neuropathologica121 ( 6 ) 775 - 783   2011.6A new phenotype of mitochondrial disease characterized by familial late-onset predominant axial myopathy and encephalopathy. Reviewed

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  • Abdelbary NH, Abdullah HM, Matsuzaki T, Hayashi D, Tanaka Y, Takashima H, Izumo S, Kubota R. .  Reduced Tim-3 expression on human T-lymphotropic virus type I (HTLV-I) Tax-specific cytotoxic T lymphocytes in HTLV-I infection. .  Journal of Infectious Diseases 203 ( 7 ) 948 - 959   2011.4Reduced Tim-3 expression on human T-lymphotropic virus type I (HTLV-I) Tax-specific cytotoxic T lymphocytes in HTLV-I infection.Reviewed

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  • Maehata Yoshitomo, Hirahashi M, Aishima S, Kishimoto J, Hirohashi S, Yao T, Takashima Hiroshi, Tsuneyoshi M, Oda Y. .  Significance of dysadherin and E-cadherin expression in differentiated-type gastric carcinoma with submucosal invasion. .  Human Pathology42 ( 4 ) 558 - 567   2011.4Significance of dysadherin and E-cadherin expression in differentiated-type gastric carcinoma with submucosal invasion.Reviewed

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  • Nishikawa N, Nagai Masahiro, Tsujii T, Tanabe N, Takashima Hiroshi, Nomoto Masahiro. .  Three spinocerebellar ataxia type 2 siblings with ataxia, parkinsonism, and motor neuronopathy. .  Internal Medicine50 ( 13 ) 1429 - 1432   2011.3Three spinocerebellar ataxia type 2 siblings with ataxia, parkinsonism, and motor neuronopathy.Reviewed

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  • Abdullah HM, Higuchi Itsuro, Kubota Ryuji, Matsuura Eiji, Hashiguchi Akihiro, Abdelbary NH, Inamori Yukie, Takashima Hiroshi, Izumo Shuji .  Histopathological differences between human T-lymphotropic virus type 1-positive and human T-lymphotropic virus type 1-negative polymyositis .  Clin Exp Neuroimmunol.2 ( 1 ) 12 - 24   2011.1Histopathological differences between human T-lymphotropic virus type 1-positive and human T-lymphotropic virus type 1-negative polymyositisReviewed

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  • Hazem M. Abdullah, Itsuro Higuchi, Ryuji Kubota, Eiji Matsuura, Akihiro Hashiguchi, Nashwa H. Abdelbary, Yukie Inamori, Hiroshi Takashima, Shuji Izumo .  Histopathological differences between human T-lymphotropic virus type 1-positive and human T-lymphotropic virus type 1-negative polymyositis. .  Clinical and Experimental Neuroimmunology2 ( 1 ) 12 - 24   2011.1Histopathological differences between human T-lymphotropic virus type 1-positive and human T-lymphotropic virus type 1-negative polymyositis.Reviewed

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  • 高嶋博、荒田仁、納光弘、有村公良 .  Gerstmann-Straeussler-Scheinker症候群の臨床像と早期診断 .  老年期認知症研究会誌16 ( 9 ) 11 - 13   2010.9Gerstmann-Straeussler-Scheinker症候群の臨床像と早期診断Reviewed

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  • Tokimura H, Tajitsu K, Takashima Hiroshi, Hirayama T, Tsuchiya M, Takayama K, Kazunori A. .  Familial Moyamoya Disease Associated with Graves' Disease in a MOther and Daughter -Two Case Reports- .  Neurologia medico-chirurgica50 ( 8 ) 668 - 674   2010.8Familial Moyamoya Disease Associated with Graves' Disease in a MOther and Daughter -Two Case Reports-Reviewed

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  • Hirano Ryuki, Takashima Hiroshi, Okubo Ryuichi, Okamoto Yuji, Maki Yoshimitsu, Ishida S, Suehara Masahito, Hokezu Youichi, Arimura Kimiyoshi. .  Clinical and genetic characterization of 16q-linked autosomal dominant spinocerebellar ataxia in South Kyushu, Japan. .  Journal of Human Genetics54 ( 7 ) 377 - 381   2009.7Clinical and genetic characterization of 16q-linked autosomal dominant spinocerebellar ataxia in South Kyushu, Japan.Reviewed

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  • Elizondo LI, Cho KS, Zhang W, Yan J, Huang C, Huang Y, Choi K, Sloan EA, Deguchi K, Lou S, Baradaran-Heravi A, Takashima Hiroshi, Lucke T, Quiocho FA, Boerkoel CF. .  Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation. .  Journal of Medical Genetics46 ( 1 ) 49 - 59   2009.1Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation.Reviewed

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  • Funayama M, Li Y, Tsoi TH, Lam CW, Ohi T, Yazawa S, Uyama E, Djaldetti R, Melamed E, Yoshino H, Imamichi Y, Takashima Hroshi, Nishioka K, Sato K, Tomiyama H, Kubo S, Mizuno Y, Hattori N. .  Familial Parkinsonism with digenic parkin and PINK1 mutations. .  Movement Disorders. 23 ( 10 ) 1461 - 1465   2008.10Familial Parkinsonism with digenic parkin and PINK1 mutations.Reviewed

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  • Yuan J, Takashima Hiroshi, Higuchi Itsuro, Arimura Kimiyoshi, Li N, Zhao Z, Shen H, Hu J. .  Genetically confirmed patients with merosin-deficient congenital muscular dystrophy in China. .  Neuropediatrics.39 ( 5 ) 264 - 267   2008.5Genetically confirmed patients with merosin-deficient congenital muscular dystrophy in China.Reviewed

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  • Hayashi Daisuke, Kubota Ryuji, Takenouchi Norihiro, Tanaka Y, Hirano Ryuki, Takashima Hiroshi, Osame Mitsuhiro, Izumo Shuji, Arimura Kimiyoshi. .  Reduced Foxp3 expression with increased cytomegalovirus-specific CTL in HTLV-I-associated myelopathy. .  Journal of Neuroimmunology200 ( 42006 ) 115 - 124   2008.1Reduced Foxp3 expression with increased cytomegalovirus-specific CTL in HTLV-I-associated myelopathy.Reviewed

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  • Hirano R, Interthal H, Huang C, Nakamura T, Deguchi K, Choi K, Bhattacharjee MB, Arimura K, Umehara F, Izumo S, Northrop JL, Salih MA, Inoue K, Armstrong DL, Champoux JJ, Takashima H, Boerkoel CF. .  Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation? .  EMBO J26 ( 22 ) 4732 - 4743   2007.10Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation? Reviewed

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  • Maeda K, Kaji R, Yasuno K, Jambaldorj J, Nodera H, Takashima H, Nakagawa M, Makino S, Tamiya G. .  Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) and genetic heterogeneity. .  J Hum Genet52 ( 11 ) 907 - 914   2007.10Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) and genetic heterogeneity. Reviewed

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  • Bajestan SN, Sabouri AH, Nakamura M, Takashima H, Keikhaee MR, Behdani F, Fayyazi MR, Sargolzaee MR, Bajestan MN, Sabouri Z, Khayami E, Haghighi S, Hashemi SB, Eiraku N, Tufani H, Najmabadi H, Arimura K, Sano A, Osame M. .  .Association of AKT1 haplotype with the risk of schizophrenia in Iranian population. .  Am J Med Genet B Neuropsychiatr Genet141 ( 4 ) 383 - 386   2006.7.Association of AKT1 haplotype with the risk of schizophrenia in Iranian population.Reviewed

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  • Arata H, Takashima H, Hirano R, Tomimitsu H, Machigashira K, Izumi K, Kikuno M, Ng AR, Umehara F, Arisato T, Ohkubo R, Nakabeppu Y, Nakajo M, Osame M, Arimura K. .  Early clinical signs and imaging findings in Gerstmann-Straussler-Scheinker syndrome (Pro102Leu). .  Neurology66 ( 11 ) 1672 - 1678   2006Early clinical signs and imaging findings in Gerstmann-Straussler-Scheinker syndrome (Pro102Leu).Reviewed

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  • Okamoto Y, Takashima H, Higuchi I, Matsuyama W, Suehara M, Nishihira Y, Hashiguchi A, Hirano R, Ng AR, Nakagawa M, Izumo S, Osame M, Arimura K. .  Molecular mechanism of rigid spine with muscular dystrophy type 1 caused by novel mutations of selenoprotein N gene. .  Neurogenetics7 ( 3 ) 175 - 183   2006Molecular mechanism of rigid spine with muscular dystrophy type 1 caused by novel mutations of selenoprotein N gene.Reviewed

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  • Hirano R, Takashima H, Umehara F, Arimura H, Michizono K, Okamoto Y, Nakagawa M, Boerkoel CF, Lupski JR, Osame M, Arimura K. .  SBF2/MTMR13 mutation causes CMT4B with juvenile onset glaucoma. .  Neurology 63 ( 3 ) 577 - 580   2004.8SBF2/MTMR13 mutation causes CMT4B with juvenile onset glaucoma. Reviewed

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  • Hirano R, Takashima H, Okubo R, Tajima K, Okamoto Y, Ishida S, Tsuruta K, Arisato T, Arata H, Nakagawa M, Osame M, Arimura K. .  Fine mapping of 16q-linked autosomal dominant cerebellar ataxia type III in Japanese families. .  Neurogenetics ( 5 ) 215 - 221   2004.8Fine mapping of 16q-linked autosomal dominant cerebellar ataxia type III in Japanese families. Reviewed

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  • Boerkoel CF, Takashima H, Nakagawa M, Izumo S, Armstrong D, Butler I, Mancias P, Papasozomenos SCH, Stern LZ, Lupski JR. .  GDAP1 mutations and CMT4A: a clinical and pathologic description and identification of a Hispanic founder mutation .  Ann. Neurol53 ( 3 ) 400 - 405   2003.1GDAP1 mutations and CMT4A: a clinical and pathologic description and identification of a Hispanic founder mutationReviewed

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  • Jordanova A, De Jobghe P, Boerkoel CF, Takashima H, De Vriendt E, Ceuterick C, Martin J -J, Butler IJ, Mancias P, Papasozomenos SC, Terespolski D, Potocki L, Brown CW, Shy M, Rita DA, Tournev I, Kremensky I, Lupski JR, Timmerman V. .  Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. .  Brain 126 ( 3 ) 590 - 597   2003.1Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease.Reviewed

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  • Takashima H, Boerkoel CF, Lupski JR. .  Screening for mutations in a genetically heterogeneous disorder: DHPLC versus DNA sequence for mutation detection in multiple genes causing Charcot-Marie-Tooth neuropathy .  Genet Med3 ( 5 ) 335 - 342   2002.1Screening for mutations in a genetically heterogeneous disorder: DHPLC versus DNA sequence for mutation detection in multiple genes causing Charcot-Marie-Tooth neuropathyReviewed

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  • Takashima H, Boerkoel CF, John J, Saifi GM, Salih MA, Armstrong D, Mao Y, Quiocho FA, Roa BB, Nakagawa M, Stockton DW, Lupski JR .  Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy .  Nat Genet30 ( 2 ) 267 - 272   2002.1Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathyReviewed

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  • Boerkoel CF, Takashima H, John J, Yan J, Stankiewicz P, Rosenbarker L, Andre JL, Bogdanovic R, Burguet A, Cockfield S, Cordeiro I, Frund S, Illies F, Joseph M, Kaitila I, Lama G, Loirat C, McLeod DR, Milford DV, Petty EM, Rodrigo F, Saraiva JM, Schmidt B, Smith GC, Spranger J, Stein A, Thiele H, Tizard J, Weksberg R, Lupski JR, Stockton DW .  Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia .  Nat Genet30 ( 2 ) 215 - 220   2002.1Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasiaReviewed

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  • Boerkoel CF, Takashima H, Garcia CA, Olney RK, Johnson J, Berry K, Russo P, Kennedy S, Teebi AS, Scavina M, Williams LL, Mancias P, Butler IJ, Krajewski K, Shy M, Lupski JR .  Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation .  Ann Neurol51 ( 2 ) 190 - 201   2002.1Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlationReviewed

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  • Takashima H, Boerkoel CF, De Jonghe P, Ceuterick C, Martin JJ, Voit T, Schroder JM, Williams A, Brophy PJ, Timmerman V, Lupski JR. .  Periaxin mutations cause a broad spectrum of demyelinating neuropathies .  Ann Neurol51 ( 6 ) 709 - 715   2002.1Periaxin mutations cause a broad spectrum of demyelinating neuropathiesReviewed

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  • Takashima H, Boerkoel CF, Stankiewicz P, Garcia CA, Leber SM, Rhee-Morris L, Lupski JR .  Periaxin mutations cause recessive Dejerine-Sottas neuropathy. .  Am J Hum Genet68 ( 2 ) 325 - 33   2001.1Periaxin mutations cause recessive Dejerine-Sottas neuropathy.Reviewed

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  • Hiroshi Takashima, Nakagawa M, Kanzaki A, Yawata Y, Horikiri T, Matsuzaki T, Suehara M, Izumo S, Osame M .  Germline mosaicism of MPZ gene in Dejerine-Sottas syndrome (HMSN III) associated with hereditary stomotocytosis. .  Neuromuscul Disord9   232 - 238   1999.1Germline mosaicism of MPZ gene in Dejerine-Sottas syndrome (HMSN III) associated with hereditary stomotocytosis.Reviewed

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  • Kiwaki T, Umehara F, Takashima H, Nakagawa M, Kamimura K, Kashio N, Sakamoto Y, Unoki K, Nobuhara Y, Michizono K, Watanabe O, Arimura H, Osame .  Hereditary motor and sensory neuropathy with myelin folding and juvenile onset glaucoma .  Neurology55   392 - 397   1999.1Hereditary motor and sensory neuropathy with myelin folding and juvenile onset glaucomaReviewed

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  • Utatsu Y, Takashima H, Michizono K, Kanda N, Endou K, Matsuyama Y, Fujimoto T, Nagai M, Umehara F, Higuchi I, Arimura K, Nakagawa M, Osame M .  Autosomal dominant early onset dementia and leukoencephalopathy in Japanese family: clinical, neuroimaging and genetic studies. .  J Neurol Sci147   55 - 62   1999.1Autosomal dominant early onset dementia and leukoencephalopathy in Japanese family: clinical, neuroimaging and genetic studies.Reviewed

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  • Nakagawa M, Suehara M, Saito A, Takashima H, Umehara F, Saito M, Kanzato N, Matsuzaki T, Takenaga S, Sakoda S, Izumo S, Osame M .  A novel MPZ gene mutation in dominantly inherited neuropathy with focally folded myelin sheaths .  Neurology52   1271 - 1275   1999.1A novel MPZ gene mutation in dominantly inherited neuropathy with focally folded myelin sheathsReviewed

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  • Takashima H, Nakagawa M, Suehara M, Saito M, Saito A, Kanzato N, Matuzaki T, Hirata K, Terwilliger JD, Osame M .  Gene for hereditary motor and sensory neuropathy (proximal dominant form) mapped to 3q13.1. .  Neuromuscul Disord9   232 - 238   1999.1Gene for hereditary motor and sensory neuropathy (proximal dominant form) mapped to 3q13.1.Reviewed

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  • Takashima H, Nakagawa M, Nakahara K, Suehara M, Matsuzaki T, Higuchi I, Higa H, Arimura K, Iwamasa T, Izumo S, Osame M. .  A New Type of Hereditary Motor and Sensory Neuropathy linked to chromosome 3. .  Annals of Neurology41 ( 6 ) 771 - 780   1997.3A New Type of Hereditary Motor and Sensory Neuropathy linked to chromosome 3. Reviewed

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  • Hiroshi Takashima , Nakagawa M, Nakahara K, Suehara M, Matsuzaki T, Higuchi I, Higa H, Arimura K, Iwamasa T, Izumo S, Osame M .  A new type of Hereditary motor and sensory neuropathy linked to chromosome 3 .  Ann Neurol 41   771 - 780   1997.1A new type of Hereditary motor and sensory neuropathy linked to chromosome 3Reviewed

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  • Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Salih MAM, Takashima H, Boerkoel CF .  Spinocerebellar Ataxia with Axonal Neuropathy Type 1. .      1993Spinocerebellar Ataxia with Axonal Neuropathy Type 1.

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  • The heart of a sailor : A chronicle of recovery after a major earthquake, tsunami, & nuclear catastrophe

    高嶋 博視

    Seri's Gift Association  2022  ( ISBN:9784910510729

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  • 新臨床内科学第10版 

    松浦英治,髙嶋 博( Role: Joint author ,  HTLV-1関連脊髄症)

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    南江堂  2019.5 

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  • 不動産取引における心理的瑕疵の裁判例と評価 : 自殺・孤独死等によって、不動産の価値はどれだけ下がるか?

    宮崎 裕二, 仲嶋 保, 難波 里美, 高島 博

    プログレス  2019  ( ISBN:9784905366928

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  • 神経疾患最新の治療 2018-2020

    松浦英治,髙嶋 博( Role: Contributor ,  HTLV-1関連脊髄症)

    南江堂  2018.1 

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  • 神経内科ClinicalQuestion&Pearls 末梢神経疾患

    岡本裕嗣,髙嶋 博( Role: Contributor ,  遺伝子を調べれば遺伝性末梢神経障害は診断できますか?)

    中外医学社  2018.1 

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  • ソロモンに散った聯合艦隊参謀 : 伝説の海軍軍人樋端久利雄

    高嶋 博視

    芙蓉書房出版  2017  ( ISBN:9784829507070

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  • MATLAB/Simulinkとモデルベース設計による2足歩行ロボット・シミュレーション

    三田 宇洋, 高島 博, 宅島 章夫, 田中 明美

    マイナビ出版  2017  ( ISBN:9784839956721

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  • 内科学書

    髙嶋博( Role: Contributor ,  遺伝性運動感覚性ニューロパチー)

    中山書店  2013.10 

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    Total pages:3000   Responsible for pages:428-433   Language:Japanese Book type:Textbook, survey, introduction

  • Annual Review 神経2013

    岡本裕嗣、髙嶋博( Role: Contributor ,  高CK血症を伴う新しいミトコンドリア病)

    中外医学社  2013.1 

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    Total pages:278   Responsible for pages:230-237   Language:Japanese Book type:Scholarly book

  • Annual Review 神経 2012

    橋口昭大,髙嶋 博( Role: Contributor ,  Charcot-Marie-Tooth病の網羅的遺伝子診断)

    中外医学社  2012.1 

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    Total pages:328   Responsible for pages:267-273   Language:Japanese Book type:Scholarly book

  • シャルコー・マリー・トゥース病診療マニュアル

    髙嶋博( Role: Contributor ,  遺伝疾患としての側面)

    株式会社金芳堂  2010.3 

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    Total pages:155   Responsible for pages:29-36   Language:Japanese Book type:Scholarly book

  • シャルコー・マリー・トゥース病診療マニュアル

    髙嶋博( Role: Contributor ,  遺伝疾患としての側面:PMP 22/CMT1A)

    株式会社金芳堂  2010.3 

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    Total pages:155   Responsible for pages:37-40   Language:Japanese Book type:Scholarly book

  • National Organization of Rare Disorders

    Hirano Ryuki, Salih MA, Takashima Hiroshi, Boerkoel CF.( Role: Joint author ,  Spinocerebellar ataxia with axonal neuropathy (SCAN1))

    Disease Database (On line textbook for patients)  2008 

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MISC

  • Development of Ivy Sign and Infarction in the Lateral Part of the Hemisphere or the Middle Cerebral Artery Territory in Association with Steno-occlusive Involvement of the Posterior Cerebral Artery in Moyamoya Disease(タイトル和訳中)

    Hamada Yuki, Matsuoka Hideki, Takashima Hiroshi

    Internal Medicine   62 ( 11 )   1703 - 1704   2023.6

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    Language:English   Publisher:(一社)日本内科学会  

  • 【Genetics of neurological and psychiatric disorders】(【Genetics of neurological and psychiatric disorders】Clinical genetics of Charcot-Marie-Tooth disease)

    Higuchi Yujiro, Takashima Hiroshi

    Journal of Human Genetics   68 ( 3 )   199 - 214   2023.3

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    Language:English   Publisher:Nature Publishing Group  

  • The first case of infantile-onset multisystem neurologic, endocrine, and pancreatic disease caused by novel PTRH2 mutation in Japan International journal

    Ando M.

    Neurological Sciences   43 ( 3 )   2133 - 2136   2022

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    Authorship:Last author   Language:English   Publisher:Neurological Sciences  

    DOI: 10.1007/s10072-021-05817-8

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    PubMed

  • 抗HTLV-1抗体髄液検査はCLIA法が適している

    兒玉大介, 田中正和, 松崎敏男, 松崎敏男, 野妻智嗣, 松浦英治, 高嶋博, 出雲周二, 久保田龍二

    Neuroinfection (Web)   27 ( 2 )   2022

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  • HAM診断に適した髄液中抗HTLV-1抗体検査法

    兒玉大介, 田中正和, 松崎敏男, 松崎敏男, 野妻智嗣, 松浦英治, 高嶋博, 出雲周二, 久保田龍二

    日本神経学会学術大会プログラム・抄録集   63rd   2022

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  • Pathological evidence of demyelination in the recurrent laryngeal, phrenic, and oculomotor nerves in Charcot-Marie-Tooth disease 4F Reviewed International journal

    Maeda K.

    eNeurologicalSci   25   100358   2021.12

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    We present pathology of the peripheral nerves of a patient with Adult-onset Charcot-Marie-Tooth disease 4F caused by periaxin gene mutation p.D651N. The patient was a 72-year-old woman. She had hoarseness and underwent continuous positive airway pressure therapy at night due to sleep apnea. The patient died abruptly. Remarkable demyelination with tomacula formation was found in the phrenic nerve, vagal nerve, recurrent laryngeal nerve, and oculomotor nerves. The cause of death could have been insufficient reactivity to the aspiration or sudden onset of bilateral vocal cord palsy. We must pay attention to respiratory function and cranial nerve palsies in hereditary demyelinating neuropathies.

    DOI: 10.1016/j.ensci.2021.100358

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    PubMed

  • プリオン蛋白遺伝子のオクタペプチドリピート4回挿入を認めた遺伝性クロイツフェルト・ヤコブ病の1例

    堂園美香, 延原康幸, 丸田恭子, 岡本裕嗣, 園田至人, 髙嶋 博

    臨床神経学   61 ( 5 )   314 - 318   2021.5

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  • 治療法の再整理とアップデートのために 専門家による私の治療 自己免疫性脳炎

    日本医事新報   ( 5059 )   43 - 43   2021.4

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • CK17万U/lと異常高値を呈したacute edematous dermatomyositisの1例

    堂園 美香 , 重久 彩乃 , 谷口 雄大 , 野妻 智嗣 , 田代 雄一 , 中村 友紀 , 橋口 昭大 , 大窪 隆一 , 髙嶋 博

    日本内科学会雑誌   110 ( 3 )   598 - 604   2021.3

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  • 【Neuro-COVID-19】コロナウイルスの基礎知識 新型コロナウイルスSARS-CoV-2

    﨑山 佑介, 岩崎 琢也, 髙嶋 博

    Clinical Neuroscience   39 ( 3 )   285 - 292   2021.3

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  • 各種難病の最新治療情報 シャルコー・マリー・トゥース病の最新情報

    樋口 雄二郎(鹿児島大学 大学院医歯学総合研究科神経病学講座脳神経内科・老年病学), 高嶋 博

    難病と在宅ケア   26 ( 10 )   46 - 51   2021.1

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    Authorship:Last author   Publishing type:Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

  • 髄液中抗HTLV-1抗体検査とHAM診断

    児玉大介, 田中正和, 松崎敏男, 松崎敏男, 野妻智嗣, 松浦英治, 高嶋博, 出雲周二, 久保田龍二

    日本HTLV-1学会学術集会   7th   2021

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  • 【神経症候学と神経診断学-AIは味方か敵か?】特異的症状の症候学・診断学とAI 対麻痺

    野妻 智嗣, 髙嶋 博

    Clinical Neuroscience   38 ( 11 )   1411 - 1413   2020.11

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  • シャルコー・マリー・トゥース病

    樋口雄二郎・髙嶋 博

    生体の科学   71 ( 5 )   394 - 395   2020.10

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (bulletin of university, research institution)   Publisher:医学書院  

  • SUCLA2関連ミトコンドリアDNA枯渇症候群の1例

    野崎 章仁(滋賀県立小児保健医療センター 小児科), 森 未央子, 熊田 知浩, 橋口 昭大, 高嶋 博, 村山 圭, 藤井 達哉

    脳と発達   52 ( 5 )   318 - 322   2020.9

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    Authorship:Corresponding author   Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • AP5Z1遺伝子に新規変異を認めたspastic paraplegia 48の1例

    丸田 恭子(国立病院機構南九州病院 神経内科), 安藤 匡宏, 大友 孝信, 高嶋 博

    臨床神経学   60 ( 8 )   543 - 548   2020.8

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    Authorship:Corresponding author   Language:Japanese  

  • 運動感覚性末梢神経障害と呼吸不全を呈しセナタキシン遺伝子にヘテロ接合性の新規変異を認めた1例

    北尾 るり子(国立病院機構箱根病院 神経内科), 本間 豊, 橋口 昭大, 溝口 功一, 高嶋 博, 小森 哲夫

    臨床神経学   60 ( 7 )   466 - 472   2020.7

  • 2020348670 Motor axonopathyとして発症し、17年後に感覚障害が出現したHSPB1変異を有するCMT2F孤発例

    古屋 佑一郎(防衛医科大学校 神経・抗加齢血管内科), 本郷 悠, 堀内 碧, 松井 太郎, 山崎 啓史, 高崎 寛, 橋口 昭大, 高嶋 博, 海田 賢一

    末梢神経   31 ( 1 )   154 - 159   2020.6

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  • GARS変異による遺伝性末梢神経障害7例の臨床的特徴

    橋口 昭大(鹿児島大学 医歯学総合研究科神経病学講座脳神経外科・老年病学), 吉村 明子, 安藤 匡宏, 樋口 雄二郎, 中村 友紀, 岡本 裕嗣, 松浦 英治, 高嶋 博

    末梢神経   31 ( 1 )   98 - 104   2020.6

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  • HTLV-1関連脊髄症における疾患進行の予測因子

    古園 麻衣, 松元 陸, 眞弓 芳子, 田代 雄一, 荒田 仁, 山野 嘉久, 田中 正和, 久保田 龍二, 松浦 英治, 高嶋 博

    NEUROINFECTION   25 ( 1 )   146 - 149   2020.5

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    Authorship:Corresponding author   Language:Japanese  

  • 認知機能低下を契機に発見されたミトコンドリア糖尿病の1例

    菊池 晃(鹿児島大学 糖尿病・内分泌内科学), 岡本 裕嗣, 橋口 裕, 吉重 幸一, 谷口 雄大, 出口 尚寿, 高嶋 博, 西尾 善彦

    糖尿病   63 ( 5 )   344 - 349   2020.5

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  • 辺縁系脳炎として治療中にHIV陽性が判明したHIV脳症の一例

    園田 理子, 中野 文, 牧 美充, 兒玉 憲人, 武井 潤, 平松 有, 田代 雄一, 荒田 仁, 橋口 照人, 髙嶋 博

    臨床神経学   60 ( 4 )   309 - 309   2020.4

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  • Long-read Sequencing Identifies GGC Repeat Expansions in NOTCH2NLC as the Cause of Neuronal Intranuclear Inclusion Disease Reviewed International journal

    Jun Sone, Satomi Mitsuhashi, Atsushi Fujita, Hiroshi Takashima, Hiroshi Sugiyama, Yoshihisa Takiyama, Kengo Maeda, Fumiaki Tanaka, Yasushi Iwasaki, Mari Yoshida, Naomichi Matsumoto, Gen Sobue

    NEUROLOGY   94 ( 15 )   2020.4

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    Language:English   Publishing type:Research paper, summary (international conference)   Publisher:LIPPINCOTT WILLIAMS & WILKINS  

    Web of Science

  • Charcot–Marie–Tooth disease with a mutation in FBLN5 accompanying with the small vasculitis and widespread onion-bulb formations Reviewed International journal

    Yuko Yamagishi , Makoto Samukawa, Motoi Kuwahara, Kazuo Takada, Kazumasa Saigoh, Yoshiyuki Mitsui, Nobuyuki Oka, Akihiro Hashiguchi, Hiroshi Takashima, Susumu Kusunoki

    410   116623   2020.3

  • グロブリン大量静注療法に反応性を示したX-linked Charcot-Marie-Tooth disease type 1の一例

    青木 怜佳(獨協医科大学 脳神経内科), 駒ヶ嶺 朋子, 国分 則人, 橋口 昭大, 高嶋 博, 平田 幸一

    臨床神経生理学   48 ( 1 )   8 - 14   2020.2

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  • 2020317323 LRRK2 R1441H変異の新たな家系に関する臨床遺伝学的研究(Clinicogenetic Studies on New Families with LRRK2 R144H Mutations)

    順天堂醫事雑誌   65 ( 6 )   571 - 571   2019.12

  • 遺伝性ニューロパチーの2つの新規遺伝子MMEとCOA7の同定

    樋口 雄二郎, 橋口 昭大, 袁 軍輝, 吉村 明子, 岡本 裕嗣, 松浦 英治, 矢部 勇, 上田 健博, 小出 隆司, 矢口 裕章, 三井 純, 石浦 浩之, 中川 正法, 森下 真一, 戸田 達史, 辻 省次, 高嶋 博

    臨床神経学   59 ( Suppl. )   S364 - S364   2019.11

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    Language:Japanese   Publisher:(一社)日本神経学会  

  • 失調症状を主としたX連鎖性Charcot-Marie-Tooth病1型(CMTX1)の1例

    大嶌 祐貴, 水島 慶一, 芳野 正修, 江口 克紀, 脇田 雅大, 白井 慎一, 岩田 育子, 松島 理明, 矢部 一郎, 高嶋 博, 佐々木 秀直

    臨床神経学   59 ( 6 )   395 - 395   2019.6

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    Language:Japanese   Publisher:(一社)日本神経学会  

  • Progress of Medical Treatment of Neuropathy Reviewed

    Takashima Hiroshi

    Nihon Naika Gakkai Zasshi   108 ( 8 )   1515 - 1516   2019

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    Language:Japanese   Publisher:The Japanese Society of Internal Medicine  

    DOI: 10.2169/naika.108.1515

  • COA7は小脳失調を伴う軸索型ニューロパチーの新規原因遺伝子である

    樋口雄二郎, 橋口昭大, YUAN Junhui, 吉村明子, 岡本裕嗣, 松浦英治, 上田健博, 石浦浩之, 三井純, 戸田達史, 戸田達史, 辻省次, 高嶋博

    末梢神経   29 ( 2 )   308 - 308   2018.12

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    Language:Japanese   Publisher:日本末梢神経学会  

    J-GLOBAL

  • Repeated hyperhidrosis and chilblain-like swelling with ulceration of the fingers and toes in hereditary sensory and autonomic neuropathy type II Reviewed International journal

    Shima T.

    Journal of Dermatology   45 ( 11 )   e308 - e309   2018.11

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    Language:English   Publisher:Journal of Dermatology  

    DOI: 10.1111/1346-8138.14336

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    PubMed

  • 2型遺伝性感覚性自律神経性ニューロパチーにおける手足の指の潰瘍を伴う反復多汗症および凍瘡様腫脹(Repeated hyperhidrosis and chilblain-like swelling with ulceration of the fingers and toes in hereditary sensory and autonomic neuropathy type II) Reviewed

    Shima Tomoko, Yamamoto Yuki, Kanazawa Nobuo, Murata Ken-ya, Ito Hidefumi, Kondo Toshikazu, Yuan Junhui, Hashiguchi Akihiro, Takashima Hiroshi, Furukawa Fukumi

    The Journal of Dermatology   45 ( 11 )   e308 - e309   2018.11

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    Publisher:John Wiley & Sons Australia, Ltd  

  • Congenital hypomyelination neuropathy 5例の神経伝導検査所見の特徴

    岩田 啓, 石山 昭彦, 竹下 絵里, 本橋 裕子, 齋藤 貴志, 小牧 宏文, 中川 栄二, 須貝 研司, 樋口 雄二郎, 橋口 昭大, 高嶋 博, 佐々木 征行

    臨床神経生理学   46 ( 5 )   540 - 540   2018.10

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    Language:Japanese   Publisher:(一社)日本臨床神経生理学会  

  • 神経疾患治療の進歩 2017】脊髄小脳変性症の治療の進歩

    﨑山雄介,髙嶋 博

    神経治療学   35 ( 5 )   605 - 608   2018.9

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)   Publisher:日本神経治療学会  

    DOI: 10.15082/jsnt.35.5_605

  • 【ニューロパチー-Basics & Updates】遺伝性ニューロパチー Charcot-Marie-Tooth病

    岡本裕嗣,髙嶋 博

    Clinical neuroscience   36 ( 9 )   1066 - 1070   2018.9

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)   Publisher:中外医学社  

  • 【脳炎・脳症・脊髄症の新たな展開】子宮頸がんワクチンに関連した自己免疫性脳症

    荒田 仁,髙嶋 博

    神経内科   89 ( 3 )   313 - 318   2018.9

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)   Publisher:科学評論社  

  • 脳炎・脳症・脊髄症の新たな展開 ヒトパピローマウイルスワクチン接種後の神経症状は、なぜ心因性疾患と間違われるのか

    髙嶋 博

    神経治療学   35 ( 4 )   536 - 542   2018.7

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    DOI: doi.org/10.15082/jsnt.35.4_536

  • 本年の動向 Whole exome sequencingでわかること

    樋口雄二郎,髙嶋 博

    Annual Review神経2018   75 - 81   2018.1

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  • Letter to the Editor:Reply

    髙嶋 博

    神経治療学   34 ( 4 )   472 - 473   2018

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    Publisher:日本神経治療学会  

    DOI: 10.15082/jsnt.34.4_472

  • シンポジウム10 脳炎・脳症・脊髄症の新たな展開 司会の言葉 Invited

    亀井 聡, 髙嶋 博

    神経治療学   35 ( 4 )   528 - 528   2018

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    Authorship:Lead author   Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)   Publisher:日本神経治療学会  

    DOI: 10.15082/jsnt.35.4_528

  • 自己免疫性脳炎・脳症における運動異常症

    田代雄一, 髙嶋 博

    BRAIN and NERVE-神経研究の進歩   69 ( 12 )   1387 - 1399   2017.12

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

    DOI: https://doi.org/10.11477/mf.1416200923

  • 古細菌による感染症研究の現状は? 菌の形態をとらえ100以上のDNA配列を提示し臨床像と治療法を報告。培養は不成功

    﨑山佑介, 髙嶋 博

    日本医事新報   4884   62 - 63   2017.11

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  • 自己免疫性脳症のスペクトラムとびまん性脳障害の神経症候学

    牧 美充, 髙嶋 博

    BRAIN and NERVE-神経研究の進歩   69 ( 10 )   1131 - 1141   2017.10

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    DOI: https://doi.org/10.11477/mf.1416200881

  • 子宮頸がんワクチン関連神経障害の病態とその治療

    髙嶋 博

    自律神経   54 ( 4 )   289   2017.10

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  • 画像検査

    﨑山佑介,髙嶋 博

    Clinical Neuroscience   35 ( 9 )   1080 - 1083   2017.9

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  • 遺伝性末梢神経障害の新しい遺伝子

    樋口 雄二郎、安藤 匡宏, 橋口 昭大, 高嶋 博

    神経内科   87 ( 2 )   155 - 160   2017.8

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  • 内科診療に潜む脳症・脳炎を見落とさないために

    髙嶋 博、桑原 聡、栗山 勝、飯塚高浩

    日本内科学会雑誌   106 ( 8 )   1598 - 1610   2017.8

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  • 自己免疫性脳症を見極めるための神経徴候

    荒田 仁、髙嶋 博

    日本内科学会雑誌   106 ( 8 )   1542 - 1549   2017.8

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  • 【内科診療に潜む脳炎・脳症】内科診療に潜む脳症・脳炎を見落とさないために

    高嶋 博, 桑原 聡, 栗山 勝, 飯塚 高浩

    日本内科学会雑誌   106 ( 8 )   1598 - 1610   2017.8

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  • Charcot-Marie-Tooth病のゲノム治療

    岡本 裕嗣、髙嶋 博

    神経内科   86 ( 6 )   686 - 692   2017.6

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  • Charcot-Marie-Tooth病におけるMFN2変異の疫学と臨床像

    安藤 匡宏、岡本 裕嗣, 髙嶋 博

    末梢神経   28 ( 1 )   60 - 65   2017.6

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  • 精神・神経疾患の遺伝医学研究・診療各論 末梢神経疾患

    橋口 昭大、 髙嶋 博

    遺伝子医学MOOK   155 - 163   2017.4

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

  • シャルコー・マリー・トゥース病に類似した三頭酵素欠損症の成人例

    山本 雄貴, 松井 尚子, 平松 有, 宮崎 由道, 野寺 裕之, 和泉 唯信, 高嶋 博, 梶 龍兒

    臨床神経学   57 ( 2 )   82 - 87   2017.2

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

    DOI: https://doi.org/10.5692/clinicalneurol.cn-000976

  • An AOA2 patient with a novel compound heterozygous SETX frame shift mutations Reviewed International journal

    Motokura E.

    Journal of the Neurological Sciences   372   294 - 296   2017.1

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    Publisher:Journal of the Neurological Sciences  

    DOI: 10.1016/j.jns.2016.11.074

    Scopus

    PubMed

  • 日常診療でよくみる自己免疫脳症の診察ポイントと治療の実際

    髙嶋 博

    神経免疫学   22 ( 1 )   83 - 83   2017.1

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • 身体表現性障害と鑑別になる自己免疫性脳炎の診断と治療の実際

    高嶋 博

    日本心療内科学会誌   21 ( 別冊 )   45 - 45   2017

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • 運動失調症の医療基盤に関する調査研究 運動失調症の遺伝子学的研究および臨床的解析

    高嶋博, 崎山佑介, 樋口雄二郎, 安藤匡宏, 橋口昭大, 袁軍輝, 石原聡, 田邊肇, 吉村明子, 西郷隆二, 平松有, 田代雄一, 中村友紀, 岡本裕嗣, 石浦浩之, 三井純, 辻省次

    運動失調症の医療基盤に関する調査研究班 平成26-28年度 総合研究報告書(Web)   36‐41 (WEB ONLY)   2017

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    Language:Japanese  

    J-GLOBAL

  • Progress in inherited neuropathies and myopathies

    Hiroshi Takashima

    42 ( 13 )   613 - 615   2016.12

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

  • 神経疾患遺伝子診断の進歩

    橋口昭大、髙嶋 博

    Mebio   33 ( 11 )   78 - 87   2016.11

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

  • Autoimmune encephalopathy after HPV vaccination.

    Hitoshi Arata, Hiroshi Takashima

    Neurological Medicine   85 ( 5 )   547 - 554   2016.11

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

  • 【糖尿病の神経学revisited】 糖尿病と自己免疫性ニューロパチー

    出口尚寿、西尾善彦、髙嶋 博

    BRAIN and NERVE: 神経研究の進歩   66 ( 2 )   135 - 147   2014.2

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • 神経疾患治療ノート 遺伝性脂質異常症(Bassen-Kornzweig syndrome、Tangier disease、Refsum disease)に伴う末梢神経障害

    松浦英治、髙嶋 博

    Clinical Neuroscience   32 ( 1 )   110 - 111   2014.1

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • Gerstmann-Straussler-Scheinker病(GSS) Reviewed

    荒田仁、髙嶋博

    Clinical Neuroscience   31 ( 9 )   1057 - 1059   2013.9

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • 対麻痺 Reviewed

    野妻智嗣、髙嶋博

    Clinical Neuroscience   31 ( 5 )   556 - 557   2013.5

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • Gerstmann-Streussler-Scheinker syndrome Reviewed

    荒田仁 髙嶋博 有村公良

    Annual Review 神経 2008 中外医学社   116 - 123   2008.1

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    Language:English   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • 遺伝性ニューロパチーの進歩 Reviewed

    高嶋博 有村公良

    Clinical Neuroscience   25 ( 7 )   752 - 754   2007.7

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • 末梢神経疾患 常染色体劣性遺伝形式の末梢神経障害および小脳失調症を示す疾患 spinocerebellar ataxia with axonal neuropathy(SCAN1)

    高嶋博

    Annual Review神経2007   208 - 213   2007.1

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • 遺伝性ニューロパチーの診断と病態 Reviewed

    高嶋博

    Peripheral Nerve 末梢神経末梢神経学会   18 ( 2 )   145 - 151   2007.1

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • 遺伝性ニューロパチーの分子遺伝学

    高嶋博

    臨床神経学   46 ( 11 )   760 - 767   2007.1

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • 遺伝性ニューロパチーの分子遺伝学ー神経学会賞特別寄稿

    高嶋博

    臨床神経学   46 ( 1 )   1 - 8   2006.1

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • 常染色体劣性遺伝性脊髄小脳変性症 Spinocerebellar ataxia with axonal neuropathy(SCAN1)

    高嶋博、有村公良

    神経研究の進歩   50 ( 3 )   379 - 386   2006

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • 神経疾患 遺伝性運動・感覚ニューロパチー

    高嶋博、有村公良

    小児内科   38 ( 増 )   726 - 727   2006

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • 神経 ニューロパチーの遺伝子学

    橋口昭大、高嶋博

    最新医学   9 ( 増 )   2047 - 2056   2006

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

▼display all

Presentations

  • 松浦英治,田代雄一,髙畑克徳,安藤匡宏,平松 有,野妻智嗣,樋口雄二郎,﨑山佑介,橋口昭大,髙嶋 博   HAM患者を対象としたL-アルギニンの有効性を検討する複数回(7日間連続)投与試験(特定臨床研究)  

    第25回日本神経感染症学会  2021.10  日本神経感染症学会

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    Event date: 2021.10

    Venue:WEB開催  

  • 川畑裕太郎,堂園美香,保原貴裕,髙畑克徳,大山 賢,﨑山佑介,松浦英治,髙嶋 博   免疫療法が奏功した抗Ri抗体陽性脳幹脳炎の一例  

    第233回日本神経学会九州地方会  2021.9  一般社団法人日本神経学会

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    Event date: 2021.9

    Language:Japanese  

    Venue:WEB開催  

  • 山下悠亮,野口 悠,児島史一,永田龍世,安藤匡宏,大山 賢,﨑山佑介,髙嶋 博   当院で経験した自己免疫性glial fibrillary acidic protein(GFAP)アストロサイトパチーの一例  

    第233回日本神経学会九州地方会  2021.9  一般社団法人日本神経学会

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    Event date: 2021.9

    Language:Japanese  

    Venue:WEB開催  

  • 湯治美佳,安藤匡宏,金子浩之,樋口雄二郎,田代雄一,﨑山佑介,荒田 仁,橋口昭大,梅原藤雄,髙嶋 博   PTRH2遺伝子変異によるIMNEPD(infantileーonset Multisystem Neurologenic,Endocrine,and Pancreatic Disease)の一例  

    第32回日本末梢神経学会学術集会  2021.9  日本末梢神経学会

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    Event date: 2021.9

    Language:Japanese  

    Venue:WEB開催  

  • 山田七海,岩佐尚毅,仲西康顕,井口直彦,江浦信之,尾崎麻希,菊辻直弥,橋口昭大,髙嶋 博,眞野智生,杉江和馬   短期間で再発を繰り返した突発性神経痛性筋萎縮症の一例  

    第32回日本末梢神経学会学術集会  2021.9  日本末梢神経学会

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    Event date: 2021.9

    Language:Japanese  

    Venue:WEB開催  

  • 橋口昭大,吉村明子,中村友紀,樋口雄二郎,安藤匡宏,髙嶋 博   PMP22点変異及び欠失変異を有する遺伝性ニューロパチー13例の臨床的電気生理学的検討  

    第32回日本末梢神経学会学術集会  2021.9  日本末梢神経学会

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    Event date: 2021.9

    Venue:WEB開催  

  • 橋元 彩,尾山琴海,保原貴裕,堂園美香,髙畑克徳,大山 賢,﨑山佑介,東 桂子,松浦英治,髙嶋 博   外傷後の脳脊髄液漏出症に体位性頻脈症候群を合併した1例  

    第334回日本内科学会九州地方会  2021.8  日本内科学会

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    Event date: 2021.8

  • 武 義人,平松 有,吉元裕亮,吉田崇史,田中咲衣,上山未紗,岩田大輝,今田美南子,髙畑克徳,安藤匡宏,田代雄一,﨑山佑介,荒田 仁,松浦英治,髙嶋 博   脾臓低形成がみられ椎間板炎と硬膜外膿瘍,傍椎体膿瘍を合併した肺炎球菌性髄膜炎の一例  

    第35回日本神経救急学会学術集会  2021.6  一般社団法人 日本神経救急学会

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    Event date: 2021.6

    Venue:WEB開催  

  • 中江健太郎,久保純平,野口 悠,児島史一,武井 潤,安藤匡宏,大山 賢,﨑山佑介,髙嶋 博   PRNP codon129多型(V/V)とv180Ⅰ変異を認めたhereditary CreutzfeldtーJakob disease(hCJD)の一例  

    第232回日本神経学会九州地方会  2021.6  一般社団法人日本神経学会

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    Event date: 2021.6

    Language:Japanese  

    Venue:WEB開催  

  • 川畑裕太郎,穂原貴裕,髙畑克徳,平松 有,大山 賢,﨑山佑介,松浦英治,吉満 誠,髙嶋 博   診断に苦慮した中枢神経原発B細胞悪性リンパ腫の一例  

    第232回日本神経学会九州地方会  2021.6 

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    Event date: 2021.6

    Language:Japanese  

    Venue:WEB開催  

  • 小門亮寛,吉元裕亮,平松 有,髙畑克徳,安藤匡宏,田代雄一,﨑山佑介,道園久美子,小牧祐雅,髙嶋 博   炎症性腸疾患のフォロー中にサルコイドーシスを発症した1例  

    第333回日本内科学会九州地方会  2021.6  日本内科学会

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    Event date: 2021.6

    Language:Japanese  

    Venue:WEB開催  

  • 足立 拓馬(鹿児島大学 脳神経内科), 安藤 匡宏, 湯地 美佳, 平松 有, 田代 雄一, 崎山 佑介, 岡本 裕嗣, 松浦 英治, 高嶋 博   成人ミトコンドリア病におけるGDF15とFGF21  

    第38回日本神経治療学会学術集会  日本神経治療学会

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    Event date: 2020.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:東京都  

  • 松浦 英治, 荒田 仁, 東 桂子, 田中 正和, 安藤 匡宏, 平松 有, 野妻 智嗣, 田代 雄一, 﨑山 佑介, 久保田 龍二, 髙嶋 博   HPVワクチン関連疾患の臨床経過とワクチン接種後血液サイトカイン・自己抗体の検討  

    第32回日本神経免疫学会学術集会  日本神経免疫学会 

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    Event date: 2020.10

    Presentation type:Poster presentation  

    Venue:WEB開催  

  • 野妻 智嗣, 松浦 英治, 田中 正和, 久保田 龍二, 髙嶋 博   HTLV-1関連脊髄症における疾患特異的TCRレパトアの同定  

    第32回日本神経免疫学会学術集会 

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    Event date: 2020.10

    Language:Japanese   Presentation type:Poster presentation  

    Venue:WEB開催  

  • 松浦 英治, 田代 雄一, 野妻 智嗣, 安藤 匡宏, 平松 有, 﨑山 佑介, 荒田 仁, 田中 正和, 久保田 龍二, 髙嶋 博   HAM患者に対するL-アルギニン内服治療の試み  

    第32回日本神経免疫学会学術集会 

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    Event date: 2020.10

    Presentation type:Poster presentation  

  • 久保 純平, 足立 拓馬, 神田 佳樹, 湯地 美佳, 安藤 匡宏, 平松 有, 田代 雄一, 崎山 佑介, 高嶋 博   精神運動発達遅滞にてんかんと舞踏様運動を合併したGNAO1変異によるてんかん性脳症の一例  

    第229回日本神経学会九州地方会  一般社団法人日本神経学会九州地方会

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    Event date: 2020.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:大分市  

  • 谷口 雄大, 安藤 匡宏, 岡本 裕嗣, 吉村 明子, 樋口 雄二郎, 橋口 昭大, 服部 信孝, 中川 正法, 辻 省次, 髙嶋 博   MPZ変異を持つ遺伝性末梢神経障害の遺伝学的・臨床的特徴  

    第31回日本末梢神経学会学術集会  2020.9  日本末梢神経学会

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    Event date: 2020.9 - 2020.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:千葉市(WEB開催)  

  • 橋本 里奈(国立病院機構東名古屋病院 脳神経内科), 佐藤 実咲, 榊原 聡子, 見城 昌邦, 横川 ゆき, 片山 泰司, 齋藤 由扶子, 饗場 郁子, 犬飼 晃, 橋口 昭大, 髙嶋 博   REEP1遺伝子変異を認めたCharcot-Marie-Tooth病の1例  

    第31回日本末梢神経学会学術集会 

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    Event date: 2020.9 - 2020.10

    Language:Japanese   Presentation type:Poster presentation  

    Venue:千葉市(WEB開催)  

  • Kodama Daisuke, Tanaka Masakazu, Matsuzaki Toshio, Nozuma Satoshi, Matsuura Eiji, Takashima Hiroshi, Izumo Shuji, Kubota Ryuji   HTLV-1型感染者における抗HERV-K10抗体への高い反応性(High reactivity to anti-HERV-K10 in HTLV-1-infected individuals)  

    第61回日本神経学会学術大会  一般社団法人日本神経学会

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    Event date: 2020.8 - 2020.9

    Venue:岡山市  

  • 日本人の神経疾患に対する血漿交換療法の成績と診療パターンの分析 使用実績に関する調査(Japan-Plasmapheresis Outcome and Practice Patterns Study for Neurological diseases: real world survey)  

    第61回日本神経学会学術大会  (一社)日本神経学会

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    Event date: 2020.8 - 2020.9

    Venue:岡山市  

  • HTLV-1感染細胞のマイクロアレイ解析によるHAMに対する治療標的分子の検索(Retrieval of therapeutic target molecules for HAM by microarray analysis of HTLV-1-infected cells)  

    第61回日本神経学会学術大会  (一社)日本神経学会

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    Event date: 2020.8 - 2020.9

    Venue:岡山市  

  • 名ヶ迫 強, 武井 潤, 平松 有, 田代 雄一, 荒田 仁, 松浦 英治, 高嶋 博   レボドパ・カルビドパ配合経腸用液療法の有効性の検討  

    第61回日本神経学会学術大会  一般社団法人日本神経学会

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    Event date: 2020.8 - 2020.9

    Language:Japanese  

    Venue:岡山市  

  • 樋口 雄二郎, 橋口 昭大, 岡本 裕嗣, 高嶋 博   日本発 遺伝性神経筋疾患 最新の発見 ニューロパチーの遺伝学 最新の知見  

    第61回日本神経学会学術大会  一般社団法人日本神経学会

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    Event date: 2020.8 - 2020.9

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:岡山市  

  • 崎山 佑介, 吉村 明子, 湯地 美佳, 安藤 匡宏, 平松 有, 田代 雄一, 樋口 雄二郎, 荒田 仁, 松浦 英治, 高嶋 博   神経感染症、新たな時代 次世代シーケンサーを活用した神経感染症のショットガンメタゲノム解析  

    第61回日本神経学会学術大会  一般社団法人日本神経学会

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    Event date: 2020.8 - 2020.9

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

    Venue:岡山市  

  • 安藤 匡宏(鹿児島大学病院 脳神経内科), 吉村 明子, 谷口 雄大, 樋口 雄二郎, 崎山 佑介, 橋口 昭大, 岡本 裕嗣, 高嶋 博   Charcot-Marie-Tooth病遺伝子解析におけるSOD1変異  

    第61回日本神経学会学術大会  一般社団法人日本神経学会

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    Event date: 2020.8 - 2020.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:岡山市  

  • 湯地 美佳, 平方 翔太, 安藤 匡宏, 平松 有, 田代 雄一, 崎山 佑介, 荒田 仁, 岡本 裕嗣, 松浦 英治, 高嶋 博   成人ミトコンドリア病におけるGrowth Differentiation Factor 15の有用性  

    第61回日本神経学会学術大会  一般社団法人日本神経学会

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    Event date: 2020.8 - 2020.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:岡山市  

  • 平松 有, 岡本 裕嗣, 吉村 明子, 髙嶋 博   成人における尿中細胞のミトコンドリア遺伝子の解析について  

    第61回日本神経学会学術大会  一般社団法人日本神経学会

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    Event date: 2020.8 - 2020.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:岡山市  

  • 牧 美充, 野村 美和, 小田 健太郎, 中野 文, 重畠 裕也, 宮下 史生, 渡邊 修, 増田 曜章, 安東 由喜雄, 髙嶋 博   髄膜アミロイドーシスの2症例  

    第61回日本神経学会学術大会  一般社団法人日本神経学会

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    Event date: 2020.8 - 2020.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:岡山市  

  • 谷口 雄大, 吉村 明子, 安藤 匡宏, 平松 有, 樋口 雄二郎, 崎山 佑介, 橋口 昭大, 岡本 裕嗣, 松浦 英治, 高嶋 博   遺伝性末梢神経障害におけるアミロイドポリニューロパチーの臨床像  

    第61回日本神経学会学術大会  一般社団法人日本神経学会

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    Event date: 2020.8 - 2020.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:岡山市  

  • 横山 徳幸(函館市医師会病院 脳神経内科), 佐藤 達朗, 丸尾 康則, 高嶋 博   retinal vasculopathy with cerebral leukoencephalopathyのMRIの継時的変化について  

    第61回日本神経学会学術大会 

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    Event date: 2020.8 - 2020.9

    Presentation type:Poster presentation  

    Venue:岡山市  

  • 園田 理子, 池田 め衣, 武井 潤, 平松 有, 樋口 雄二郎, 田代 雄一, 荒田 仁, 松浦 英治, 高嶋 博   当科で経験した抗NMDA受容体脳炎と抗てんかん薬の使用経験についての臨床的検討  

    第61回日本神経学会学術大会  一般社団法人日本神経学会

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    Event date: 2020.8 - 2020.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:岡山市  

  • 兒玉 憲人, 橋口 昭大, 樋口 逸郎, 髙嶋 博   炎症性筋疾患におけるHLA-classII抗原発現と臨床像の解析  

    第61回日本神経学会学術大会 

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    Event date: 2020.8 - 2020.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:岡山市  

  • 森 拓馬, 増田 未来, 長友 理沙, 湯地 美佳, 安藤 匡宏, 平松 有, 樋口 雄二郎, 田代 雄一, 荒田 仁, 橋口 昭大, 髙嶋 博   脊髄性筋萎縮症III型の成人例におけるヌシネルセンの治療経験  

    第61回日本神経学会学術大会  一般社団法人日本神経学会

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    Event date: 2020.8 - 2020.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:岡山市  

  • X連鎖性Charcot-Marie-Tooth病1型患者112例の遺伝子プロファイルと表現型プロファイル(Genetic and Phenotypic Profile of 112 Patients with X-linked Charcot-Marie-Tooth disease type 1)  

    第59回日本神経学会学術大会  (一社)日本神経学会

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    Event date: 2018.5

    Presentation type:Oral presentation (general)  

  • エクソームデータを用いたALS患者のSMN1、SMN2およびNAIP遺伝子におけるコピー数多型解析(Analyses of copy number variations in SMN1, SMN2 and NAIP genes in ALS patients using exome data)  

    第59回日本神経学会学術大会  (一社)日本神経学会

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    Event date: 2018.5

    Venue:札幌市  

  • , 田代 雄一, 野妻 智嗣, 安藤 匡宏, 平松 有, 崎山 佑介, 荒田 仁, 田中 正和, 久保田 龍二, 高嶋 博   HAM患者に対するL-アルギニン内服治療の試み  

    第59回日本神経学会学術大会  一般社団法人日本神経学会

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    Event date: 2018.5

    Language:Japanese   Presentation type:Poster presentation  

    Venue:札幌市  

  • Takashima Hiroshi, Arata Hitoshi, Matsuura Eiji, Higashi Keiko   ヒトパピローマウィルスワクチン由来の新規視床下部症候群に関する基礎的、臨床的洞察 ヒトパピローマウイルスワクチン接種後自律神経障害をともなう自己免疫性脳症(Basic and clinical insights into new hypothalamic syndrome caused by human papilloma virus vaccination Autoimmune encephalopathy and autonomic failure after human papilloma virus vaccination)  

    日本自律神経学会総会プログラム・抄録集  日本自律神経学会

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    Event date: 2017.8

    Language:Japanese  

  • Hiroshi Takashima, Akihiro Hashiguchi, Miwa Nomura, Hitoshi Arata, Akiko Yoshimura, Yujiro Higuchi, Yusuke Sakiyama, Tomonori Nakamura, Yuji Okamoto, Eiji Matsuura   Neurofilament light gene mutation causes hereditary motor and sensory neuropathy with pyramidal signs.   International conference

    The 63rd Annual Meeting of the American society of human genetics Annnual meeting 2013  The 63rd Annual Meeting of the American society of human genetics Annnual meeting 2013

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    Event date: 2013.10

    Language:English  

    Venue:ボストン(アメリカ)  

    国際学会

  • 髙嶋 博   沖縄型神経原性筋萎縮症(HMSN-P)の疾患概念の確立と歴史  

    第54回日本神経学会学術大会シンポジウム講演  第54回日本神経学会学術大会シンポジウム講演

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    Event date: 2013.5

    Language:Japanese  

    Venue:東京都  

    国内学会

  • 﨑山佑介、神田直昭、樋口雄二郎、高田良治、渡邊修、袁軍輝、荒田仁、野妻智嗣、道園久美子、東桂子、橋口照人、平野隆城、松浦英治、大窪隆一、樋口逸郎、岩崎琢也、出雲周二、髙嶋博   ST合剤が奏功した新しい感染性脳炎の原因究明  

    第54回日本神経学会学術大会  第54回日本神経学会学術大会

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    Event date: 2013.5

    Language:Japanese  

    Venue:東京  

    国内学会

  • Takashima H, Hashiguchi A, Hu Jing, Zhao Zhe, Higuichi Y, Sakiyama Y, Tokunaga S, Okamoto Y, Yoshimura A.   Alanyl-t RNA synthetase mutation in dominant distal hereditary motor neuropathy and Charcot-Marie-Tooth disease.   International conference

    62nd Annual Meeting on American Society of Human Genetics 2012  62nd Annual Meeting on American Society of Human Genetics 2012

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    Event date: 2012.11

    Language:English  

    Venue:San Francisco, U. S. A.  

    国際学会

  • 髙嶋 博   遺伝性ニューロパチー概要 ―診療に役立つ知識から分子病態まで―  

    第30回日本神経治療学会総会教育講演  第30回日本神経治療学会総会教育講演

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    Event date: 2012.11

    Language:Japanese  

    Venue:北九州市  

    国内学会

  • 髙嶋 博   次世代遺伝子解析技術を用いた神経疾患の遺伝子診断の実際とその展望  

    第7回九州遺伝子診断研究会特別講演  第7回九州遺伝子診断研究会特別講演

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    Event date: 2012.10

    Language:Japanese  

    Venue:鹿児島市  

    研究会

  • 髙嶋 博   なぜそこが障害されるのか:末梢神経障害部位を決める分子メカニズム  

    第23回日本末梢神経学会学術集会シンポジウム2  第23回日本末梢神経学会学術集会シンポジウム2

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    Event date: 2012.9

    Language:Japanese  

    Venue:福岡市  

    国内学会

  • 髙嶋 博   遺伝性末梢神経障害について  

    第29回小児神経筋疾患懇話会 教育講演  第29回小児神経筋疾患懇話会 教育講演

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    Event date: 2012.8

    Language:Japanese  

    Venue:東京都  

    国内学会

  • 髙嶋 博   遺伝性ニューロパチーからみた神経変形性メカニズム  

    第21回日本神経学会中国・四国地区生涯教育講演会  第21回日本神経学会中国・四国地区生涯教育講演会

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    Event date: 2012.7

    Language:Japanese  

    Venue:徳島市  

    国内学会

  • 髙嶋 博   臨床神経遺伝学の進歩  

    第29回日本神経治療学会総会 教育講演  第29回日本神経治療学会総会 教育講演

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    Event date: 2011.11

    Language:Japanese  

    Venue:福井市  

    国内学会

  • 高嶋博   遺伝性ニューロパチーの分子病態と治療への展望  

    2010年度日本神経学会九州地区生涯教育講演会  2010年度日本神経学会九州地区生涯教育講演会

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    Event date: 2011.3

    Language:Japanese  

    Venue:福岡  

    国内学会

  • Hiroshi Takashima   Pathomechanism of spinocerebellar ataxia with axonal neuropathy.  

    The 1st RIRBM International Symposium, Genome Damage and Non-Cancerous Diseases  The 1st RIRBM International Symposium, Genome Damage and Non-Cancerous Diseases

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    Event date: 2011.3

    Language:Japanese  

    Venue:広島  

    その他

  • 高口剛、樋口雄二郎、平松有、吉村道由、市来征仁、高田良治、東桂子、出口尚寿、渡邊修、高嶋博   痙性対麻痺が先行し急速進行性の経過を辿ったP102L型Gerstmann-Straussler-Scheinker 症候群(GSS)の一例  

    第191回日本神経学会九州地方会  第191回日本神経学会九州地方会

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    Event date: 2010.9

    Language:Japanese  

    Venue:佐賀  

    国内学会

  • 久保田龍二、松浦英治、田中勇悦、髙嶋博、出雲周二   HTLV-I感染リンパ球とCTLの浸潤によるneural bystander damage  

    第3回HTLV-I研究会  第3回HTLV-I研究会

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    Event date: 2010.8

    Language:Japanese  

    Venue:東京都  

    研究会

  • 林大輔、市來征仁、高田良治、森山宏遠、樋口雄二郎、東桂子、出口尚寿、渡邊修、髙嶋博   本態性血小板血症および抗リン脂質抗体症候群に合併した脳静脈洞血栓症の1症例  

    第290回 日本内科学会九州地方会  第290回 日本内科学会九州地方会

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    Event date: 2010.8

    Language:Japanese  

    Venue:佐賀県  

    国内学会

  • 川端隆史、東元一晃、髙嶋博、出雲周二、久保田龍二   HTLV-I関連肺疾患における肺胞洗浄液・肺生検組織でのHTLV-I特異的CTLの集積  

    第3回HTLV-I研究会  第3回HTLV-I研究会

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    Event date: 2010.8

    Language:Japanese  

    Venue:東京都  

    研究会

  • Abdelbary N、Abdullah H、松崎敏男、林大輔、田中勇悦、髙嶋博、出雲周二、久保田龍二   Reduce Tim-3 expression on HTLV-I Tax-specific CTL in HTLV-I infection.  

    第3回HTLV-I研究会  第3回HTLV-I研究会

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    Event date: 2010.8

    Language:Japanese  

    Venue:東京  

    研究会

  • 有村愛子、出口尚寿、宇都正、有村公良、髙嶋博   治療後有痛性神経障害患者の臨床像と皮膚生検の検討  

    第16回糖尿病性神経障害を考える会  第16回糖尿病性神経障害を考える会

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    Event date: 2010.8

    Language:Japanese  

    Venue:東京  

    研究会

  • Eiji Matsuura, Steven Jacobson, Akihiro Hashiguchi, Itsuro Higuchi,Kimiyoshi Arimura, Hiroshi Takashima   Two siblings presenting paraspinal muscle atrophy(axial myopathy) with HTLV-I-associated myelopathy/tropical spastic paraparesis.   International conference

    The 12th International conference of neuromuscular disease  The 12th International conference of neuromuscular disease

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    Event date: 2010.7

    Language:English  

    Venue:イタリア  

    国際学会

  • 髙口剛、樋口雄二郎、平松有、吉村道由、市来征仁、髙田良治、東桂子、出口尚寿、渡邊修、樋口逸郎、髙嶋博   抗SRP 抗体陽性多発性筋炎の一例  

    第190回日本神経学会九州地方会  第190回日本神経学会九州地方会

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    Event date: 2010.6

    Language:Japanese  

    Venue:大分県  

    国内学会

  • 雑賀徹、立石貴久、鳥居孝子、河村信利、長柄祐子、重藤寛史、大八木保政、吉良潤一、橋口昭大、髙嶋博   新規のsenataxin遺伝子変異(R2136C)によるALS4の1例  

    第190回日本神経学会九州地方会  第190回日本神経学会九州地方会

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    Event date: 2010.6

    Language:Japanese  

    Venue:大分県  

    国内学会

  • 平松有、吉村道由、高田良治、中村友紀、東桂子、渡邊修、有村公良、髙嶋博   平山病5症例におけるメチルコバラミン 大量療法の有効性の検討  

    第51回日本神経学会総会  第51回日本神経学会総会

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    Event date: 2010.5

    Language:Japanese  

    Venue:東京都  

    国内学会

  • 徳永章子、橋口昭大、岡本裕嗣、中村友紀、有村公良、髙嶋博   マイクロアレイDNAチップによるCharcot-Marie-Tooth病の遺伝子診断  

    第51回日本神経学会総会  第51回日本神経学会総会

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    Event date: 2010.5

    Language:Japanese  

    Venue:東京都  

    国内学会

  • 松浦英治、田中勇悦、Steven Jacobson、髙嶋博   HTLV-I-associated Myelopathy (HAM/TSP)患者末梢血中の細胞障害性T細胞はCD4陽性細胞よりも単球と相互作用している  

    第51回日本神経学会総会  第51回日本神経学会総会

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    Event date: 2010.5

    Language:Japanese  

    Venue:東京都  

    国内学会

  • 吉村道由、 荒田仁、 大窪隆一、 有村公良、髙嶋博   Gerstmann-Straussler-Scheinker 症候群における臨床像と画像所見(SPECT,PET)の検討  

    第51回日本神経学会総会  第51回日本神経学会総会

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    Event date: 2010.5

    Language:Japanese  

    Venue:東京都  

    国内学会

  • 市橋享子、新村昌弘、籾博晃、東元一晃、田代雄一、西郷隆二、道園久美子、渡邊修、樋口逸郎、有村公良、髙嶋博   縦隔気腫を合併した多発性筋炎の一例  

    第288回日本内科学会九州地方会  第288回日本内科学会九州地方会

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    Event date: 2010.3

    Language:Japanese  

    Venue:福岡県  

    国内学会

  • 平松有、吉村道由、髙田良治、森山宏遠、道園久美子、岡本裕嗣、渡邊修、有村公良、髙嶋博   Creutzfeldt-Jakob病 (CJD) 様の臨床像を呈したGerstmann-Straussler-Scheinker病 (GSS) の一例  

    第189回日本神経学会九州地方会  第189回日本神経学会九州地方会

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    Event date: 2010.3

    Language:Japanese  

    Venue:福岡県  

    国内学会

  • 平松 有、吉村道由、髙田良治、森山宏遠、道園久美子、渡邊 修、樋口逸郎、有村公良、高嶋 博   トリヘキシフェニジル塩酸塩誘発性の口部ジスキネジーと考えられた1例  

    第288回日本内科学会九州地方会  第288回日本内科学会九州地方会

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    Event date: 2010.1

    Language:Japanese  

    Venue:福岡県  

    国内学会

  • Kodama Daisuke, Tanaka Masakazu, Matsuzaki Toshio, Nozuma Satoshi, Matsuura Eiji, Takashima Hiroshi, Izumo Shuji, Kubota Ryuji   HTLV-1型感染者における抗HERV-K10抗体への高い反応性(High reactivity to anti-HERV-K10 in HTLV-1-infected individuals)  

    臨床神経学  2020.11  (一社)日本神経学会

  • Kubota Ryuji, Tanaka Masakazu, Matsuura Eiji, Takashima Hiroshi   HTLV-1感染細胞のマイクロアレイ解析によるHAMに対する治療標的分子の検索(Retrieval of therapeutic target molecules for HAM by microarray analysis of HTLV-1-infected cells)  

    臨床神経学  2020.11  (一社)日本神経学会

  • Lin Youwei, Tomoko Narita, Oji Satoru, Miyamoto Katsuichi, Takashima Hiroshi, Utsugisawa Kimiaki, Niino Masaaki, Yokoyama Kazumasa, Watanabe Osamu, Suwazono Shugo, Mori Masahiro, Yoshikawa Hiroo, Matsuo Hidenori   日本人の神経疾患に対する血漿交換療法の成績と診療パターンの分析 使用実績に関する調査(Japan-Plasmapheresis Outcome and Practice Patterns Study for Neurological diseases: real world survey)  

    臨床神経学  2020.11  (一社)日本神経学会

  • Lin Youwei, Narita Tomoko, Oji Satoru, Miyamoto Katsuichi, Takashima Hiroshi, Utsugisawa Kimiaki, Niino Masaaki, Yokoyama Kazumasa, Suwazono Shugo, Watanabe Osamu, Mori Masahiro, Yoshikawa Hiroo, Nakatsuji Yuji, Takahashi Yuji, Nomura Kyoichi, Kusunoki Susumu, Komatsu Masakazu, Matsuo Hidenori   神経疾患に対するTPEの最近の進歩 神経疾患に対するJapan Plasmapheresis Outcome and Practice Patterns Study(J-POPPS) 多施設を対象としたリアルワールド研究(Recent advance in TPE for neurological disorders 1 Japan-Plasmapheresis Outcome and Practice Patterns Study(J-POPPS) for Neurological diseases: A multi-center real world survey)  

    日本アフェレシス学会雑誌  2019.10  (一社)日本アフェレシス学会

  • Nozuma Satoshi, Matsuura Eiji, Matsuzaki Toshio, Kubota Ryuji, Jacobson Steven, Takashima Hiroshi   ウイルス性神経疾患における免疫病原性CSFのTCRレパトア特性(Immunopathogenic CSF TCR repertoire signatures in virus-associated neurologic disease)  

    臨床神経学  2021.9  (一社)日本神経学会

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  • Inada Rino, Hirano Makito, Oka Nobuyuki, Samukawa Makoto, Saigoh Kazumasa, Suzuki Hidekazu, Udaka Fukashi, Hashiguchi Akihiro, Takashima Hiroshi, Hamada Yukihiro, Nakamura Yusaku, Nagai Yoshitaka, Kusunoki Susumu   Gene analyses for spinocerebellar ataxia type 2 identify neuropathy phenotype in Japan(タイトル和訳中)  

    臨床神経学  2022.10  (一社)日本神経学会

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  • Kubota Ryuji, Kodama Daisuke, Tanaka Masakazu, Takashima Hiroshi   HTLV-1はHAM/TSP患者におけるToll様受容体遺伝子の発現を抑制する(HTLV-1 reduces the expression of Toll-like receptor genes in HAM/TSP patients)  

    臨床神経学  2018.12  (一社)日本神経学会

  • Kodama Daisuke, Matsuzaki Toshio, Tanaka Masakazu, Matsuura Eiji, Takashima Hiroshi, Kubota Ryuji, Izumo Shuji   HAM/TSPにおける生存遺伝子ABL1の阻害はHTLV-1感染CD4+T細胞を劇的に減少させる(Inhibition of survival gene ABL1 dramatically decreases HTLV-1 infected CD4+T cells in HAM/TSP)  

    臨床神経学  2018.12  (一社)日本神経学会

  • Lin Youwei, Tomoko Narita, Oji Satoru, Miyamoto Katsuichi, Takashima Hiroshi, Utsugisawa Kimiaki, Niino Masaaki, Yokoyama Kazumasa, Watanabe Osamu, Suwazono Shugo, Mori Masahiro, Yoshikawa Hiroo, Matsuo Hidenori   日本人の神経疾患に対する血漿交換療法の成績と診療パターンの分析 使用実績に関する調査(Japan-Plasmapheresis Outcome and Practice Patterns Study for Neurological diseases: real world survey)   Invited

    臨床神経学  2020.11  (一社)日本神経学会

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  • Nozuma Satoshi, Matsuura Eiji, Matsuzaki Toshio, Kubota Ryuji, Jacobson Steven, Takashima Hiroshi   Immunopathogenic CSF TCR repertoire signatures in virus-associated neurologic disease(和訳中)  

    臨床神経学  2021.9  (一社)日本神経学会

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  • Sahashi Kentaro, Saito Toshio, Takashima Hiroshi, Tanaka Fumiaki, Kuwatsuka Yachiyo, Hashizume Atsushi, Homma Taihei, Ando Masahiko, Katsuno Masahisa   Japan REgistry for Adult subjeCTs of spinal muscular atrophy(jREACT): Baseline characteristics(タイトル和訳中)  

    臨床神経学  2022.10  (一社)日本神経学会

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  • Kubota Ryuji, Tanaka Masakazu, Matsuura Eiji, Takashima Hiroshi   HTLV-1感染細胞のマイクロアレイ解析によるHAMに対する治療標的分子の検索(Retrieval of therapeutic target molecules for HAM by microarray analysis of HTLV-1-infected cells)  

    臨床神経学  2020.11  (一社)日本神経学会

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  • Kodama Daisuke, Tanaka Masakazu, Matsuzaki Toshio, Nozuma Satoshi, Matsuura Eiji, Takashima Hiroshi, Izumo Shuji, Kubota Ryuji   HTLV-1型感染者における抗HERV-K10抗体への高い反応性(High reactivity to anti-HERV-K10 in HTLV-1-infected individuals)  

    臨床神経学  2020.11  (一社)日本神経学会

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  • Lin Youwei, Tomoko Narita, Oji Satoru, Miyamoto Katsuichi, Takashima Hiroshi, Utsugisawa Kimiaki, Niino Masaaki, Yokoyama Kazumasa, Watanabe Osamu, Suwazono Shugo, Mori Masahiro, Yoshikawa Hiroo, Matsuo Hidenori   日本人の神経疾患に対する血漿交換療法の成績と診療パターンの分析 使用実績に関する調査(Japan-Plasmapheresis Outcome and Practice Patterns Study for Neurological diseases: real world survey)   Invited

    臨床神経学  2020.11  (一社)日本神経学会

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  • Nozuma Satoshi, Matsuura Eiji, Matsuzaki Toshio, Kubota Ryuji, Jacobson Steven, Takashima Hiroshi   ウイルス性神経疾患における免疫病原性CSFのTCRレパトア特性(Immunopathogenic CSF TCR repertoire signatures in virus-associated neurologic disease)  

    臨床神経学  2021.9  (一社)日本神経学会

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  • Sahashi Kentaro, Saito Toshio, Takashima Hiroshi, Tanaka Fumiaki, Kuwatsuka Yachiyo, Hashizume Atsushi, Homma Taihei, Ando Masahiko, Katsuno Masahisa   脊髄性筋萎縮症のJapan REgistry for Adult subjeCTs(jREACT) ベースラインの特徴(Japan REgistry for Adult subjeCTs of spinal muscular atrophy(jREACT): Baseline characteristics)  

    臨床神経学  2022.10  (一社)日本神経学会

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  • Inada Rino, Hirano Makito, Oka Nobuyuki, Samukawa Makoto, Saigoh Kazumasa, Suzuki Hidekazu, Udaka Fukashi, Hashiguchi Akihiro, Takashima Hiroshi, Hamada Yukihiro, Nakamura Yusaku, Nagai Yoshitaka, Kusunoki Susumu   脊髄小脳失調症2型の遺伝子解析により明らかとなった日本における神経障害表現型(Gene analyses for spinocerebellar ataxia type 2 identify neuropathy phenotype in Japan)  

    臨床神経学  2022.10  (一社)日本神経学会

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  • Nozuma Satoshi, Matsuura Eiji, Matsuzaki Toshio, Kubota Ryuji, Jacobson Steven, Takashima Hiroshi   ウイルス性神経疾患における免疫病原性CSFのTCRレパトア特性(Immunopathogenic CSF TCR repertoire signatures in virus-associated neurologic disease)  

    臨床神経学  2021.9  (一社)日本神経学会

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  • Sahashi Kentaro, Saito Toshio, Takashima Hiroshi, Tanaka Fumiaki, Kuwatsuka Yachiyo, Hashizume Atsushi, Homma Taihei, Ando Masahiko, Katsuno Masahisa   脊髄性筋萎縮症のJapan REgistry for Adult subjeCTs(jREACT) ベースラインの特徴(Japan REgistry for Adult subjeCTs of spinal muscular atrophy(jREACT): Baseline characteristics)  

    臨床神経学  2022.10  (一社)日本神経学会

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  • Inada Rino, Hirano Makito, Oka Nobuyuki, Samukawa Makoto, Saigoh Kazumasa, Suzuki Hidekazu, Udaka Fukashi, Hashiguchi Akihiro, Takashima Hiroshi, Hamada Yukihiro, Nakamura Yusaku, Nagai Yoshitaka, Kusunoki Susumu   脊髄小脳失調症2型の遺伝子解析により明らかとなった日本における神経障害表現型(Gene analyses for spinocerebellar ataxia type 2 identify neuropathy phenotype in Japan)  

    臨床神経学  2022.10  (一社)日本神経学会

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  • Nozuma Satoshi, Matsuura Eiji, Matsuzaki Toshio, Kubota Ryuji, Jacobson Steven, Takashima Hiroshi   ウイルス性神経疾患における免疫病原性CSFのTCRレパトア特性(Immunopathogenic CSF TCR repertoire signatures in virus-associated neurologic disease)  

    臨床神経学  2021.9  (一社)日本神経学会

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  • Sahashi Kentaro, Saito Toshio, Takashima Hiroshi, Tanaka Fumiaki, Kuwatsuka Yachiyo, Hashizume Atsushi, Homma Taihei, Ando Masahiko, Katsuno Masahisa   脊髄性筋萎縮症のJapan REgistry for Adult subjeCTs(jREACT) ベースラインの特徴(Japan REgistry for Adult subjeCTs of spinal muscular atrophy(jREACT): Baseline characteristics)  

    臨床神経学  2022.10  (一社)日本神経学会

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  • Inada Rino, Hirano Makito, Oka Nobuyuki, Samukawa Makoto, Saigoh Kazumasa, Suzuki Hidekazu, Udaka Fukashi, Hashiguchi Akihiro, Takashima Hiroshi, Hamada Yukihiro, Nakamura Yusaku, Nagai Yoshitaka, Kusunoki Susumu   脊髄小脳失調症2型の遺伝子解析により明らかとなった日本における神経障害表現型(Gene analyses for spinocerebellar ataxia type 2 identify neuropathy phenotype in Japan)  

    臨床神経学  2022.10  (一社)日本神経学会

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  • Nozuma Satoshi, Matsuura Eiji, Matsuzaki Toshio, Kubota Ryuji, Jacobson Steven, Takashima Hiroshi   ウイルス性神経疾患における免疫病原性CSFのTCRレパトア特性(Immunopathogenic CSF TCR repertoire signatures in virus-associated neurologic disease)  

    臨床神経学  2021.9  (一社)日本神経学会

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    Language:English  

  • Sahashi Kentaro, Saito Toshio, Takashima Hiroshi, Tanaka Fumiaki, Kuwatsuka Yachiyo, Hashizume Atsushi, Homma Taihei, Ando Masahiko, Katsuno Masahisa   脊髄性筋萎縮症のJapan REgistry for Adult subjeCTs(jREACT) ベースラインの特徴(Japan REgistry for Adult subjeCTs of spinal muscular atrophy(jREACT): Baseline characteristics)  

    臨床神経学  2022.10  (一社)日本神経学会

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    Language:English  

  • Inada Rino, Hirano Makito, Oka Nobuyuki, Samukawa Makoto, Saigoh Kazumasa, Suzuki Hidekazu, Udaka Fukashi, Hashiguchi Akihiro, Takashima Hiroshi, Hamada Yukihiro, Nakamura Yusaku, Nagai Yoshitaka, Kusunoki Susumu   脊髄小脳失調症2型の遺伝子解析により明らかとなった日本における神経障害表現型(Gene analyses for spinocerebellar ataxia type 2 identify neuropathy phenotype in Japan)  

    臨床神経学  2022.10  (一社)日本神経学会

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    Language:English  

  • Nozuma Satoshi, Matsuura Eiji, Matsuzaki Toshio, Kubota Ryuji, Jacobson Steven, Takashima Hiroshi   ウイルス性神経疾患における免疫病原性CSFのTCRレパトア特性(Immunopathogenic CSF TCR repertoire signatures in virus-associated neurologic disease)  

    臨床神経学  2021.9  (一社)日本神経学会

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    Language:English  

  • Nozuma Satoshi, Matsuura Eiji, Matsuzaki Toshio, Kubota Ryuji, Jacobson Steven, Takashima Hiroshi   ウイルス性神経疾患における免疫病原性CSFのTCRレパトア特性(Immunopathogenic CSF TCR repertoire signatures in virus-associated neurologic disease)  

    臨床神経学  2021.9  (一社)日本神経学会

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Intellectual Property

  • 自己免疫性疾患治療薬

    高嶋博 荒田仁

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    Applicant:鹿児島大学

    Application no:特願2017-558275  Date applied:2016.12

    Announcement no:特許第6749022号 

    Patent/Registration no:特許第6749022号  Date registered:2020.8 

  • 遺伝性疾患の検出方法

    高嶋 博 樋口雄二郎 橋口昭大 吉村明子

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    Applicant:鹿児島大学

    Application no:特願2014-093044  Date applied:2014.4

    Announcement no:特許第6378529号  Date announced:2018.8

  • 抗菌剤を含む医薬品組成物

    高嶋 博 出雲周二

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    Applicant:国立大学法人鹿児島大学

    Application no:特願2015-501434  Date applied:2014.2

    Announcement no:特許第6552053号  Date announced:2019.7

    Patent/Registration no:特許第6552053号  Date registered:2019.7 

    Rights holder:国立大学法人鹿児島大学

Research Projects

  • 神経核内封入体病(NIID)の 臨床疫学調査および疾患概念確立

    2021.4

    厚生労働省  厚生労働省科学研究費補助金  難治性疾患等政策研究事業

    曽根 淳

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    Authorship:Coinvestigator(s) 

  • charcot-MarieーTooth病の治療を見据えた分子遺伝学的研究

    2021.4

    科学研究費補助金  基盤研究(B)

    髙嶋 博、樋口雄二郎

  • 沖縄型神経原性筋萎縮症の診療に直結するエビデンス創出研究

    2021.4 - 2024.3

    受託研究 

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    Authorship:Coinvestigator(s) 

  • charcot-MarieーTooth病の分子遺伝学的アプローチによる病態解明

    2018.4 - 2021.3

    科学研究費補助金  基盤研究(B)

    髙嶋 博、岡本裕嗣,橋口昭大

  • Charcot-Marie-Tooth diseaseの分子遺伝学 脊髄小脳変性症、Prion病

    1994

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    Grant type:Competitive

  • 遺伝性ニューロパチーの分子メカニズム 脊髄小脳変性症の分子遺伝学的研究 遺伝性神経疾患の遺伝学的研究

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    Grant type:Competitive

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