Faculty Profiles - TAKASHIMA Hiroshi

Papers - TAKASHIMA Hiroshi

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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

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

Publisher：(一社)日本内科学会

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

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

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

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

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

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

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

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

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

Publisher：エルゼビア・ジャパン(株)

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

Publisher：Nature Publishing Group

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

Language：English Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Internal Medicine

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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CiNii Research

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

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

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

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.

DOI： 10.15082/jsnt.36.5_580

CiNii Research

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

Language：English Publisher：The Japanese Society of Internal Medicine

Objective 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. Materials and Methods 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). Results 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. Conclusion 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.

DOI： 10.2169/internalmedicine.3029-19

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CiNii Research

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 2019Reviewed

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

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

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

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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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

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

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

Language：English Publisher：Elsevier Inc.

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 2018.3Reviewed

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Papers - TAKASHIMA Hiroshi