Faculty Profiles - TAKASHIMA Hiroshi

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

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

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

Language：Japanese Publisher：Societas Neurologica Japonica

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.

DOI： 10.5692/clinicalneurol.cn-001705

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

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

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

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

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

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

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

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

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

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

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

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 (SETX) gene variant . Rinsho Shinkeigakuadvpub ( 0 ) 205 - 210 2022A case of sporadic amyotrophic lateral sclerosis (ALS) with Senataxin (SETX) gene variant

Language：Japanese Publisher：Societas Neurologica Japonica

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 (SETX), 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 (in silico analysis).

DOI： 10.5692/clinicalneurol.cn-001675

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

Language：English Publisher：The Japanese Society of Internal Medicine

The PRPS1 gene encodes phosphoribosyl pyrophosphate synthetase 1 (PRS-1). The phenotypes associated with PRPS1 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 PRPS1. Despite showing a typical clinical picture, the decrease in enzyme activity measured in the patient's erythrocytes was milder than in previously reported cases.

DOI： 10.2169/internalmedicine.8029-21

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

Language：English Publisher：The Japanese Society of Internal Medicine

Charcot-Marie-Tooth disease (CMT) is a common hereditary peripheral polyneuropathy encompassing distinct monogenetic disorders. Pathogenic mutations in mitofusin 2 (MFN2) 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 MFN2 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 MFN2-related CMT and highlights the need to evaluate infrequent manifestations during long-term care of CMT patients.

DOI： 10.2169/internalmedicine.6487-20

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Language：Japanese Publisher：Societas Neurologica Japonica

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 genetic analysis.

DOI： 10.5692/clinicalneurol.cn-001558

Satomi D. . Limits to the exaggeration and diversification of a male sexual trait in the false blister beetle Oedemera sexualis . Entomological Science24 ( 3 ) 219 - 227 2021

Language：Japanese Publisher：Entomological Science

Differentiation in sexual traits among populations is one of the major predictions of theories of sexual selection and sexual conflict. A balance between maximizing reproductive benefits and minimizing survival costs could explain variation in sexual traits within and between populations. The false blister beetle Oedemera sexualis (Coleoptera: Oedemeridae) has exaggerated sexual traits, that is, sexually dimorphic hindlegs. In this study, we characterized scaling relationships in populations of O. sexualis to evaluate the determinants of sexual trait variation in the species. We quantified sexual dimorphism in body size and hindleg sizes in three representative populations based on distance measurements and an elliptical Fourier analysis. We found significant variation in the degree of sexual dimorphism for body and hindleg sizes among populations. In particular, differentiation in the male hind femur shape, especially the femur width, was conspicuous. Scaling relationships between male hind femur width and body size were best described by logistic models, showing that increases in male hind femur width were constrained for large individuals in all three populations. The degree of constrained growth of the hind femur width differed among populations in accordance with the population means, while the basal growth rates did not. Populations with smaller mean values for sexual traits showed more limited sexual trait exaggeration, contrary to the predictions based on resource competition among body parts. The latitudinal cline in femur widths suggests that environmental constraints on exaggeration might be responsible for sexual trait diversification in O. sexualis.

DOI： 10.1111/ens.12469

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

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

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 (FGD4) 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 FGD4 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 FGD4 c.1730G>A (p.Arg577Gln) mutation showing mild progression and cauda equina thickening.

DOI： 10.2169/internalmedicine.7247-21

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

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

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

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

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

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

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

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

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

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

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 ATXN8OS 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 ATXN8OS CTG expansion develop cerebellar ataxia, these cases suggest the pathogenesis of ATXN8OS repeat expansions in hereditary cerebellar ataxia.

DOI： 10.2169/internalmedicine.2905-19

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

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

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.

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

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

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

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.

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

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

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier B.V.

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

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

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

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

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

Authorship：Last author,　Corresponding author Language：English

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

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

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

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

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

Authorship：Last author Language：English

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

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

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

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.

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

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

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

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

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

Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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>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.

DOI： 10.1016/j.nmd.2017.07.011

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

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.

DOI： 10.1111/ene.13360

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

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

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

Authorship：Last author,　Corresponding author Publisher：WILEY

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.

DOI： 10.1111/jns.12228

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

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

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>T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C>T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G>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.

DOI： 10.1111/cge.13002

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

Authorship：Last author,　Corresponding author Language：English Publisher：NATURE PUBLISHING GROUP

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.

DOI： 10.1038/jhg.2017.15

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

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

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

Publisher：SAGE Publications Inc.

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.

DOI： 10.1177/1971400916687585

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

Language：English

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.

DOI： 10.1212/NXG.0000000000000171

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

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

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.

DOI： 10.15082/jsnt.34.3_160

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

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

Yano C., Matsuura E., Nakamura T., Sonoda A., Shigehisa A., Ando M., Nozuma S., Higuchi Y., Sakiyama Y., Hashiguchi A., Michizono K., Takashima H. . Visual evoked potential in myelin oligodendrocyte glycoprotein antibody-associated disease . Multiple Sclerosis and Related Disorders98 106408 2025.6

Language：Japanese Publisher：Multiple Sclerosis and Related Disorders

The visual evoked potential (VEP) patterns of optic neuritis are known to often differ between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) but have been less reported in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). This study aimed to characterize the VEP pattern in MOGAD and evaluate its utility in distinguishing MOGAD from MS and NMOSD. We retrospectively reviewed the clinical manifestations and VEP findings in patients with MS (n = 29), NMOSD (n = 14), and MOGAD (n = 10). In eyes with acute visual impairment, VEP responses were detectable in 100 % of eyes with MOGAD, a striking difference from MS (72.7 %) and NMOSD (57.1 %). In addition, VEP abnormalities in eyes without acute visual impairment were rare in MOGAD (23.1 %) compared to MS (55.3 %) and NMOSD (42.9 %). Our results indicated that subclinical VEP abnormalities or undetectable VEP responses were less common in patients with MOGAD compared to patients with MS and NMOSD. VEP testing demonstrates potential diagnostic utility in distinguishing among these conditions.

DOI： 10.1016/j.msard.2025.106408

Matsui N., Tanaka K., Kokubun N., Hatanaka Y., Ishida M., Osaki Y., Watanabe T., Watanabe O., Matsuura E., Takashima H., Sato Y., Kuwabara S., Izumi Y. . Prevalence, clinical profiles, and prognosis of Isaacs syndrome: A nationwide survey study in Japan . Journal of the Neurological Sciences472 123442 2025.5

Language：Japanese Publisher：Journal of the Neurological Sciences

Objectives: To elucidate current epidemiological, clinical, and immunological profiles, and the treatment of Isaacs syndrome in Japan. Methods: We conducted a nationwide survey using established methods. Questionnaires were sent to neurological facilities throughout Japan to identify Isaacs syndrome patients seen between April 2018 and March 2021. Results: The estimated total number of Isaacs syndrome patients was 114 (95 % confidence interval [CI]: 89.63–138.91), and the estimated prevalence was 0.091 per 100,000 population. Detailed clinical data were available for 44 patients. The median age at onset was 40 (range, 17–78 years), and 55 % were female. The median time from symptom onset to diagnosis was 24 months (range, 1–372 months). Electrodiagnostic studies showed evidence of nerve hyperexcitability in 90 % (myokymic discharges in 50 % and stimulus-induced repetitive discharges in 32 %). Of the 28 patients examined in the cell-based assay, 22 % tested positive (11 % for both leucine-rich glioma-inactivated 1 [LGI1] and contactin-associated protein-like 2 [CASPR2] antibodies and 11 % for LGI1 antibodies only). The median modified Rankin Scale (mRS) score was 2 at diagnosis and 1.5 at the last visit. A high mRS score (mRS ≥4) at baseline was an independent risk factor for poor outcomes (mRS ≥3) (Odds ratio, 20.7; 95 % CI, 2.90–209.18; p < 0.001). Conclusion: We elucidated the current epidemiological and clinical characteristics of Isaacs syndrome in Japan. Isaacs syndrome is a rare neuromuscular disorder. Electrophysiologic abnormalities were frequent, and serum antibodies were not detectable in the majority of patients. A high mRS score before treatment was a risk factor for poor outcomes.

DOI： 10.1016/j.jns.2025.123442

Peymani F, Ebihara T, Smirnov D, Kopajtich R, Ando M, Bertini E, Carrozzo R, Diodato D, Distelmaier F, Fang F, Ghezzi D, Hempel M, Iwanicka-Pronicka K, Klopstock T, Stenton SL, Lamperti C, Liu Z, Murtazina A, Okamoto Y, Okazaki Y, Piekutowska-Abramczuk D, Rötig A, Ryzhkova O, Schlein C, Shagina O, Takashima H, Tsygankova PG, Zech M, Meitinger T, Shimura M, Murayama K, Prokisch H . Pleiotropic effects of MORC2 derive from its epigenetic signature. . Brain : a journal of neurology 2025.4Pleiotropic effects of MORC2 derive from its epigenetic signature.

Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Chikashi Yano, Takahiro Hobara, Fumikazu Kojima, Yu Hiramatsu, Satoshi Nozuma, Tomonori Nakamura, Yusuke Sakiyama, Akihiro Hashiguchi, Yuji Okamoto, Takeshi Matsushige, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima . SOD1-related inherited peripheral neuropathies in a Japanese cohort: genetic variants and clinical insights. . Journal of neurology272 ( 3 ) 191 - 191 2025.3International journal

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

BACKGROUND: Inherited peripheral neuropathies (IPNs) encompass a wide range of disorders affecting the peripheral nervous system, often with complex genetic causes and frequent underdiagnosis. The variants in the superoxide dismutase 1 (SOD1) gene, primarily linked to amyotrophic lateral sclerosis (ALS), have also been associated with peripheral neuropathy. The recent approval of Tofersen, targeting SOD1-related ALS, highlights the importance of precise genetic diagnosis. This study explores the clinical and genetic profiles of SOD1-related IPNs (SOD1-IPN) in a nationwide Japanese IPN cohort. METHODS: Clinical and genetic data were assessed from 1483 Japanese patients with IPN, with a focus on those harboring SOD1 pathogenic variants. The clinical evaluations included age of onset, gender, muscle weakness patterns, sensory disturbances, reflex responses, and electrophysiological findings. RESULTS: Seventeen patients with SOD1 pathogenic variants were identified, reinforcing SOD1's role in IPN. The average onset age was 47, with a slight male predominance. Distal muscle weakness was noted in 9 of 13 patients, and asymmetric muscle weakness and atrophy in 10 of 14 cases. Mild sensory disturbances were observed in eight patients, with some showing hyperreflexia and abnormal reflexes. Electrophysiology predominantly indicated a length-dependent, motor-dominant axonal neuropathy. CONCLUSION: This study reveals the clinical variability and likely underdiagnosis of SOD1-IPN, supporting the integration of SOD1 screening in IPN genetic testing, especially for patients with asymmetric, length-dependent axonal neuropathy evident in clinical and electrophysiological assessments.

DOI： 10.1007/s00415-025-12925-4

Nozuma S., Matsuzaki T., Tanaka M., Kodama D., Dozono M., Yoshida T., Takashima H., Kubota R. . T-Cell Receptor/CD3 Downregulation and Impaired Signaling in HTLV-1-Infected CD4+ T Cells of HAM Patients . International Journal of Molecular Sciences26 ( 4 ) 2025.2

Language：Japanese Publisher：International Journal of Molecular Sciences

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with adult T-cell leukemia (ATL), a hematological malignancy, and HTLV-1-associated myelopathy (HAM), a progressive neurological disorder. HTLV-1 predominantly infects CD4+ T cells in vivo. The T-cell receptor (TCR)/CD3 complex on CD4+ helper T cells plays a pivotal role in immune responses by recognizing antigens and facilitating coordination with other immune cells. Dysfunction of the TCR/CD3 complex may impair immune function. Although CD3 downregulation has been identified as a characteristic of ATL cells, it remains uncertain whether a similar downregulation occurs in HTLV-1-infected cells from HAM patients. We hypothesized that HTLV-1 infection leads to TCR and CD3 downregulation, contributing to immune dysfunction in HAM patients. To test this hypothesis, we analyzed TCR/CD3 expression, TCR signaling, and immune responses in HTLV-1-infected cells from HAM patients. Intracellular HTLV-1 Tax detection revealed that HTLV-1 preferentially targets CD4+ over CD8+ T cells. CD3 and TCR expression levels were significantly lower in CD4+ T cells from HAM patients compared to healthy controls. Furthermore, HTLV-1-infected cells exhibited markedly reduced CD3 and TCR expression compared to uninfected cells. Impairments in TCR signaling, assessed through Lck and ZAP70 phosphorylation upon CD3 stimulation, were observed in CD4+ T cells from HAM patients compared to those from healthy controls. Notably, this reduction in TCR signaling was more pronounced in HTLV-1-infected CD4+ T cells than in uninfected CD4+ T cells in HAM patients. Additionally, cytomegalovirus (CMV)-specific CD4+ T cells detected by an addition of CMV antigens demonstrated reduced interferon-γ production in HTLV-1-infected cells compared to their uninfected counterparts. These findings suggest that TCR/CD3 downregulation and impaired TCR signaling contribute to immune dysfunction in HTLV-1-infected CD4+ T cells. As CD4+ T cells play a central role in immune responses, this mechanism may partially explain the cellular immune dysfunction to other pathogens observed in HAM patients.

DOI： 10.3390/ijms26041706

Hiyoshi M., Eltalkhawy Y.M., Abdelnaser R.A., Ono A., Monde K., Maeda Y., Mahmoud R.M., Takahashi N., Hatayama Y., Ryo A., Nozuma S., Takashima H., Kubota R., Suzu S. . M-Sec promotes the accumulation of intracellular HTLV-1 Gag puncta and the incorporation of Env into viral particles . PLoS Pathogens21 ( 1 ) e1012919 2025.1

Language：Japanese Publisher：PLoS Pathogens

We have demonstrated that the cellular protein M-Sec promotes the transmission of human T-cell leukemia virus type 1 (HTLV-1) in vitro and in vivo. Here, we show how HTLV-1 utilizes M-Sec for its efficient transmission. HTLV-1-infected CD4+ T cells expressed M-Sec at a higher level than uninfected CD4+ T cells. The ex vivo culture of the infected cells upregulated the expression of M-Sec, the level of which was sustained for a long time. The viral structural protein Gag is distributed in a punctate pattern in cells. M-Sec promoted the accumulation of large intracellular Gag puncta. This accumulation was dependent on phosphatidylinositol 4,5-bisphosphate (PIP2), since it was lost upon the removal of PIP2 binding motifs in M-Sec or the depletion of cellular PIP2. The viral envelope protein Env co-localized with the large Gag puncta induced by M-Sec. Furthermore, viral particles produced by M-Sec-expressing cells contained a higher amount of Env. Given that M-Sec alters the cellular distribution of PIP2, these results suggest that M-Sec promotes the formation of infectious viral particles through PIP2. Since the expression of M-Sec is mediated by HTLV-1 Tax protein, M-Sec appears to function in a positive feedback loop that ensures efficient HTLV-1 transmission.

DOI： 10.1371/journal.ppat.1012919

Sakiyama Y., Yuan J.H., Yoshimura A., Takeuchi M., Maki Y., Mori T., Takei J., Ando M., Hiramatsu Y., Nozuma S., Higuchi Y., Yonezawa H., Kirishima M., Suzuki M., Kano T., Tarisawa M., Hashiguchi S., Kunii M., Sato S., Takahashi-Iwata I., Hashiguchi A., Matsuura E., Izumo S., Tanimoto A., Takashima H. . Brain biopsy and metagenomic sequencing enhance aetiological diagnosis of encephalitis . Brain Communications7 ( 3 ) fcaf165 2025

Language：Japanese Publisher：Brain Communications

Identifying the aetiology of CNS diseases, regardless of their infectious or non-infectious nature, is often intricate. Next-generation sequencing (NGS) has emerged as a powerful tool for sensitive and unbiased screening of tissue or body fluid specimens. This study aimed to investigate the underlying aetiology of patients with suspected infectious CNS diseases. Between April 2013 and October 2021, we collected brain tissue samples from 33 patients diagnosed with encephalitis or encephalitis-like CNS diseases, obtained via biopsy or autopsy, and underwent metagenomic NGS (mNGS) in conjunction with pathological evaluations. Moreover, we employed PCR-based assays and pathogen-specific immunostaining to corroborate the presence of pathogens within the tissue samples. Among the 33 patients, mNGS elucidated pathogen-specific genomic sequences in 7 cases (21.2%), including halobacteria (archaea), Balamuthia mandrillaris, Epstein-Barr virus, Toxoplasma gondii and herpes simplex virus. Additionally, brain tissue mNGS ruled out known pathogens, identifying 14 cases (42.4%) of non-infectious CNS diseases, which included neoplastic, autoimmune/inflammatory and amyloid angiopathy conditions. The adjustment of therapeutic strategies based on these findings led to improvements in clinical symptoms, imaging outcomes and patient prognosis. Brain biopsy serves as both a direct pathological research target and a valuable source of samples for unbiased high-throughput sequencing. Our study illustrates the reliability of mNGS on brain tissue, which significantly improves the diagnostic rate for suspected encephalitis or encephalitis-like diseases of unknown aetiology. These findings underscore the importance of mNGS in guiding more precise and effective therapeutic interventions for patients in clinical practice.

DOI： 10.1093/braincomms/fcaf165

矢野直志, 中村友紀, 髙嶋博 . Charcot-Marie-Tooth病の電気生理 . 臨床神経生理学52 ( 6 ) 686 - 690 2024.12Charcot-Marie-Tooth病の電気生理

Language：Japanese Publisher：一般社団法人日本臨床神経生理学会

Charcot-Marie-Tooth病 (CMT) は遺伝性ニューロパチーの一つである。CMTでは遺伝子型と表現型の多様性が知られており, 臨床所見のみから原因遺伝子を予測することが難しく, CMTとCIDPとの鑑別に悩むケースも少なくない。加えてCMTの病態に炎症機序が重畳することで免疫治療に部分的に反応する症例もあり, 治療反応性を重視しすぎると診断の誤りを招くことがある。今回, 日本における主要なCMTサブタイプとして, PMP22重複, MPZ, GJB1, MFN2, MME変異の電気生理学的特徴について概説し, CIDPとの鑑別点を検討した。多くのCMTの原因遺伝子が明らかになり, 従来の伝導ブロックや時間的分散の有無による先天性と後天性の鑑別は困難となってきている。繰り返し言及される点だが, 最終診断は病歴, 臨床所見, 電気生理学的所見, 遺伝子解析も含め総合的に行う必要がある。

DOI： 10.11422/jscn.52.686

Takahiro Hobara, Yujiro Higuchi, Mari Yoshida, Masahito Suehara, Masahiro Ando, Jun-Hui Yuan, Akiko Yoshimura, Fumikazu Kojima, Eiji Matsuura, Yuji Okamoto, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima . Genetic and pathophysiological insights from autopsied patient with primary familial brain calcification: novel MYORG variants and astrocytic implications. . Acta neuropathologica communications12 ( 1 ) 136 - 136 2024.12International journal

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

Primary familial brain calcification (PFBC) is a genetic neurological disorder characterized by symmetric brain calcifications that manifest with variable neurological symptoms. This study aimed to explore the genetic basis of PFBC and elucidate the underlying pathophysiological mechanisms. Six patients from four pedigrees with brain calcification were enrolled. Whole-exome sequencing identified two novel homozygous variants, c.488G > T (p.W163L) and c.2135G > A (p.W712*), within the myogenesis regulating glycosidase (MYORG) gene. Cerebellar ataxia (n = 5) and pyramidal signs (n = 4) were predominant symptoms, with significant clinical heterogeneity noted even within the same family. An autopsy of one patient revealed extensive brainstem calcifications, sparing the cerebral cortex, and marked by calcifications predominantly in capillaries and arterioles. The pathological study suggested morphological alterations characterized by shortened foot processes within astrocytes in regions with pronounced calcification and decreased immunoreactivity of AQP4. The morphology of astrocytes in regions without calcification remains preserved. Neuronal loss and gliosis were observed in the basal ganglia, thalamus, brainstem, cerebellum, and dentate nucleus. Notably, olivary hypertrophy, a previously undescribed feature in MYORG-PFBC, was discovered. Neuroimaging showed reduced blood flow in the cerebellum, highlighting the extent of cerebellar involvement. Among perivascular cells constituting the blood-brain barrier (BBB) and neurovascular unit, MYORG is most highly expressed in astrocytes. Astrocytes are integral components of the BBB, and their dysfunction can precipitate BBB disruption, potentially leading to brain calcification and subsequent neuronal loss. This study presents two novel homozygous variants in the MYORG gene and highlights the pivotal role of astrocytes in the development of brain calcifications, providing insights into the pathophysiological mechanisms underlying PFBC associated with MYORG variants.

DOI： 10.1186/s40478-024-01847-3

Chikada A., Orimo K., Mitsui J., Matsukawa T., Ishiura H., Toda T., Mizusawa H., Takahashi Y., Katsuno M., Hara K., Onodera O., Ishihara T., Tada M., Kuwabara S., Sugiyama A., Yamanaka Y., Takahashi R., Sawamoto N., Sakato Y., Ishimoto T., Hanajima R., Watanabe Y., Takigawa H., Adachi T., Abe K., Yamashita T., Takashima H., Higashi K., Kira J., Yabe I., Matsushima M., Ogata K., Ishikawa K., Nishida Y., Ishiguro T., Ozaki K., Nagata T., Tsuji S. . The Japan MSA registry: A multicenter cohort study of multiple system atrophy . Neurology and Clinical Neuroscience12 ( 5 ) 271 - 277 2024.9

Language：Japanese Publisher：Neurology and Clinical Neuroscience

Background: Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic failure and various motor symptoms. While MSA-C (cerebellar type) predominates in East Asia, MSA-P (parkinsonian type) predominates in Europe and North America. This nationwide patient registry aimed to (1) conduct a prospective natural history study of MSA in Japan, (2) facilitate patient recruitment for clinical trials, and (3) deposit bioresources and clinical information in a biobank. Methods: Thirteen institutions participated in this study. Clinical information was obtained by neurologists from the patients visiting the hospital every 12 months to assess the UMSARS Part 2 scores and by telephone interviews by nurses every 6 months to assess UMSARS Part 1 scores and to determine whether clinical events had occurred. Results: Demographic data from 329 MSA patients (216 MSA-C and 113 MSA-P) were analyzed. The mean age at symptom onset was 58.2 years (standard deviation, 8.9); the mean duration of symptoms at enrollment was 3.5 years (standard deviation, 2.2). The mean 12-month changes in the UMSARS Part 1 and Part 2 scores were 7.9 (standard deviation, 5.6) and 6.4 (standard deviation, 5.9), respectively. The patient registry proved useful in recruiting participants for clinical trials, including those with gene variants. Clinical information and biospecimens were deposited in a biobank. Discussion: The study highlighted the importance of telephone interviews in minimizing drop-out rates in natural history studies and demonstrated similar MSA progression rates across populations. The deposited bioresources are available to researchers upon request, aiming to contribute to future MSA researches.

DOI： 10.1111/ncn3.12809

Chikada Ayaka, Orimo Kenta, Mitsui Jun, Matsukawa Takashi, Ishiura Hiroyuki, Toda Tatsushi, Mizusawa Hidehiro, Takahashi Yuji, Katsuno Masahisa, Hara Kazuhiro, Onodera Osamu, Ishihara Tomohiko, Tada Masayoshi, Kuwabara Satoshi, Sugiyama Atsuhiko, Yamanaka Yoshitaka, Takahashi Ryosuke, Sawamoto Nobukatsu, Sakato Yusuke, Ishimoto Tomoyuki, Hanajima Ritsuko, Watanabe Yasuhiro, Takigawa Hiroshi, Adachi Tadashi, Abe Koji, Yamashita Toru, Takashima Hiroshi, Higashi Keiko, Kira Junichi, Yabe Ichiro, Matsushima Masaaki, Ogata Katsuhisa, Ishikawa Kinya, Nishida Yoichiro, Ishiguro Taro, Ozaki Kokoro, Nagata Tetsuya, Tsuji Shoji . 日本のMSAレジストリ　多系統萎縮症の多施設コホート研究(The Japan MSA registry: A multicenter cohort study of multiple system atrophy) . Neurology and Clinical Neuroscience12 ( 5 ) 271 - 277 2024.9日本のMSAレジストリ　多系統萎縮症の多施設コホート研究(The Japan MSA registry: A multicenter cohort study of multiple system atrophy)

Language：English Publisher：(一社)日本神経学会

多系統萎縮症(MSA)レジストリを構築し、MSA患者の臨床的および疫学的特徴を評価した。本研究には13施設が参加した。臨床イベントの発生について、神経科医が12ヵ月毎の患者来院時にUMSARSパート2スコアを用いて、また看護師が6ヵ月毎に電話でUMSARSパート1スコアを用いて前向きに評価した。患者329例を解析した。小脳型(MSA-C)は216例、パーキンソン型(MSA-P)は113例で、症状発症時の平均年齢は58.2±8.9歳、登録時の症状の平均持続期間は3.5±2.2年であった。12ヵ月時点での脱落率はそれぞれ15.8%と48.6%、12ヵ月時点のUMSARSパート1スコアおよびパート2スコアの変化量はそれぞれ平均7.9±5.6点と6.4±5.9点であった。本レジストリでは遺伝子解析を行っていたため、COQ2変異を有する患者を対象とした臨床試験参加者の募集に役立った。臨床情報と生体標本はバイオバンクに保管された。以上より、MSA-CはMSAの約65%、MSA-Pは約35%で、脱落率を抑えるには電話によるインタビューが重要なことが示唆された。

Language：English Publisher：The Japanese Society of Internal Medicine

Spinocerebellar ataxia type 14 (SCA14) is a rare form of autosomal dominant cerebellar ataxia caused by mutations in PRKCG. We herein report a case of SCA14 presenting with writer's cramp that predated the onset of progressive ataxia by four years. A 47-year-old Japanese woman had an 11-year history of writer's cramps, followed by unsteadiness. Whole-exome sequencing revealed a heterozygous mutation in PRKCG (p.C142S), leading to an SCA14 diagnosis. Therefore, writer's cramp might be a characteristic extracerebellar sign of SCA14 and can precede the onset of cerebellar ataxia.

DOI： 10.2169/internalmedicine.2943-23

Ito Miwa, Sugiyama Atsuhiko, Higuchi Yujiro, Takashima Hiroshi, Takahashi Yuji, Mizusawa Hidehiro, Kuwabara Satoshi . Writer's Cramps as an Initial Symptom of Spinocerebellar Ataxia Type 14(タイトル和訳中) . Internal Medicine63 ( 15 ) 2183 - 2186 2024.8Writer's Cramps as an Initial Symptom of Spinocerebellar Ataxia Type 14(タイトル和訳中)

Language：English Publisher：(一社)日本内科学会

症例は47歳女性で、36歳時に緩徐進行性の筆記困難と不安定歩行を認めた。患者の母親は47歳時に脊髄小脳変性症と診断されていた。脳神経検査は正常であったが、円滑性追跡眼球運動は衝動性眼球運動により中断され、軽度の小脳性構音障害を認めた。運動検査では、筆記中の右手姿位が正常でなく、右親指手関節の過屈曲が認められた。深部腱反射および感覚系は正常であった。指追跡試験における右手のジストニア姿勢を伴う軽度ジスメトリア、踵脛試験における下肢協調不全も認められた。歩行は不安定で、タンデム歩行障害を認めた。表面筋電図検査では、筆記中に右長母指屈筋が長母指伸筋と共収縮することが明らかとなった。脳MRIで小脳萎縮が認められた。全エクソームシーケンシングで、PRKCG遺伝子のヘテロ接合体変異(p.C142S)が判明し、脊髄小脳失調症14型と診断した。同変異は患者の母親にも認められた。トリヘキシフェニジルとクロナゼパムによる治療を行った。その結果、軽度の改善が認められた。

Tanaka M., Takenouchi N., Arishima S., Matsuzaki T., Nozuma S., Matsuura E., Takashima H., Kubota R. . HLA-A*24 Increases the Risk of HTLV-1-Associated Myelopathy despite Reducing HTLV-1 Proviral Load . International Journal of Molecular Sciences25 ( 13 ) 2024.7

Language：Japanese Publisher：International Journal of Molecular Sciences

Increased human T-cell leukemia virus type 1 (HTLV-1) proviral load (PVL) is a significant risk factor for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is controversy surrounding whether HTLV-1-specific cytotoxic T lymphocytes (CTLs) are beneficial or harmful to HAM/TSP patients. Recently, HTLV-1 Tax 301–309 has been identified as an immunodominant epitope restricted to HLA-A*2402. We investigated whether HLA-A*24 reduces HTLV-1 PVL and the risk of HAM/TSP using blood samples from 152 HAM/TSP patients and 155 asymptomatic HTLV-1 carriers. The allele frequency of HLA-A*24 was higher in HAM/TSP patients than in asymptomatic HTLV-1 carriers (72.4% vs. 58.7%, odds ratio 1.84), and HLA-A*24-positive patients showed a 42% reduction in HTLV-1 PVL compared to negative patients. Furthermore, the PVL negatively correlated with the frequency of Tax 301–309-specific CTLs. These findings are opposite to the effects of HLA-A*02, which reduces HTLV-1 PVL and the risk of HAM/TSP. Therefore, we compared the functions of CTLs specific to Tax 11–19 or Tax 301–309, which are immunodominant epitopes restricted to HLA-A*0201 or HLA-A*2402, respectively. The maximum responses of these CTLs were not different in the production of IFN-γ and MIP-1β or in the expression of CD107a—a marker for the degranulation of cytotoxic molecules. However, Tax 301–309-specific CTLs demonstrated 50-fold higher T-cell avidity than Tax 11–19-specific CTLs, suggesting better antigen recognition at low expression levels of the antigens. These findings suggest that HLA-A*24, which induces sensitive HTLV-1-specific CTLs, increases the risk of HAM/TSP despite reducing HTLV-1 PVL.

DOI： 10.3390/ijms25136858

Kojima F., Okamoto Y., Ando M., Higuchi Y., Hobara T., Yuan J., Yoshimura A., Hashiguchi A., Matsuura E., Takashima H. . A novel homozygous HPDL variant in Japanese siblings with autosomal recessive hereditary spastic paraplegia: case report and literature review . Neurogenetics25 ( 2 ) 149 - 156 2024.4

Language：Japanese Publisher：Neurogenetics

Biallelic variants of 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) gene have been linked to neurodegenerative disorders ranging from severe neonatal encephalopathy to early-onset spastic paraplegia. We identified a novel homozygous variant, c.340G > T (p.Gly114Cys), in the HPDL gene in two siblings with autosomal recessive hereditary spastic paraplegia (HSP). Despite sharing the same likely pathogenic variant, the older sister had pure HSP, whereas her brother had severe and complicated HSP, accompanied by early-onset mental retardation and abnormalities in magnetic resonance imaging. Given the clinical heterogeneity and potential for treatable conditions in HPDL-related diseases, we emphasize the importance of genetic testing for the HPDL gene.

DOI： 10.1007/s10048-024-00746-y

Yoshimoto Yukiyo, Yoshimoto Shoko, Kakiuchi Kensuke, Miyagawa Rumina, Ota Shin, Hosokawa Takafumi, Ishida Shimon, Higuchi Yujiro, Hashiguchi Akihiro, Takashima Hiroshi, Arawaka Shigeki . 新規GJB1変異を伴うX連鎖性シャルコー・マリー・トゥース病における中枢神経系病変の空間的変動(Spatial Fluctuation of Central Nervous System Lesions in X-linked Charcot-Marie-Tooth Disease with a Novel GJB1 Mutation) . Internal Medicine63 ( 4 ) 571 - 576 2024.2新規GJB1変異を伴うX連鎖性シャルコー・マリー・トゥース病における中枢神経系病変の空間的変動(Spatial Fluctuation of Central Nervous System Lesions in X-linked Charcot-Marie-Tooth Disease with a Novel GJB1 Mutation)

Language：English Publisher：(一社)日本内科学会

症例は25歳男性で、7歳時に初回発作が出現し、頭部MRIのT2強調画像で頭頂葉と後頭葉の両側脳白質および脳梁膨大部に高信号域を認めた。13歳時に2回目の発作が出現し、MRIの拡散強調画像とT2強調画像で脳梁と頭頂葉の白質に高信号域を認めた。現症の発作では、歩行中に感覚障害と構音障害が出現し、地域病院に入院した。翌日に症状が悪化し、右上下肢の軽度筋力低下も認めたため、搬送されてきた。神経学的検査で見当識障害と右片麻痺が判明し、腱反射が完全に消失し、下肢の振動覚が低下していた。凹足も認めた。家族歴の聴取から、症例の弟がシャルコー・マリー・トゥース病(CMT)と診断されており、症例の母親が下垂足を有していることが判明した。DNA解析を行い、新規のギャップ結合β1(GJB1)変異(c.169C>T、p.Gln57*)が特定された。症例の母親と弟も同様の変異を有していたことから、新規GJB1変異を伴うX連鎖性CMT 1型と診断した。2週後の追跡MRIでは、拡散強調画像における白質の高信号域が消失し、脳梁膨大部に高信号域が出現していた。5ヵ月後、膨大部病変は完全に消失した。

Nozuma S., Yoshimura A., Pai S.C., Chen H.J., Matsuura E., Tanaka M., Kodama D., Dozono M., Matsuzaki T., Takashima H., Yang Y.C., Kubota R. . Geographic characteristics of HTLV-1 molecular subgroups and genetic substitutions in East Asia: Insights from complete genome sequencing of HTLV-1 strains isolated in Taiwan and Japan . PLoS Neglected Tropical Diseases18 ( 2 ) e0011928 2024.2

Language：Japanese Publisher：PLoS Neglected Tropical Diseases

Background Although Japan is a major endemic area for human T-lymphotropic virus type 1 (HTLV-1) and the virus has been well-studied in this region, there is limited research on HTLV-1 in sur-rounding regions. In this study, we determined the complete genome sequences of HTLV-1 strains isolated from Taiwan and Japan and investigated the geographic characteristics of molecular subgroups and substitution mutations to understand the spread of HTLV-1 and its correlation with human migration. Methodology/Principal findings The complete genome sequences of 26 HTLV-1 isolates from Taiwan were determined using next-generation sequencing and were compared with those of 211 isolates from Japan in terms of subgroup and genetic mutations. In total, 15/26 (58%) isolates from Taiwan belonged to the transcontinental subgroup and 11/26 (42%) isolates belonged to the Japanese subgroup. The transcontinental subgroup was significantly more prevalent among Taiwanese isolates than Japanese isolates (58% vs 18%, P < 0.0001). The mutation rate for the complete HTLV-1 sequence was as low as 0.2%. On examining individual base substitutions, the G-to-A mutation was predominant. Bayesian phylogenetic tree analysis estimated the time to the most recent common ancestor for the transcontinental and Japanese subgroups to be 28447 years. The transcontinental subgroups from Taiwan and Japan appeared to form clusters according to their respective regions.Conclusions/Significance The transcontinental subgroup of HTLV-1 is predominant in Taiwan, while the Japanese subgroup is common in Japan. The difference in subgroup distribution may be attributed to the initial spread of the transcontinental subgroup in East Asia, followed by the influx of the Japanese subgroup.

DOI： 10.1371/journal.pntd.0011928

Hamada Y., Matsuoka H., Sato S., Kawabata Y., Iwamoto K., Ikeda M., Sato T., Takaguchi G., Takashima H. . Combining the deployment of only the distal basket segment of the EMBOTRAP III and an aspiration catheter for M2 occlusions: the ONE-SEG technique . Frontiers in Neurology15 1424030 2024

Language：Japanese Publisher：Frontiers in Neurology

Background: Endovascular therapy (EVT) for distal medium vessel occlusions requires prioritizing effectiveness and safety. We developed a technique combining the deployment of only the distal basket segment of the EMBOTRAP III and an aspiration catheter (AC) for M2 occlusions, called the “ONE-SEG technique,” and evaluated its clinical and technical impacts. Methods: This was a retrospective review of 30 consecutive patients with M2 segment middle cerebral artery occlusion treated using the ONE-SEG technique. This method involves deploying the EMBOTRAP III through a microcatheter in only one segment and guiding the AC to the M2 origin or distal M1. The rates of final-pass expanded thrombolysis in cerebral infarction (eTICI) scores of 2c/3 or 2b/2c/3, safety (symptomatic intracranial hemorrhage [sICH]), and clinical outcomes (modified Rankin Scale [mRS] score 0–2, 0–3 at 90 days, and mortality at 90 days) were evaluated. Results: Of the 30 cases, 36.7% were female, and the mean age was 75.6 ± 11.0 years. The ONE-SEG technique was used for 17 cases (56.7%, median NIHSS 10 [5–15.5]) with primary M2 occlusion and 13 cases (43.3%, median NIHSS 20 [14–22.5]) with secondary M2 occlusion after proximal thrombus removal. The successful final reperfusion rate (eTICI 2b/2c/3) was 90% overall (27/30 cases). One case (3.3%) developed sICH with secondary M2 occlusion. At 3 months, mRS scores 0–2 were seen in 64.7% of patients with primary M2 occlusion (11/17 cases) and in 23.1% (3/13 cases) with secondary M2 occlusion. Conclusion: EVT using the ONE-SEG technique appears to be safe and effective for M2 occlusion.

DOI： 10.3389/fneur.2024.1424030

Takahiro Hobara, Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Fumikazu Kojima, Yutaka Noguchi, Jun Takei, Yu Hiramatsu, Satoshi Nozuma, Tomonori Nakamura, Tadashi Adachi, Keiko Toyooka, Toru Yamashita, Yusuke Sakiyama, Akihiro Hashiguchi, Eiji Matsuura, Yuji Okamoto, Hiroshi Takashima . Linking LRP12 CGG repeat expansion to inherited peripheral neuropathy. . Journal of neurology, neurosurgery, and psychiatry96 ( 2 ) 140 - 149 2024Reviewed International journal

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

BACKGROUND: The causative genes for over 60% of inherited peripheral neuropathy (IPN) remain unidentified. This study endeavours to enhance the genetic diagnostic rate in IPN cases by conducting screenings focused on non-coding repeat expansions. METHODS: We gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12, GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies. RESULTS: We identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12-oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases. CONCLUSION: We initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN.

DOI： 10.1136/jnnp-2024-333403

Kakumoto T., Orimo K., Matsukawa T., Mitsui J., Ishihara T., Onodera O., Suzuki Y., Morishita S., Tsuji S., Nagata T., Ozaki K., Ishiguro T., Nishida Y., Ishikawa K., Ogata K., Matsushima M., Yabe I., Kira J., Higashi K., Takashima H., Adachi T., Takigawa H., Watanabe Y., Hanajima R., Sawamoto N., Ishimoto T., Sakato Y., Takahashi R., Yamanaka Y., Sugiyama A., Kuwabara S., Tada M., Hara K., Katsuno M., Takahashi Y., Mizusawa H., Yamashita T., Abe K., Ishiura H., Toda T., Chikada A. . Frequency of FGF14 intronic GAA repeat expansion in patients with multiple system atrophy and undiagnosed ataxia in the Japanese population . European Journal of Human Genetics33 ( 3 ) 325 - 333 2024

Language：Japanese Publisher：European Journal of Human Genetics

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic nervous system dysfunction and cerebellar ataxia or parkinsonism. Recently, expanded GAA repeats (≥250 repeat units) in intron 1 of FGF14 have been shown to be responsible for spinocerebellar ataxia type 27B (SCA27B), a late-onset ataxia with an autosomal dominant inheritance. Patients with SCA27B may also exhibit autonomic nervous system dysfunction, potentially overlapping with the clinical presentations of MSA patients. In this study, to explore the possible involvement of expanded GAA repeats in MSA, we investigated the frequencies of expanded GAA repeats in FGF14 in 548 patients with MSA, 476 patients with undiagnosed ataxia, and 455 healthy individuals. To fully characterize the structures of the expanded GAA repeats, long-range PCR products suggesting the expansion of GAA repeats were further analyzed using a long-read sequencer. Of the 548 Japanese MSA patients, we identified one MSA patient (0.2%) carrying an expanded repeat with (GAA)≥250. Among the 476 individuals with undiagnosed ataxia, (GAA)≥250 was observed in six (1.3%); this frequency was higher than that in healthy individuals (0.2%). The clinical characteristics of the MSA patient with (GAA)≥250 were consistent with those of MSA, but not with SCA27B. Further research is warranted to explore the possibility of the potential association of expanded GAA repeats in FGF14 with MSA.

DOI： 10.1038/s41431-024-01743-3

Takashima Hiroshi . Brain localization of functional disorders including hysterical symptoms from the perspective of higher brain functions : A new neural anatomy and motor physiological model . Neurological Therapeutics41 ( 4 ) 634 - 641 2024Brain localization of functional disorders including hysterical symptoms from the perspective of higher brain functions : A new neural anatomy and motor physiological model

Language：Japanese Publisher：Japanese Society of Neurological Therapeutics

Hysterical symptoms, commonly referred to as functional neurological disorder, encompass various neurological manifestations not explainable by current neurology frameworks, suggesting involvement of psychogenic mechanisms. On the other hand, advances in neurophysiological anatomy have revealed that beyond the traditionally identified primary motor cortex (pyramidal tract), once regarded as the final output pathway, other essential output pathways have been functionally verified, such as the cortico–reticulospinal tract. Currently, motor output from the brain to the spinal cord should be considered through dual pathways. In this review, we elucidate hysterical symptoms through the prospective of a new functional brain anatomy paradigm that integrates motor output with dual pathways. Most hysterical motor symptoms can be attributed to disorders affecting the premotor cortex and supplementary motor area–reticulospinal tract. Since this cortico–reticular spinal tract is bilaterally innervated, symptoms arise from bilateral brain lesions. Bilateral abnormalities within this pathway are frequently identified through techniques such as 123I–IMP–SPECT or diffusion tensor imaging. In addition, the function of the reticular formation is considered to correlate with symptoms observed in PNES (psychogenic non–epileptic seizure), including impaired consciousness, tonic seizures of internal muscles, abnormalities in blood pressure and breathing, hypersensitivity to sound and light, as well as hyperalgesia. The origin of hysterical symptoms is primarily attributed to disorders involving the reticular formation and cortico–reticulospinal tract, caused by bilateral diffuse brain damage. Most hysterical symptoms could be explained through adept application of the new neurophysiological model, which delineates motor output into dual pathways. To comprehend complex brain symptoms, neurologists require an update of functional neurophysiological models.

DOI： 10.15082/jsnt.41.4_634

Nakahashi Takumi, Matsuura Ryuki, Kikuchi Kenjiro, Takeda Rikako, Takeuchi Hirokazu, Nonoyama Hazuki, Hirata Yuko, Koichihara Reiko, Hashiguchi Akihiro, Takashima Hiroshi, Hamano Shin-ichiro . A case of childhood Charcot-Marie-Tooth disease type 2A with nerve root enlargement in longitudinal evaluation of spinal MR neurography . NO TO HATTATSU56 ( 6 ) 427 - 431 2024

Language：Japanese Publisher：The Japanese Society of Child Neurology

A 7-years-old girl was admitted with the principal complaint of abnormal gait. She presented with distal muscle weakness, bilateral Achilles tendon reflex depression, and peripheral sensory disturbance. The results of the spinal cord magnetic resonance (MR) neurography were normal ; however, she had median nerve conduction disorders. As a genetic analysis revealed a mitofusin 2 mutation (c.718T＞G, p.F240V), she was diagnosed with Charcot-Marie-Tooth (CMT) type 2A. Despite continued physical therapy, her symptoms progressed slowly. At the age of 10 years and 4 months, she was unable to walk without support, and spinal MR neurography demonstrated bilateral nerve root enlargement in L2-5 regions. In children with CMT type 2A, the morphology of the spinal cord nerve root is not abnormal in the early stages, but nerve root enlargement may be observed as symptoms progress. Spinal MR neurography may be useful in evaluating disease activity.

DOI： 10.11251/ojjscn.56.427

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 2023.12

Language：English Publisher：The Japan Neurosurgical Society

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.

DOI： 10.2176/jns-nmc.2023-0071

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

Language：Japanese Publisher：BMC Musculoskeletal Disorders

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.

DOI： 10.1186/s12891-023-06461-3

Hamada Yuki, Miyashita Fumio, Matsuoka Hideki, Nishinakama Yuki, Kai Yusuke, Yamashita Yusuke, Ikeda Mei, Takaguchi Go, Masuda Keisuke, Kubo Fumikatsu, Takashima Hiroshi . 経上腕動脈および経橈骨動脈アプローチを併用した頸動脈ステント留置術における代替的近位保護法(Alternative Proximal Protection Method during Carotid Artery Stenting Using Combined Transbrachial and Transradial Artery Approaches) . NMC Case Report Journal10 ( 1 ) 273 - 278 2023.12経上腕動脈および経橈骨動脈アプローチを併用した頸動脈ステント留置術における代替的近位保護法(Alternative Proximal Protection Method during Carotid Artery Stenting Using Combined Transbrachial and Transradial Artery Approaches)

Language：English Publisher：(一社)日本脳神経外科学会

症例は67歳男性。頸動脈超音波検査で左内頸動脈の高度狭窄が偶然発見され、当院を受診した。高血圧、脂質異常症、腹部大動脈、慢性閉塞性肺疾患の既往があった。経上腕動脈および経橈骨動脈アプローチを用いて、左内頸動脈の高度狭窄に対する近位フローを伴う頸動脈ステント留置術を施行した。術後合併症は認められず、超音波検査でもプラークの突出はみられなかった。頸動脈ステント留置術施行5日後のCT血管造影で、上腕動脈および橈骨動脈に異常はみられなかった。最終的にmodified Rankin scale(mRS)スコア0点で退院した。退院後3ヵ月もmRSは依然として0のままであった。

Arimura Yoshihiro, Sobue Gen, Hattori Naoki, Takashima Hiroshi, Harigai Masayoshi, Nagata Koichi, Makino Hirofumi . 慢性末梢神経障害が残存する顕微鏡的多発血管炎に対する免疫グロブリン静注療法　多施設無作為化二重盲検試験(Intravenous immunoglobulin for chronic residual peripheral neuropathy in microscopic polyangiitis: A multicentre randomised double-blind trial) . Modern Rheumatology33 ( 6 ) 1125 - 1136 2023.11慢性末梢神経障害が残存する顕微鏡的多発血管炎に対する免疫グロブリン静注療法　多施設無作為化二重盲検試験(Intravenous immunoglobulin for chronic residual peripheral neuropathy in microscopic polyangiitis: A multicentre randomised double-blind trial)

Language：English Publisher：Oxford University Press

顕微鏡的多発血管炎に伴うグルココルチコイド抵抗性神経障害を有する患者に対する免疫グロブリン静注療法(IVIg)の有効性と安全性を評価する目的で、第III相多施設無作為化二重盲検プラセボ対照並行群間比較試験を実施した。37例をIVIg群(19例)またはプラセボ群(18例)に割り付け、第1週および第5週にIVIgまたはプラセボ投与を5日間行い、第9週はIVIg群にプラセボ投与、プラセボ群にIVIgを行った。有効性解析対象は36例(それぞれ19例、17例)であった。8週後(第9週の治療開始前)における徒手筋力テストの合計スコア変化量(最小二乗平均値)は、IVIg群で9.02、プラセボ群で6.71(群間差2.32、95%CI -2.60～7.23、p=0.345)、4週後(第5週の治療開始前)ではそれぞれ6.81、2.83(同3.99、-1.22～9.19、p=0.129)であり、IVIgにより合計スコアは改善したものの両群間に有意差は認めなかった。IVIg群において安全性に関する新たな懸念は認めなかった。

Nozuma Satoshi, Yuji-Takeuchi Mika, Nakamura Tomonori, Saigo Ryuji, Masuda Mirai, Ando Masahiro, Sakiyama Yusuke, Miyata Ryo, Tabata Kazuhiro, Matsuura Eiji, Takashima Hiroshi . 外科的介入前の免疫療法により改善した重症腫瘍随伴性グルタミン酸脱炭酸酵素抗体スペクトラム障害の1例(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 2023.11外科的介入前の免疫療法により改善した重症腫瘍随伴性グルタミン酸脱炭酸酵素抗体スペクトラム障害の1例(A case of severe paraneoplastic glutamic acid decarboxylase antibody-spectrum disorder with improvement through prior immunotherapy before surgical intervention)

Language：English Publisher：(一社)日本神経免疫学会

症例は65歳女性で、高血圧の既往があった。めまいとふらつき歩行を初発症状として呈していた。嚥下障害や歩行障害が悪化したため、発症12ヵ月後に入院となった。各種検査の結果、小脳失調とスティッフパーソン症候群を重複するGAD抗体-スペクトル障害と診断された。外科的介入は不可能と判断され、免疫療法が開始された。メチルプレドニゾロン静注および免疫グロブリン静注を含む免疫療法が実施され、神経症状は著しく改善した。しかし、経口プレドニゾロン(PSL)漸減により構音障害および歩行失調の悪化が認められた。発症27ヵ月後に胸腔鏡下胸腺摘出術が施行された。神経学的症状はさらに改善し、PSL漸減に成功した。

Makito Hirano, Motoi Kuwahara, Yuko Yamagishi, Makoto Samukawa, Kanako Fujii, Shoko Yamashita, Masahiro Ando, Nobuyuki Oka, Mamoru Nagano, Taro Matsui, Toshihide Takeuchi, Kazumasa Saigoh, Susumu Kusunoki, Hiroshi Takashima, Yoshitaka Nagai . CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy. . Scientific reports13 ( 1 ) 17801 - 17801 2023.10International journal

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

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.

DOI： 10.1038/s41598-023-45011-8

Nozaki Ichiro, Hashiguchi Akihiro, Takashima Hiroshi, Yamashita Yoko, Higashide Tomomi, Iwasa Kazuo, Ono Kenjiro . 視野欠損を認めたギャップジャンクションタンパクβ1の新規バリアントを伴うCharcot-Marie-Tooth病(Charcot-Marie-Tooth Disease with a Novel Variant in Gap Junction Protein Beta 1 Presenting with Visual Field Defects) . Internal Medicine62 ( 20 ) 3033 - 3036 2023.10視野欠損を認めたギャップジャンクションタンパクβ1の新規バリアントを伴うCharcot-Marie-Tooth病(Charcot-Marie-Tooth Disease with a Novel Variant in Gap Junction Protein Beta 1 Presenting with Visual Field Defects)

Language：English Publisher：(一社)日本内科学会

症例は45歳男性。12歳時に両側下肢遠位筋の筋力低下を認め、18歳時に握力低下を自覚した。症例の母親も手に軽度の筋力低下と萎縮を有していたことから、臨床所見と電気生理学的検査の所見をあわせ、遺伝性運動感覚多発神経障害と診断された。その後、症状が緩徐に悪化し、38歳時に健康診断で視神経乳頭陥凹の両側対称性縦拡大および網膜神経線維束欠損と診断された。両眼の視力は正常であったが、視野検査で視神経乳頭異常に一致する部分的視野欠損が明らかとなった。43歳時、両足関節不安定のために支えなしでの立位維持が困難となった。45歳時、神経学的検査で四肢の遠位筋萎縮、腱反射消失、振動覚低下が判明した。18歳時にCharcot-Marie-Tooth(CMT)病1型と診断されていたが、原因遺伝子が特定されていなかった。45歳時、64のCMT関連原因遺伝子における病的バリアントのスクリーニングを行い、ギャップジャンクションタンパクβ1に新規バリアント(c.173C>A[p.P58H])が判明した。

Numahata Kyoko, Sugawara Miki, Watanabe Kazuyoshi, Takizawa Yoshinori, Katayanagi Junya, Ogawa Tomohiro, Onoue Hiroyuki, Akaiwa Yasuhisa, Hashiguchi Akihiro, Takashima Hiroshi, Miyamoto Tomoyuki . 特発性側彎症に対する術中神経生理モニタリングで異常がみられ、Charcot-Marie-Tooth病1B型と診断された症例(A Case of Idiopathic Scoliosis with Intraoperative Neurophysiological Monitoring Abnormalities Leading to the Diagnosis of Charcot-Marie-Tooth Disease 1B) . Dokkyo Medical Journal2 ( 3 ) 245 - 250 2023.9特発性側彎症に対する術中神経生理モニタリングで異常がみられ、Charcot-Marie-Tooth病1B型と診断された症例(A Case of Idiopathic Scoliosis with Intraoperative Neurophysiological Monitoring Abnormalities Leading to the Diagnosis of Charcot-Marie-Tooth Disease 1B)

Language：English Publisher：獨協医学会

症例は16歳女児。特発性側彎症であり、当院整形外科で前方腰椎固定術が施行された。経頭蓋電気刺激運動誘発電位と体性感覚誘発電位を用いて術中神経生理モニタリング(IONM)が行われたが、異常所見が認められた。また、術後神経伝導検査でも異常所見がみられ、当科紹介となった。両側上下肢で腱反射が消失していた。ビタミンB1値が低く(17ng/mL)、右正中神経の運動および感覚神経伝導速度が顕著に減少しており、遠位潜時の延長と振幅の減少を伴っていた。Charcot-Marie-Tooth病(CMT)疑いのための遺伝子検査を行ったところ、ミエリンタンパク質ゼロ(MPZ)変異が同定され、CMT 1B型と診断した。患者の両親にはMPZ遺伝子に変異がみられなかったため、de novo変異と考えられた。

Language：English Publisher：The Japanese Society of Internal Medicine

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 ERCC6 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.

DOI： 10.2169/internalmedicine.0061-22

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)

Language：English Publisher：(一社)日本内科学会

症例1は50歳女性。30歳時から難聴と歩行不安定が出現し、緩徐に進行していた。症例の妹(症例2)も同様の症状を有していた。特徴的顔貌と小脳性運動失調を認め、ミニメンタルステート検査(MMSE)スコアは20/30、改訂長谷川式簡易知能評価スケール(HDS-R)スコアは20/30、運動失調評価スケール(SARA)スコアは9/40であった。遺伝子検査でERCC6遺伝子の複合ヘテロ接合体病的バリアント(c.1583G>A[p.G528E]、c.1873T>G[p.Y625D])が特定されたことから、Cockayne症候群BタイプIIIと診断した。症例2は48歳女性(症例1の妹)。30歳時から難聴と歩行不安定が出現していた。身体的所見、神経学的所見、生化学的所見、画像所見は症例1とほぼ同様で、SARAスコアは9/40、MMSEスコアは21/30、HDS-Rスコアは21/30であった。遺伝子検査でERCC6遺伝子の複合ヘテロ接合体病的バリアント(c.1583G>A[p.G528E]、c.1873T>G[p.Y625D])が特定されたことから、Cockayne症候群BタイプIIIと診断した。

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

Language：Japanese Publisher：Genes

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.

DOI： 10.3390/genes14071391

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

Language：Japanese Publisher：Pathogens

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.

DOI： 10.3390/pathogens12040592

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

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

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.

DOI： 10.1136/jnnp-2022-330769

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)

Language：English Publisher：(一社)日本内科学会

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

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

Language：English Publisher：The Japanese Society of Internal Medicine

Pathogenic variants in Gap Junction Protein Beta 1 (GJB1) 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 GJB1 gene. Patients with variants at codon 58 in GJB1 showed clinically varied phenotypes, ranging from demyelinating neuropathy to cerebellar ataxia. This patient may represent one of the various clinical phenotypes of GJB1 variants.

DOI： 10.2169/internalmedicine.1403-22

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

Language：English Publisher：Frontiers in Neurology

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

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

Language：English Publisher：Frontiers in Neurology

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

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

Language：Japanese Publisher：JCI Insight

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

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

Language：Japanese Publisher：eClinicalMedicine

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

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

Language：Japanese Publisher：Japanese Society of Neurological Therapeutics

The discovery and approval of novel treatments and vaccines are altering the trajectory of neuroinfectious illnesses.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.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.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.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.There is also disagreement over the effectiveness of long–term SARS–CoV–2 vaccines, and further understanding of the etiology is preferred.

DOI： 10.15082/jsnt.40.2_99

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

Language：Japanese Publisher：Societas Neurologica Japonica

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.

DOI： 10.5692/clinicalneurol.cn-001822

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 GJB1 Mutation . Internal Medicineadvpub ( 0 ) 571 - 576 2023

Language：English Publisher：The Japanese Society of Internal Medicine

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1), the most common form of CMTX, is caused by gap-junction beta 1 (GJB1) 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 GJB1 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.

DOI： 10.2169/internalmedicine.1713-23

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

Language：Japanese Publisher：Frontiers in Neurology

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

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 System28 ( 4 ) 597 - 607 2023

Language：Japanese Publisher：Journal of the Peripheral Nervous System

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.

DOI： 10.1111/jns.12590

Masuda Aiko, Hamada Yuki, Matsuoka Hideki, Takashima Hiroshi . Eagle Syndrome Induced by the Head Retroflexion . Internal Medicineadvpub ( 0 ) 1669 - 1670 2023

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 Neurology271 ( 1 ) 419 - 430 2023

Language：Japanese Publisher：Journal of Neurology

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.

DOI： 10.1007/s00415-023-11998-3

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 2023

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>T) characterized by higher brain dysfunction followed by neuropathy, presented gadolinium enhancement on brain imaging in an adult patient . Frontiers in Neurology14 1187822 2023

Language：Japanese Publisher：Frontiers in Neurology

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.

DOI： 10.3389/fneur.2023.1187822

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

Language：Japanese Publisher：Clinical and Experimental Neuroimmunology

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.

DOI： 10.1111/cen3.12764

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 ) 245 - 250 2023

Language：English Publisher：Dokkyo Medical Society

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 (MPZ) 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.

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 MME gene mutation . Rinsho Shinkeigaku63 ( 11 ) 743 - 747 2023

Language：Japanese Publisher：Societas Neurologica Japonica

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 MME 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 MME mutation. This represents the first documented occurrence of cyanosis as a distinctive feature of CMT with MME mutation.

DOI： 10.5692/clinicalneurol.cn-001870

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―

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 Bcl2-Associated Athanogene 3 (BAG3) mutation complicated by peripheral neuropathy . Rinsho Shinkeigakuadvpub ( 0 ) 836 - 842 2023

Language：Japanese Publisher：Societas Neurologica Japonica

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 Bcl2-Associated Athanogene 3 (BAG3), 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.

DOI： 10.5692/clinicalneurol.cn-001915

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

Language：Japanese Publisher：Annals of Clinical and Translational Neurology

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

Language：Japanese Publisher：Annals of Clinical and Translational Neurology

DOI： 10.1002/acn3.51936

Higuchi Yujiro, Takashima Hiroshi . Review/Advances in Neurological Therapeutics (2022). Spinocerebellar degeneration . Neurological Therapeutics40 ( 5 ) 707 - 711 2023Review/Advances in Neurological Therapeutics (2022). Spinocerebellar degenerationReviewed

Language：Japanese Publisher：Japanese Society of Neurological Therapeutics

We will review the recent therapeutic advances in spinocerebellar degeneration (SCD) that were published in 2022. This article provides an overview of therapies including riluzole/troriluzole, omaveloxolone, mesenchymal stem cells, Coenzyme Q10, erythropoietin, cinpanemab, prasinezumab, cerebello–spinal transcranial direct current stimulation (tDCS), and rehabilitation. We anticipate that these treatments will contribute to improving motor dysfunction and ataxia in patients with cerebellar disorders.

DOI： 10.15082/jsnt.40.5_707

Abe Chihiro, Mori Masato, Kohashi Kousuke, Hiramoto Ryugo, Higuchi Yujiro, Hashiguchi Akihiro, Takashima Hiroshi . Neurodevelopmental disorder accompanying hereditary motor and sensory neuropathy due to GNB4 variant . NO TO HATTATSU55 ( 6 ) 448 - 451 2023

Language：Japanese Publisher：The Japanese Society of Child Neurology

Among the many reported etiologic genes for hereditary motor-sensory neuropathy, the GNB4 variant has been rarely reported, with only one case reported in a Japanese family. We present the case of a 14-year-old girl with hereditary motor-sensory neuropathy who was diagnosed as having a GNB4 variant after proper examination. Her chief complaints were repeated falls and learning difficulties. She had been diagnosed with tethered spinal cord syndrome due to a terminal filum lipoma at the age of 8 years and had undergone untethering surgery, but her tendency to fall and poor academic performance had not improved. No notable findings were observed in the cerebral neurological examination, but the patient had weakness of the anterior cervical muscles and decreased sensation in the S1 area. Blood tests and MRI of the head and spinal cord showed no abnormalities. Nerve conduction studies revealed decreased nerve conduction velocity with lower extremity predominance. Genetic analysis showed no duplication or deletion of PMP22, but a heterozygous variant was found in GNB4 gene (NM_021629.4 : c.229G＞A, p.Gly77Arg) by the etiological gene analysis for Charcot-Marie-Tooth disease. This is a de novo variant that has not been included in any database ; the same variant was not found in the parents. Her intelligence quotient scores by the WISC-IV were in the borderline range. There was variability in each item, with especially low scores in perceptual reasoning. Although few studies have reported on GNB4 variants and no association with neurodevelopmental disorders, it is necessary to compile more cases because GNB4 variants may be related to the symptoms of the central nervous system.

DOI： 10.11251/ojjscn.55.448

Yoshida T., Watanabe O., Nomura M., Yoshimoto Y., Maki Y., Takashima H. . Neuromyelitis optica spectrum disorder safely and successfully treated with satralizumab during pregnancy and breastfeeding: a case report . Frontiers in Neurology14 1322412 2023

Language：Japanese Publisher：Frontiers in Neurology

Background: Satralizumab, a monoclonal antibody that recognizes interleukin-6 receptors, is known to reduce the relapse rate in neuromyelitis optica spectrum disorder (NMOSD), but its safety during pregnancy has not been established. We present the case of an NMOSD patient who safely completed pregnancy, parturition, and breastfeeding under satralizumab treatment. Importantly, satralizumab transfer to umbilical cord blood, infant serum, or breast milk was not observed. Case presentation: A 37-year-old Japanese female developed anti-aquaporin 4 antibody-positive NMOSD with left optic neuritis. Despite responding to steroid and azathioprine therapy, she experienced moon face and weight gain and desired the prompt reduction of the steroid dosage. She also wanted to conceive a child with a safe and preferably early pregnancy and parturition. Because pregnancy and parturition after the onset of NMOSD elevate the risk of relapse and miscarriage, treatment with satralizumab was initiated with the patient's consent. She experienced normal parturition and continued with satralizumab, steroid, and azathioprine treatments while breastfeeding without experiencing any relapses. Concentrations of satralizumab in the umbilical cord blood, infant serum, and breast milk were below the detection sensitivity. Conclusion: These findings suggest that satralizumab may be safe and effective for the perinatal management of NMOSD, especially when there are concerns about continuing pregnancy and the risk of relapse after parturition.

DOI： 10.3389/fneur.2023.1322412

樋口雄二郎, 髙嶋博 . 第1土曜特集遺伝性神経･筋疾患--診療と研究の最前線その他の神経･筋疾患の病態･診断･治療法開発遺伝性ニューロパチーの遺伝子診断 . 医学のあゆみ283 ( 10 ) 1038 - 1045 2022.12第1土曜特集遺伝性神経･筋疾患--診療と研究の最前線その他の神経･筋疾患の病態･診断･治療法開発遺伝性ニューロパチーの遺伝子診断

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

Language：Japanese Publisher：Journal of Neurology

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

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

Language：English Publisher：Modern Rheumatology

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

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

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)

Language：English Publisher：(一社)日本神経学会

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。

Muguruma K., Sugimoto T., Terada Y., Yuan J., Nomura E., Takashima H., Yamawaki T., Kohriyama T., Maruyama H. . A case of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: Long-term treatment with repeated courses of immunotherapy . Neurology and Clinical Neuroscience10 ( 6 ) 321 - 324 2022.11

Language：Japanese Publisher：Neurology and Clinical Neuroscience

We present here the case of a 48-year-old man who first developed retinopathy, and motor deficit and aphasia occurred 8 years later. A tumor-like lesion was seen by brain MRI. He was diagnosed with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) because a three prime repair exonuclease 1 (TREX1) gene abnormality was identified. After intravenous methylprednisolone pulse (IVMP) and intravenous immunoglobulin (IVIg) therapy, cerebrospinal fluid (CSF) test results and clinical manifestations improved. However, a new lesion appeared 3 years later. Immunotherapy became ineffective, and repeated relapses occurred. We evaluated the results of laboratory tests and brain MRI for 6 years after the first treatment. Coagulation tests, including measurements of vWF activity, remained high, so immunotherapy was thought to have a limited effect.

DOI： 10.1111/ncn3.12664

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

Language：Japanese Publisher：Journal of the American Heart Association

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

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)

Language：English Publisher：(一社)日本神経学会

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。

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)

Language：English Publisher：(一社)日本神経学会

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 C., Taira Y., Sasaki R., Matsumoto N., Tadokoro K., Nomura E., Kawahara Y., Takemoto M., Morihara R., Hashiguchi A., Takashima H., Takeuchi H., Araki M., Abe K., Yamashita T. . A case of successful renal transplantation of Charcot-Marie-Tooth disease associated with FSGS due to mutation of the INF2 gene . Neurology and Clinical Neuroscience10 ( 5 ) 252 - 254 2022.9

Language：Japanese Publisher：Neurology and Clinical Neuroscience

Focal and segmental areas of glomerular sclerosis (FSGS) have various subcategories. Here, we report on a 35-year-old man who suffered from Charcot-Marie-Tooth disease (CMT) with FSGS carrying the INF2 mutation (c.206 T > C, p.L69P). The INF2 mutation might cause abnormal actin filaments of the podocytes and Schwann cells, leading to CMT associated with FSGS. He successfully underwent living donor kidney transplantation from a mother with a normal INF2 gene without any serious adverse events. Following genetic testing, the identification of the INF2 mutation allows a recipient to reduce the use of immunosuppressive drugs. Genetic testing may provide a treatment plan for kidney transplantation.

DOI： 10.1111/ncn3.12651

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

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

Charcot–Marie–Tooth disease type 2Z (CMT2Z) shows highly variable clinical features. We report the first Japanese CMT2Z patient with a c.754C>T (p.R252W) substitution of the MORC2 gene, complicating severe retinitis pigmentosa. The MORC2 mutants were involved in a decrease in cell survival through induction of apoptosis. Thus, the MORC2 mutation might be involved in the degeneration of photoreceptors and the development of retinitis pigmentosa.

DOI： 10.1111/ncn3.12660

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

Language：Japanese Publisher：Frontiers in Neurology

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

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)

Language：English Publisher：Nature Publishing Group

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。

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

Language：Japanese Publisher：Annals of Clinical and Translational Neurology

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

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

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

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.

DOI： 10.3390/biomedicines10071546

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

Language：Japanese Publisher：The Japanese Congress on Neurological Emergencies

Patients with splenic hypoplasia are more susceptible to infections with capsular bacteria such as Streptococcus pneumoniae 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.

DOI： 10.11170/jjsnecc.34.2_21

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)

Language：English Publisher：Nature Publishing Group

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。

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)

Language：English Publisher：(一社)日本内科学会

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)

Language：English Publisher：(一社)日本内科学会

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。

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

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

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

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

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

Language：English Publisher：The Japanese Society of Internal Medicine

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.

DOI： 10.2169/internalmedicine.9326-22

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

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

<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

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

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

Language：Japanese Publisher：Japanese Society of Neurological Therapeutics

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.

DOI： 10.15082/jsnt.39.5_773

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

Language：Japanese Publisher：Japanese Society of Neurological Therapeutics

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.

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

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

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

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

Language：Japanese Publisher：The Japanese Society of Child Neurology

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 GJB1 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.

DOI： 10.11251/ojjscn.54.56

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

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

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

Language：Japanese Publisher：Journal of Clinical 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

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

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

DOI： 10.1128/JCM.03230-20

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

Publishing type：Research paper (scientific journal)

DOI： 10.1128/JCM.03230-20

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.

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/l . Nihon Naika Gakkai Zasshi110 ( 3 ) 598 - 604 2021.3

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

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

Language：English Publisher：The Japanese Society of Internal Medicine

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.

DOI： 10.2169/internalmedicine.4629-20

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

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)

Language：English Publisher：(一社)日本救急医学会

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

Publishing type：Research paper (scientific journal)

Publishing type：Research paper (scientific journal)

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

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.

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

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

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.

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

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

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

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

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)

Publisher：エルゼビア・ジャパン(株)

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

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.

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)

Publisher：(一社)日本内科学会

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。

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

Language：Japanese Publisher：The Japanese Society of Child Neurology

SUCLA2-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＊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 SUCLA2-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.

DOI： 10.11251/ojjscn.52.318

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 AP5Z1 gene . Rinsho Shinkeigaku60 ( 8 ) 543 - 548 2020Reviewed

Language：Japanese Publisher：Societas Neurologica Japonica

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 (AP5Z1), 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 AP5Z1, 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.

DOI： 10.5692/clinicalneurol.60.cn-001419

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

Language：Japanese Publisher：Japanese Society for Neuroinfectious Diseases

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.

DOI： 10.34397/jsnd.25.1_146

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

Language：Japanese Publisher：Societas Neurologica Japonica

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 (SETX). Although SETX is a causative gene of familial amyotrophic lateral sclerosis type 4 (ALS4), this case suggests that SETX mutation can also cause motor and sensory polyneuropathy.

DOI： 10.5692/clinicalneurol.60.cn-001415

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

Language：Japanese Publisher：THE JAPAN DIABETES SOCIETY

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.

DOI： 10.11213/tonyobyo.63.344

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

Language：Japanese Publisher：Societas Neurologica Japonica

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.

DOI： 10.5692/clinicalneurol.cn-001493

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

Language：Japanese Publisher：Japanese Society of Clinical Neurophysiology

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 GJB1. The diagnosis of CMTX1 was made. His symptom improved again after second IVIg, and then, repeated IVIg maintained his symptoms.

DOI： 10.11422/jscn.48.8

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

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

Language：Japanese Publisher：Japanese Society of Neurological Therapeutics

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.

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

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

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.

DOI： 10.1002/mus.26683

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)

Publisher：(一社)日本内科学会

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。

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)

Publisher：兵庫医科大学医学会

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

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

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

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

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)

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

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

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

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)

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)

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

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

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

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

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

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

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)

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

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

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

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

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

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

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.

DOI： 10.1016/j.braindev.2017.08.004

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)

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

Language：English Publisher：(一社)日本内科学会

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

Language：English Publisher：エルゼビア・ジャパン(株)

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

Publisher：Nature Publishing Group

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.

DOI： 10.1038/s10038-017-0353-3

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

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

Language：English Publisher：Nature Publishing Group

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

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

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.

DOI： 10.2169/internalmedicine.8765-16

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

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

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Societas Neurologica Japonica

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 GJB1 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 GJB1 was identified. CMTX1 patients should be advised to avoid excessive drinking because this could induce central nervous system lesions.

DOI： 10.5692/clinicalneurol.cn-001130

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 GJB1 gene: case report of a female patient . Rinsho Shinkeigaku58 ( 5 ) 302 - 307 2018Reviewed

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Societas Neurologica Japonica

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.

DOI： 10.5692/clinicalneurol.cn-001138

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

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

Language：Japanese Publisher：Societas Neurologica Japonica

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/mm3, predominantly mononuclear cells) and elevated cerebrospinal fluid (CSF) IL-6 levels (213 pg/ml), 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/ml) 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.

DOI： 10.5692/clinicalneurol.cn-001086

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

Language：Japanese Publisher：Japanese Society of Neurological Therapeutics

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.

DOI： 10.15082/jsnt.35.5_605

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

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

Language：English Publisher：BIOMED CENTRAL LTD

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.

DOI： 10.1186/s12985-017-0902-6

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

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

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 <1,108 mg/dl had significantly poorer outcomes. We suggest that mEGOS, EGRIS, and IgG in GBS are clinically relevant in Japan.

DOI： 10.1111/jns.12234

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].

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

Publisher：ELSEVIER SCI LTD

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.

DOI： 10.1016/j.parkreldis.2017.08.012

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

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

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.

DOI： 10.1186/s12985-017-0802-9

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 > A mutation in two independent Japanese families . JOURNAL OF THE NEUROLOGICAL SCIENCES378 177 - 181 2017.7Reviewed International journal

Publisher：ELSEVIER SCIENCE BV

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 > 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 > A mutation, and the sporadic case showed heteroplasmy of the same mutation. Additionally, all three cases harbored the 14605A > 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.

DOI： 10.1016/j.jns.2017.05.015

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

Language：English Publisher：WILEY

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.

DOI： 10.1111/gtc.12500

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

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

Language：English Publisher：BIOMED CENTRAL LTD

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 < 0.001) and s-HAM/TSP (p < 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.

DOI： 10.1186/s12977-017-0350-9

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

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

Language：English Publisher：ELSEVIER SCIENCE BV

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

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

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

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

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

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

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

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

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

Authorship：Last author Publisher：Societas Neurologica Japonica

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 (SETX) 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.

DOI： 10.5692/clinicalneurol.cn-000996

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

Language：Japanese Publisher：Societas Neurologica Japonica

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 MME 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 MME 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 MME 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.

DOI： 10.5692/clinicalneurol.cn-001036

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

Language：Japanese Publisher：Societas Neurologica Japonica

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 HADHB. Mitochondrial trifunctional protein (MTP) deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid beta-oxidation caused by HADHA or HADHB 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.

DOI： 10.5692/clinicalneurol.cn-000976