Faculty Profiles - TAKASHIMA Hiroshi

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

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

DOI： 10.15082/jsnt.35.4_536

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

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