Faculty Profiles - TAKASHIMA Hiroshi

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

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

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

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 . Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case Series . Internal Medicine 58 ( 23 ) 3369 - 3378 2019.12Reviewed

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

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 2019.9

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