Faculty Profiles - TAKASHIMA Hiroshi

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

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 2018.2Reviewed 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 2018.2Reviewed 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 2018.1Reviewed

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 2018.1Reviewed 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

Web of Science

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

Web of Science