Faculty Profiles - TAKASHIMA Hiroshi

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

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

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 2023Reviewed

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

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

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

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

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 2022.11

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