Faculty Profiles - TAKASHIMA Hiroshi

Papers - TAKASHIMA Hiroshi

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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

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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

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Language：Japanese Publisher：Annals of Clinical and Translational Neurology

DOI： 10.1002/acn3.51936

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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<TAKASHIMA Hiroshi>

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