Faculty Profiles - TAKASHIMA Hiroshi

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

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

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

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 2022.7

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。

Masahiro Ando, Yujiro Higuchi, Junhui Yuan, Akiko Yoshimura, Takaki Taniguchi, Fumikazu Kojima, Yutaka Noguchi, Takahiro Hobara, Mika Takeuchi, Jun Takei, Yu Hiramatsu, Yusuke Sakiyama, Akihiro Hashiguchi, Yuji Okamoto, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroshi Takashima . Comprehensive Genetic Analyses of Inherited Peripheral Neuropathies in Japan: Making Early Diagnosis Possible. . Biomedicines10 ( 7 ) 2022.6International journal

Language：English Publishing type：Research paper (scientific journal)

Various genomic variants were linked to inherited peripheral neuropathies (IPNs), including large duplication/deletion and repeat expansion, making genetic diagnosis challenging. This large case series aimed to identify the genetic characteristics of Japanese patients with IPNs. We collected data on 2695 IPN cases throughout Japan, in which PMP22 copy number variation (CNV) was pre-excluded. Genetic analyses were performed using DNA microarrays, next-generation sequencing-based gene panel sequencing, whole-exome sequencing, CNV analysis, and RFC1 repeat expansion analysis. The overall diagnostic rate and the genetic spectrum of patients were summarized. We identified 909 cases with suspected IPNs, pathogenic or likely pathogenic variants. The most common causative genes were MFN2, GJB1, MPZ, and MME. MFN2 was the most common cause for early-onset patients, whereas GJB1 and MPZ were the leading causes of middle-onset and late-onset patients, respectively. Meanwhile, GJB1 and MFN2 were leading causes for demyelinating and axonal subtypes, respectively. Additionally, we identified CNVs in MPZ and GJB1 genes and RFC1 repeat expansions. Comprehensive genetic analyses explicitly demonstrated the genetic basis of our IPN case series. A further understanding of the clinical characteristics of IPN and genetic spectrum would assist in developing efficient genetic testing strategies and facilitate early diagnosis.

DOI： 10.3390/biomedicines10071546

Take Yoshito, Hiramatsu Yu, Yoshimoto Yusuke, Yoshida Takashi, Tanaka Sakie, Ueyama Misa, Iwata Hiroki, Imada Minako, Takahata Katsunori, Ando Masahiro, Tashiro Yuichi, Sakiyama Yusuke, Arata Hitoshi, Matsuura Eiji, Takashima Hiroshi . A case of pneumococcal meningitis complicated by intervertebral discitis, spinal epidural abscess, and paravertebral abscess with splenic hypoplasia . Journal of Japan Society of Neurological Emergencies & Critical Care34 ( 2 ) 21 - 25 2022.6

Language：Japanese Publisher：The Japanese Congress on Neurological Emergencies

<p>Patients with splenic hypoplasia are more susceptible to infections with capsular bacteria such as <i>Streptococcus pneumoniae</i> and are more likely to develop severe infections, including bacterial meningitis. Here, we report the case of a 62-year-old male who was transferred to our hospital by emergency transport due to worsening headache and bilateral deafness. Based on the results of cerebrospinal fluid tests, the patient was diagnosed with pneumococcal meningitis and was started on antibiotic treatment. Computed tomography showed hypoplastic spleen and low levels of IgM and IgG, suggesting that hyposplenism was involved in the patient’s pneumococcal infection. Despite the administration of appropriate antibiotics, the patient developed recurrent fever and back pain; subsequent magnetic resonance imaging scans showed intervertebral discitis, spinal epidural abscess, and paravertebral abscess. After administration of intravenous immunoglobulin and subsequent vancomycin (6 weeks), and oral amoxicillin (3 weeks), symptoms and imaging findings improved and the patient was discharged on day 66. There are several reports in the literature of splenic hypoplasia associated with aggravation of pneumococcal infection and abscess formation. In cases of splenic hypoplasia, active treatment and periodic abscess search are key factors, as is a vaccination to prevent infections.</p>

DOI： 10.11170/jjsnecc.34.2_21

Shirakawa Shunichi, Murakami Tatsufumi, Hashiguchi Akihiro, Takashima Hiroshi, Hasegawa Hiroshi, Ichida Kimiyoshi, Sunada Yoshihide . 日本人CMTX5患者における新規PRPS1変異(A Novel PRPS1 Mutation in a Japanese Patient with CMTX5) . Internal Medicine61 ( 11 ) 1749 - 1751 2022.6

Language：English Publisher：(一社)日本内科学会

症例は33歳男性で、先天性両側聴力障害を有し、3歳まで歩行の遅延が認められ、11歳時に視力低下が判明した。高校生までは短下肢装具で歩行できたが、その後は車椅子使用となった。30歳まではパソコンや携帯電話を使用できたが、視力が徐々に低下し、両側視神経萎縮が判明したため、確定診断のために入院した。神経学的検査により、両側視神経萎縮と聴力障害が明らかとなった。猿手と鷲手、凹足変形、四肢の遠位筋萎縮を認め、徒手筋力検査では遠位筋の筋力低下が示された。下肢遠位に感覚鈍麻があり、足関節の振動覚がなく、爪先の位置覚が障害されていた。四肢の腱反射は低下していた。血清クレアチンキナーゼ値が1118U/Lに上昇していた。神経伝導検査により、重度の運動感覚性ニューロパチーが判明した。Charcot-Marie-Tooth病についての遺伝子検査を行い、PRPS1遺伝子の新規半接合変異c82 G>C(p.G28R)が特定された。赤血球ホスホリボシルピロリン酸合成酵素1の酵素活性が著明に低下していた。

Taniguchi Takaki, Ando Masahiro, Okamoto Yuji, Yoshimura Akiko, Higuchi Yujiro, Hashiguchi Akihiro, Matsuda Nozomu, Yamamoto Mamoru, Dohi Eisuke, Takahashi Makoto, Yoshino Masanao, Nomura Taichi, Matsushima Masaaki, Yabe Ichiro, Sanpei Yui, Ishiura Hiroyuki, Mitsui Jun, Nakagawa Masanori, Tsuji Shoji, Takashima Hiroshi . Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments(タイトル和訳中) . Journal of Human Genetics67 ( 6 ) 353 - 362 2022.6

Language：English Publisher：Nature Publishing Group

遺伝性トランスサイレチン(ATTRv)アミロイドーシス患者では、発症時にCharcot-Marie-Tooth病(CMT)と誤診される症例が一定数存在することから、CMT疑い患者に対し効率的な治療を行うには、トランスサイレチン(TTR)遺伝子検査が不可欠か検討した。2007年4月～2019年6月までの期間内に、CMT疑診例2133例を対象とした横断研究を行い、遺伝子検査でATTRvアミロイドーシスが確認された患者10例と、CMT患者489例の臨床所見、髄液所見ならびに電気生理学所見を比較した。その結果、神経症状の発症年齢中央値はATTRvアミロイドーシ患者が69歳、CMT患者が12歳で、初期症状として感覚障害を呈した患者の割合は、ATTRvアミロイドーシス患者では70%、CMT患者では7.1%であった。また、慢性炎症性脱髄性多発根神経炎(CIDP)疑いの既往歴を有する患者の割合はATTRvアミロイドーシス患者では50%、CMT患者では8.7%で、遺伝子検査後に進行が認められたATTRvアミロイドーシス患者6例のうち、薬物治療や遺伝子治療を受けた5例は、いずれも生存例であることも確認された。以上より、発症時の神経症状や初期の感覚障害、CIDP疑い既往歴を有するCMT疑診例の高齢患者に効果的な治療を行うには、TTR遺伝子検査が不可欠と結論付けられた。

Kimura Yasuyoshi, Nishikawa Akira, Hashiguchi Akihiro, Etoh Masaki, Yoshimura Akiko, Asai Kanako, Miyashita Noriko, Takashima Hiroshi, Sumi Hisae, Naka Takashi . 視神経萎縮、神経因性膀胱機能障害、横隔膜筋力低下を認めるMFN2関連Charcot-Marie-Tooth病患者の1例(An MFN2-related Charcot-Marie-Tooth Disease Patient with Optic Nerve Atrophy, Neurogenic Bladder Dysfunction, and Diaphragmatic Weakness) . Internal Medicine61 ( 11 ) 1743 - 1747 2022.6

Language：English Publisher：(一社)日本内科学会

症例は64歳女性で、緩徐進行型筋力低下、脊柱側彎症、視神経萎縮、神経因性膀胱による尿失禁、便秘、横隔膜弛緩症を伴う拘束性肺機能障害を認めた。47歳時に神経学的検査、眼科検査、聴覚検査、複合筋活動電位と知覚神経活動電位(SNAP)の評価、筋電図検査、脳MRIを行い、臨床的にCharcot-Marie-Tooth病(CMT)と診断した。62歳時に呼吸困難が出現し、CMTの横隔神経浸潤によると思われる拘束性肺機能障害と診断した。63歳時に遺伝子検査を行い、MFN2エクソン8の新規ヘテロ接合一塩基多型(c.740 G>C)が特定され、MFN2 GTPaseドメインのミスセンス変異(p.R247P)をきたしていることが判明した。64歳時の追跡検査では、徒手筋力検査に47歳時からの大きな低下は認められず、神経伝導検査では正中神経のSNAPのみが惹起された。超音波検査では、残尿量が約120mLであることが判明した。頸部・胸部・腰部MRIで、神経因性膀胱の明らかな原因となる中枢神経病変は認めなかった。肺活量は31%に低下し、無呼吸低呼吸指数は上昇していた。

Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Ruriko Kitao, Takehiko Morimoto, Takaki Taniguchi, Mika Takeuchi, Jun Takei, Yu Hiramatsu, Yusuke Sakiyama, Akihiro Hashiguchi, Yuji Okamoto, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroshi Takashima . Novel de novo POLR3B mutations responsible for demyelinating Charcot-Marie-Tooth disease in Japan. . Annals of clinical and translational neurology9 ( 5 ) 747 - 755 2022.5International journal

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Biallelic POLR3B mutations cause a rare hypomyelinating leukodystrophy. De novo POLR3B heterozygous mutations were recently associated with afferent ataxia, spasticity, variable intellectual disability, and epilepsy, and predominantly demyelinating sensorimotor peripheral neuropathy. METHODS: We performed whole-exome sequencing (WES) of DNA samples from 804 Charcot-Marie-Tooth (CMT) cases that could not be genetically diagnosed by DNA-targeted resequencing microarray using next-generation sequencers. Using WES data, we analyzed the POLR3B mutations and confirmed their clinical features. RESULTS: We identified de novo POLR3B heterozygous missense mutations in two patients. These patients presented with early-onset demyelinating sensorimotor neuropathy without ataxia, spasticity, or cognitive impairment. Patient 1 showed mild cerebellar atrophy and spinal cord atrophy on magnetic resonance imaging and eventually died of respiratory failure in her 50s. We classified these mutations as pathogenic based on segregation studies, comparison with control database, and in silico analysis. CONCLUSION: Our study is the third report on patients with demyelinating CMT harboring heterozygous POLR3B mutations and verifies the pathogenicity of POLR3B mutations in CMT. Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT-related gene panel for comprehensive genetic screening, particularly for patients with early-onset demyelinating CMT.

DOI： 10.1002/acn3.51555

濱田拓人, 中澤祐則, 寺崎寛人, 谷口雄大, 髙嶋博, 坂本泰二 . 臨床報告両眼に重篤な眼所見を呈し視力予後が不良であった猫ひっかき病の1例 . 臨床眼科76 ( 4 ) 449 - 456 2022.4

Hamada Yuki, Shigehisa Ayano, Kanda Yoshiki, Ikeda Mei, Takaguchi Go, Matsuoka Hideki, Takashima Hiroshi . Enhancement of the Ivy Sign During an Ischemic Event in Moyamoya Disease: A Case Report . Internal Medicineadvpub ( 0 ) 617 - 621 2022

Language：English Publisher：The Japanese Society of Internal Medicine

<p>We herein report a case of increased and expanded ipsilateral ivy sign paralleling the expansion of cerebral infarction in a patient with moyamoya disease. A 67-year-old woman visited our hospital with symptoms of left hemiplegia, left homonymous hemianopia, and left unilateral spatial neglect. Magnetic resonance imaging of the head showed cerebral infarction in the right parietal lobe. In addition, ivy signs were evident on fluid-attenuated inversion recovery imaging. These findings were enhanced by the expansion of cerebral infarction and disappeared once the ischemia resolved, implying hemodynamic changes. As a result of continuing medical treatment without antithrombotic therapy, the patient obtained a good outcome. Treatment for moyamoya disease in the acute phase is considered to require complex knowledge of multiple factors, such as the anatomical background of the individual patient and the progression grade of ischemia. </p>

DOI： 10.2169/internalmedicine.9326-22

Satoshi Nozuma, Matsuura E, Tashiro Y, Nagata R, Ando M, Hiramatsu Y, Higuchi Y, Sakiyama Y, Hashiguchi A, Michizono K, Higashi K, Matsuzaki T, Kodama D, Tanaka M, Yamano Y, Moritoyo T, Kubota R, Takashima H . Efficacy of l-Arginine treatment in patients with HTLV-1-associated neurological disease. . Annals of clinical and translational neurology10 ( 2 ) 237 - 245 2022Reviewed

Language：Japanese Publishing type：Research paper (scientific journal)

<h4>Objective</h4>HTLV-1 infection causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), resulting in loss of motor function. In this Phase 2 trial, we assessed the efficacy and safety of l-arginine in patients with HAM/TSP.<h4>Methods</h4>This open-label, single-arm, Phase 2 study enrolled patients diagnosed with HAM/TSP. Patients received l-arginine at a dose of 20 g orally for 1 week and were followed-up for 3 weeks. The primary endpoint was change in walking speed in the 10-m walk test (10MWT). The main secondary endpoints were change in Timed Up and Go Test (TUGT) time, improvement in inflammatory markers in cerebrospinal fluid (CSF), safety, and tolerability.<h4>Results</h4>The study enrolled 20 patients (13 [65%] female) with a mean age of 67.8 years (95% CI 62.3 to 73.3). Although the primary endpoint, the changes in 10MWT time between baseline (Day 0) and Day 7, did not reach statistical significance (mean percent change in time -3.5%, 95% CI -10.8% to 3.7%; P = 0.32), a significant improvement was detected between baseline and Day 14 (-9.4%, 95% CI -16.6% to -2.2%; P = 0.01). Significant improvements were also observed in selected secondary endpoints, including in TUGT time (-9.1%, 95% CI -15.5% to -2.7%; P < 0.01), and in neopterin concentration in CSF (-2.1 pmol/mL, 95% CI -3.8 to -0.5; P = 0.01). Adverse events were infrequent, mild, and resolved rapidly.<h4>Interpretation</h4>l-arginine therapy improved motor function and decreased CSF inflammatory markers. l-arginine thus represents a promising therapeutic option for patients with HAM/TSP.<h4>Trial registration number</h4>UMIN000023854.

DOI： 10.1002/acn3.51715

髙嶋博 . 脊髄性筋萎縮症の遺伝子治療の実際とその未来 . 神経治療学39 ( 4 ) 540 - 540 2022

Higuchi Yujiro, Takashima Hiroshi . Review/Advances in Neurological Therapeutics (2021). Spinocerebellar degeneration . Neurological Therapeutics39 ( 5 ) 773 - 777 2022

Language：Japanese Publisher：Japanese Society of Neurological Therapeutics

<p>We would like to review the recent therapeutic advances of spinocerebellar degeneration (SCD) that were published in 2021. Currently, SCD treatment is limited only to symptomatic mitigation, and no therapy is available to stop or delay the disease progression. Various pre–clinical and clinical trials were carried out in 2021. Some interesting trials have been reported, and further developments are expected. This article introduces the outline of therapies with rovatirelin, riluzole/troriluzole, leriglitazone, sodium valproate, CRISPR/Cas9 gene editing, antisense oligonucleotides (ASOs), mesenchymal stem cells (MSCs), and cerebello–spinal transcranial direct current stimulation (tDCS). We expect that these treatments will benefit the patients with SCD.</p>

DOI： 10.15082/jsnt.39.5_773

Takashima Hiroshi . How to deal with unexplained events in neurology . Neurological Therapeutics39 ( 1 ) 3 - 6 2022

Language：Japanese Publisher：Japanese Society of Neurological Therapeutics

<p>Medical scientists are asked to make various judgments when new diseases emerge, such as COVID–19, but even for these experts, their judgments are often incorrect. Experts always attempt to convince the public using a term “science–based evidence” but, in many cases, without real solid evidence. There are massive of unexplained diseases and pathogenicity in neurology. In order to discover and elucidate new diseases and their pathophysiological conditions, it is important to carefully examine and investigate each patient, followed by a persistent tracing sincerely and deeply. Medicine is still developing, and to make the neurology more practical and useful for the world, I would like to expect flexibility, innovation, and conscience from doctors with neurological expertise.</p>

DOI： 10.15082/jsnt.39.1_3

Jun-Hui Yuan, Yujiro Higuchi, Masahiro Ando, Eiji Matsuura, Akihiro Hashiguchi, Akiko Yoshimura, Tomonori Nakamura, Yusuke Sakiyama, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroshi Takashima . Multi-type RFC1 repeat expansions as the most common cause of hereditary sensory and autonomic neuropathy. . Frontiers in neurology13 986504 - 986504 2022International journal

Language：English Publishing type：Research paper (scientific journal)

Non-coding repeat expansions within RFC1 and NOTCH2NLC genes have lately been linked to multisystem neurodegenerative diseases, which also shed light on yet undiagnosed patients with inherited peripheral neuropathies. The aim of this study was to identify the genetic basis of patients with hereditary sensory and autonomic neuropathy (HSAN). We collected 79 unrelated DNA samples clinically suspected with HSAN from multiple regions of Japan. Mutation screening was first performed using gene panel sequencing and whole-exome sequencing. Pathogenic/likely pathogenic variants were identified from genes of WNK1/HSN2 (6 cases), SCN9A (3 cases), NTRK1 (3 cases), and DNMT1 (2 cases). Subsequently, long-range flanking PCR and repeat-primed PCR were applied to analyze repeat expansions in RFC1 and NOTCH2NLC. Bi-allelic RFC1 repeat expansions were detected from 20 adult-onset HSAN patients, consisting of [(AAGGG)exp/(AAGGG)exp] (8 cases), [(ACAGG)exp/(ACAGG)exp] (8 cases), and [(AAGGG)exp/(ACAGG)exp] (4 cases). GGC repeat expansion in NOTCH2NLC was found in 1 case. Single-nucleotide variant-based haplotype analysis of patients harboring disease-associated repeat expansions in RFC1 revealed distinguishable haplotypes among subgroups with different repeat genotypes. These findings substantially redefine the genetic spectrum of HSAN, where multi-type RFC1 repeat expansions account for 25.3% of all patients, highlighting the necessity of genetic screening, particularly for adult-onset patients.

DOI： 10.3389/fneur.2022.986504

Ito Ken, Higurashi Norimichi, Kogawa Kentaro, Hashiguchi Akihiro, Takashima Hiroshi, Kikuchi Kenjiro . The brothers of X-linked Charcot-Marie-Tooth disease affected MERS type-2 . NO TO HATTATSU54 ( 1 ) 56 - 60 2022Reviewed

Language：Japanese Publisher：The Japanese Society of Child Neurology

<p> Transient cerebral manifestations resembling mild encephalopathy with a reversible splenial lesion (MERS) type-2 have been reported in patients with X-linked Charcot-Marie-Tooth disease type-1 (CMTX1). Here, we report the case of two brothers with MERS type-2, who was later diagnosed with CMTX1. The 12-year-old younger brother developed an altered state of consciousness, quadriplesia, and dysarthria after an acute phase of mycoplasma pneumonia. We diagnosed MERS type-2 after diffusion-weighted magnetic resonance imaging revealed transient symmetric hyperintensity lesions in the splenium of the corpus callosum and cerebral white matter. We suspected CMTX1 because his older brother had previously suffered from MERS type-2 and further examination of the lower limbs revealed a persistent absence of deep tendon reflexes, high-arched feet, and “inverted champagne bottle” legs in both mother and brothers. Presence of the <i>GJB1</i> missense mutation—NM_000166.6 (GJB1) : c. 77C>T (p. Ser26Leu) —was later confirmed in the younger brother. In cases of MERS type-2 with cerebral focal sign and without seizure, CMTX1 is considered as an underlying condition, but motor symptoms may be unnoticeable in childhood. Therefore, it is crucial to examine carefully lower limbs signs which can appear as early symptoms, not only in probands but also in their family.</p>

DOI： 10.11251/ojjscn.54.56