研究者詳細 - 石浦　浩之

論文 - 石浦　浩之

分割表示 221 件中 101 - 120 件目／全件表示 >>

Efficacy of canakinumab on AA amyloidosis in late-onset NLRP3-associated autoinflammatory disease with an I574F somatic mosaic mutation. 査読国際誌

Takahiro Itamiya, Toshihiko Komai, Hiroko Kanda, Yasuo Nagafuchi, Hyangri Chang, Shota Shibata, Hiroyuki Ishiura, Hirofumi Shoda, Tatsushi Toda, Keishi Fujio

Clinical rheumatology 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

There have been hundreds of reports on mutations in the NLRP3 gene related to NLRP3-associated autoinflammatory disease, but few of these mutations have occurred as both germline and somatic mosaic mutations. In this case-based review, we report a 68-year-old man with an NLRP3-associated autoinflammatory disease. He developed secondary amyloidosis, including a renal and colorectal presentation in his 50 s. Sequencing of the NLRP3 gene revealed an I574F somatic mosaic mutation, which has up to now only been reported in germline mutations. The patient was treated with canakinumab, which had great efficacy not only on the NLRP3-mediated inflammation, but also on the chronic renal failure and proteinuria provoked by secondary renal amyloidosis. To evaluate the effectiveness of canakinumab, we conducted a literature research on renal amyloidosis related to NLRP3-associated autoinflammatory disease treated with canakinumab. Although our patient had a relatively long medical history and greater amounts of proteinuria than other reported cases, canakinumab had great efficacy on renal impairment, in similar to other reported cases. Along with the first report of a late-onset I574F somatic mosaic mutation in NLRP3-associated autoinflammatory disease, this report demonstrates the effectiveness of canakinumab on renal amyloidosis, probably through the way that IL-1β blockade minimizes podocyte injury.

DOI： 10.1007/s10067-022-06130-1

Complex hereditary peripheral neuropathies caused by novel variants in mitochondrial-related nuclear genes. 査読国際誌

Yu Hiramatsu, Yuji Okamoto, Akiko Yoshimura, Jun-Hui Yuan, Masahiro Ando, Yujiro Higuchi, Akihiro Hashiguchi, Eiji Matsuura, Fumihito Nozaki, Tomohiro Kumada, Kei Murayama, Mikiya Suzuki, Yuki Yamamoto, Naoko Matsui, Yoshimichi Miyazaki, Masamitsu Yamaguchi, Youji Suzuki, Jun Mitsui, Hiroyuki Ishiura, Masaki Tanaka, Shinichi Morishita, Ichizo Nishino, Shoji Tsuji, Hiroshi Takashima

Journal of neurology 269 ( 8 ) 4129 - 4140 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Mitochondrial disorders are a group of clinically and genetically heterogeneous multisystem disorders and peripheral neuropathy is frequently described in the context of mutations in mitochondrial-related nuclear genes. This study aimed to identify the causative mutations in mitochondrial-related nuclear genes in suspected hereditary peripheral neuropathy patients. We enrolled a large Japanese cohort of clinically suspected hereditary peripheral neuropathy patients who were mutation negative in the prescreening of the known Charcot-Marie-Tooth disease-causing genes. We performed whole-exome sequencing on 247 patients with autosomal recessive or sporadic inheritance for further analysis of 167 mitochondrial-related nuclear genes. We detected novel bi-allelic likely pathogenic/pathogenic variants in four patients, from four mitochondrial-related nuclear genes: pyruvate dehydrogenase beta-polypeptide (PDHB), mitochondrial poly(A) polymerase (MTPAP), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB), and succinate-CoA ligase ADP-forming beta subunit (SUCLA2). All these patients showed sensory and motor axonal polyneuropathy, combined with central nervous system or multisystem involvements. The pathological analysis of skeletal muscles revealed mild neurogenic changes without significant mitochondrial abnormalities. Targeted screening of mitochondria-related nuclear genes should be considered for patients with complex hereditary axonal polyneuropathy, accompanied by central nervous system dysfunctions, or with unexplainable multisystem disorders.

DOI： 10.1007/s00415-022-11026-w

Muscle Transcriptomics Shows Overexpression of Cadherin 1 in Inclusion Body Myositis. 査読国際誌

Chiseko Ikenaga, Hidetoshi Date, Motoi Kanagawa, Jun Mitsui, Hiroyuki Ishiura, Jun Yoshimura, Iago Pinal-Fernandez, Andrew L Mammen, Thomas E Lloyd, Shoji Tsuji, Jun Shimizu, Tatsushi Toda, Jun Goto

Annals of neurology 91 ( 3 ) 317 - 328 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: This study aimed to elucidate the molecular features of inclusion body myositis (IBM). METHODS: We performed RNA sequencing analysis of muscle biopsy samples from 67 participants, consisting of 58 myositis patients with the pathological finding of CD8-positive T cells invading non-necrotic muscle fibers expressing major histocompatibility complex class I (43 IBM, 6 polymyositis, and 9 unclassifiable myositis), and 9 controls. RESULTS: Cluster analysis, principal component analysis, and pathway analysis showed that differentially expressed genes and pathways identified in IBM and polymyositis were mostly comparable. However, pathways related to cell adhesion molecules were upregulated in IBM as compared with polymyositis and controls (p < 0.01). Notably, CDH1, which encodes the epidermal cell junction protein cadherin 1, was overexpressed in the muscles of IBM, which was validated by another RNA sequencing dataset from previous publications. Western blotting confirmed the presence of mature cadherin 1 protein in the muscles of IBM. Immunohistochemical staining confirmed the positivity for anti-cadherin 1 antibody in the muscles of IBM, whereas there was no muscle fiber positive for anti-cadherin 1 antibody in immune-mediated necrotizing myopathy, antisynthetase syndrome, and controls. The fibers stained with anti-cadherin 1 antibody did not have rimmed vacuoles or abnormal protein accumulation. Experimental skeletal muscle regeneration and differentiation systems showed that CDH1 is expressed during skeletal muscle regeneration and differentiation. INTERPRETATION: CDH1 was detected as a differentially expressed gene, and immunohistochemistry showed that cadherin 1 exists in the muscles of IBM, whereas it was rarely seen in those of other idiopathic inflammatory myopathies. Cadherin 1 upregulation in muscle could provide a valuable clue to the pathological mechanisms of IBM. ANN NEUROL 2022;91:317-328.

DOI： 10.1002/ana.26304

Family with congenital contractural arachnodactyly due to a novel multiexon deletion of the FBN2 gene. 査読国際誌

Hiroki Yagi, Hiroshi Takiguchi, Norifumi Takeda, Ryo Inuzuka, Yuki Taniguchi, Kristine Joyce Porto, Hiroyuki Ishiura, Jun Mitsui, Hiroyuki Morita, Issei Komuro

Clinical case reports 10 ( 2 ) e05335 2022年2月

An immigrant family with Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex. 査読国際誌

Yasumasa Kokubo, Satoru Morimoto, Ryogen Sasaki, Masato Hasegawa, Hiroyuki Ishiura, Shoji Tsuji, Mari Yoshida, Naohisa Yamazoe, Mitsukazu Miyazaki, Shigeki Kuzuhara

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 43 ( 2 ) 1423 - 1425 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a unique endemic on Guam island of the USA, the Kii Peninsula of Japan, and Papua state of Indonesia. The pathomechanism of ALS/PDC remains to be solved, although interaction between some environmental factors and genetic background is plausible. This is the first autopsy-proven immigrant family of ALS/PDC of the Kii Peninsula. METHODS: A daughter and her father immigrated to the high incident area from outside the Kii Peninsula. The father developed ALS 18 years later after immigration, and his daughter also developed ALS 65 years after immigration. They showed pure ALS phenotype without parkinsonism and dementia. RESULTS: The daughter was diagnosed neuropathologically with Kii ALS/PDC with multiple proteinopathies: tauopathy, α-synucleinopathy, and TDP-43 proteinopathy. Gene analysis of familial ALS-related genes, including C9orf72, showed no mutation. DISCUSSION: The findings in an immigrant family established that certain environmental factors play a critical role in the pathogenesis of Kii ALS/PDC.

DOI： 10.1007/s10072-021-05737-7

An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families. 査読国際誌

Masahiro Ando, Yujiro Higuchi, Yuji Okamoto, Junhui Yuan, Akiko Yoshimura, Jun Takei, Takaki Taniguchi, Yu Hiramatsu, Yusuke Sakiyama, Akihiro Hashiguchi, Eiji Matsuura, Hiroto Nakagawa, Ken Sonoda, Toru Yamashita, Akiko Tamura, Hideo Terasawa, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroshi Takashima

Journal of human genetics 67 ( 7 ) 399 - 403 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND AIMS: Mutations in neurofilament genes have been linked to several neuromuscular disorders. The neurofilament heavy (NEFH) gene was identified as the causative gene of Charcot-Marie-Tooth disease type 2CC (CMT2CC) in 2016, with a toxic gain of function mechanism caused by the translation and aggregation of cryptic amyloidogenic element (CAE) in the 3' untranslated region (UTR). But the NEFH-related clinical and genetic spectrums are still unclear in Japan. METHODS: We analyzed all variants in the NEFH gene from our in-house whole-exome sequencing data, established from Japanese nationwide patients with neuromuscular disorders, including Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA). RESULTS: We identified a c.3017dup (p.Pro1007Alafs*56) variant in NEFH from three families clinically diagnosed with CMT, and one family with SMA. In addition to the patients presented with typical peripheral neuropathies, pyramidal signs were observed from one CMT patient. Whereas the SMA patients showed severe characteristic weakness of triceps brachii and quadriceps femoris. All of these four families reside in Kagoshima Prefecture of Japan, and a following haplotype analysis strongly suggests a founder effect. INTERPRETATION: This is the original report referring to a founder mutation in NEFH. The clinical diversity in our study, comprising CMT, with or without pyramidal signs, and SMA, suggest an extensive involvement of peripheral nerve, anterior horn cells, or both. Our findings broaden the phenotypic spectrum of NEFH-related disorders.

DOI： 10.1038/s10038-022-01019-y

Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments. 査読国際誌

Takaki Taniguchi, Masahiro Ando, Yuji Okamoto, Akiko Yoshimura, Yujiro Higuchi, Akihiro Hashiguchi, Nozomu Matsuda, Mamoru Yamamoto, Eisuke Dohi, Makoto Takahashi, Masanao Yoshino, Taichi Nomura, Masaaki Matsushima, Ichiro Yabe, Yui Sanpei, Hiroyuki Ishiura, Jun Mitsui, Masanori Nakagawa, Shoji Tsuji, Hiroshi Takashima

Journal of human genetics 67 ( 6 ) 353 - 362 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND AIMS: Some hereditary transthyretin (ATTRv) amyloidosis patients are misdiagnosed as Charcot-Marie-Tooth disease (CMT) at onset. We assess the findings to identify ATTRv amyloidosis among patients with suspected CMT to screen transthyretin gene variants for treatments. METHODS: We assessed clinical, cerebrospinal fluid, and electrophysiological findings by comparing ATTRv amyloidosis patients with suspected CMT (n = 10) and CMT patients (n = 489). RESULTS: The median (interquartile range) age at onset of neurological symptoms was 69 (64.2-70) years in the ATTRv amyloidosis vs 12 (5-37.2) years in CMT group (Mann-Whitney U, p < 0.01). The proportion of patients with initial sensory symptoms was 70% in the ATTRv amyloidosis group vs 7.1% in CMT group (Fisher's exact, p < 0.01). The proportion of patients with histories of suspected chronic inflammatory demyelinating polyneuropathy (CIDP) were 50% in the ATTRv amyloidosis group vs 8.7% in CMT group (Fisher's exact, p < .01). Other measures and outcomes were not different between the two groups. Five of the six patients with ATTRv amyloidosis received treatment and survived. INTERPRETATION: For effective treatments, the transthyretin gene should be screened in patients with suspected CMT with old age at onset of neurological symptoms, initial sensory symptoms, and histories of suspected CIDP.

DOI： 10.1038/s10038-021-01005-w

Multi-type RFC1 repeat expansions as the most common cause of hereditary sensory and autonomic neuropathy. 査読国際誌

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

Frontiers in neurology 13 986504 - 986504 2022年

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DMD exon 2 duplication due to a complex genomic rearrangement is associated with a somatic mosaicism. 査読国際誌

Akatsuki Kubota, Hiroyuki Ishiura, Kristine Joyce Linay Porto, Masaki Tanaka, Jun Mitsui, Atsushi Unuma, Hisataka Maki, Issei Komuro, Shoji Tsuji, Jun Shimizu, Tatsushi Toda

Neuromuscular disorders : NMD 32 ( 3 ) 263 - 269 2021年12月

記述言語：英語

We report the case of a patient with dystrophinopathy caused by DMD exon 2 duplication, showing marked asymmetric muscle atrophy. Immunostaining of the biopsied muscle tissue showed a mosaic staining, suggesting a somatic mosaicism. Polymerase chain reaction (PCR) analysis showed only one breakpoint, and long-read whole-genome sequencing revealed the entire structure of the rearranged sequence. The complex rearrangement was composed of two tandem duplications: one showed a microhomology near the breakpoint, suggesting a microhomology-mediated mechanism, whereas the other was associated with flanking short tandem repeats. The long-read sequencing also suggested the presence of a wild-type nonduplicated sequence, supporting somatic mosaicism. Whereas complementary DNA and western blot analyses were not useful, droplet digital PCR (ddPCR) analysis showed an average copy number of 1.61, enabling accurate estimation of the proportion of cells containing the duplication. Long-read sequencing and ddPCR analysis were useful for revealing the rearrangements and the precise copy number.

DOI： 10.1016/j.nmd.2021.12.004

Randomized, double‐blind, placebo‐controlled phase 1 study to evaluate the safety and pharmacokinetics of high doses of ubiquinol in healthy adults 査読

Jun Mitsui, Takashi Matsukawa, Masaki Tanaka, Naoko Saito‐Sato, Fumiko Kusunoki Nakamoto, Tsutomu Yasuda, Hiroya Naruse, Miho Kawabe Matsukawa, Hiroyuki Ishiura, Midori Nagase, Yorihiro Yamamoto, Haruko Kuzuyama, Ikue Wada, Toshio Ga, Tsutomu Yamazaki, Takashi Moritoyo, Shoji Tsuji

Neurology and Clinical Neuroscience 10 ( 1 ) 14 - 24 2021年12月

Frequency of FMR1 Premutation Alleles in Patients with Undiagnosed Cerebellar Ataxia and Multiple System Atrophy in the Japanese Population. 査読国際誌

Asem Almansour, Hiroyuki Ishiura, Jun Mitsui, Takashi Matsukawa, Miho Kawabe Matsukawa, Hideaki Shimizu, Atsuhiko Sugiyama, Tatsushi Toda, Shoji Tsuji

Cerebellum (London, England) 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by FMR1 premutation expansion of CGG repeats. FXTAS can be misdiagnosed with many neurodegenerative disorders manifesting with cerebellar ataxias owing to their overlapping clinical and radiological features. The frequency of the FMR1 premutation allele in Japan has not been fully determined. Herein, we aimed to determine the frequency of FMR1 premutation alleles in Japanese patients with undiagnosed cerebellar ataxia and multiple system atrophy, using repeat-primed PCR in 186 patients with adult onset of undiagnosed cerebellar ataxia and 668 patients with multiple system atrophy, to identify expanded CGG repeats as well as to detect AGG interruptions within the expanded alleles. The size of expansions was estimated using fragment length analysis of PCR products obtained by conventional PCR employing a pair of unique primers flanking the repeat sequence. We identified FMR1 premutation alleles in three male patients. One patient revealed 84 repeat units with one AGG interruption and another patient showed 103 repeat units. Both had presented with sporadic cerebellar ataxia, giving an estimated frequency of 3.7% among Japanese male patients with sporadic cerebellar ataxia with age at onset above 50 years. One patient with the clinical diagnosis of multiple system atrophy harbored 60 repeat units with four AGG interruptions. FMR1 intermediate alleles were observed in two males and one female among the multiple system atrophy patients. We found that genetic tests for FMR1 premutation should be considered in Japanese male patients with cerebellar ataxia with the age at onset above 50 years.

DOI： 10.1007/s12311-021-01329-5

Diagnostic Values of Venous Peak Lactate, Lactate-to-pyruvate Ratio, and fold Increase in Lactate from Baseline in Aerobic Exercise Tests in Patients with Mitochondrial Diseases.

Masanori Kurihara, Yusuke Sugiyama, Masaki Tanaka, Kenichiro Sato, Akihiko Mitsutake, Hiroyuki Ishiura, Akatsuki Kubota, Kaori Sakuishi, Toshihiro Hayashi, Atsushi Iwata, Jun Shimizu, Kei Murayama, Shoji Tsuji, Tatsushi Toda

Internal medicine (Tokyo, Japan) 61 ( 13 ) 1939 - 1946 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Objective Although aerobic exercise tests on cycle ergometry have long been used for initial assessments of cases of suspected mitochondrial disease, the test parameters in patients with final diagnoses of other diseases via the widely used 15 W for 15 min exercise protocol have not been fully characterized. Methods and Patients We retrospectively reviewed all patients who underwent the test at our institution. We classified the patients with genetic diagnoses or those who met previously reported clinical criteria as having mitochondrial diseases and those with a final diagnosis of another disease as having other diseases. Results were available from 6 patients with mitochondrial disease and 15 with other diseases. Results During the test, elevated venous peak lactate above the upper normal limit of healthy controls at rest (19.2 mg/dL [2.13 mM]) was observed in 3 patients with mitochondrial diseases (50.0%) and 5 with other diseases (33.3%). In the group of patients with elevated venous peak lactate, a lactate-to-pyruvate ratio of >20 was observed in all 3 patients with mitochondrial disease but in only 1 of the 5 with other diseases. More than a 2-fold increase in venous lactate from baseline was observed in 4 patients with mitochondrial disease (66.7%) and 1 with another disease (6.7%). Conclusion Elevated venous peak lactate levels were observed in patients with final diagnoses of other diseases, even under a low 15-min workload at 15 W. The lactate-to-pyruvate ratio and increase in lactate level from baseline may add diagnostic value to venous peak lactate levels alone.

DOI： 10.2169/internalmedicine.8629-21

COQ2 V393A confers high risk susceptibility for multiple system atrophy in East Asian population. 国際誌

Kristine Joyce Porto, Makito Hirano, Jun Mitsui, Ayaka Chikada, Takashi Matsukawa, Hiroyuki Ishiura, Tatsushi Toda, Susumu Kusunoki, Shoji Tsuji

Journal of the neurological sciences 429 117623 - 117623 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Multiple system atrophy (MSA) is a rare, late-onset, and devastating neurodegenerative disease characterized by autonomic failure, alongside with various combination of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Since we first identified biallelic mutations in the COQ2 gene in two multiplex MSA families and further reported that heterozygous COQ2 V393A variant confers a susceptibility to sporadic MSA, the results of nearly a decade of investigating this association globally were quite remarkable. COQ2 V393A was virtually absent in the American and European populations but was shown to have varying associations with sporadic MSA in the East Asian populations. In our attempt to clarify the latter and provide a coherent regional conclusion, we conducted two independent case-control series which showed clear association of the V393A variant with sporadic MSA in the Japanese population. We then pooled the results with other studies from the East Asian population and conducted a meta-analysis which broadened and established the association regionally (pooled OR 2.12, 95% CI: 1.35-3.31, PI: 0.63-7.15, p = 0.0047). The subgroup analysis identified a strong association of V393A with MSA-C (pooled OR 2.57, 95% CI: 1.98-3.35; p = 2.56 × 10-12) but not with MSA-P (pooled OR 1.41, 95% CI: 0.88-2.26; p = 0.16). Our results highlighted the importance of investigating region-specific and pan-regional genetic variants that may potentially underlie the pathomechanisms of neurodegenerative diseases. COQ2 V393A variant remains a susceptibility variant rather than causative for MSA particularly, MSA-C subtype, in the East Asian population.

DOI： 10.1016/j.jns.2021.117623

Severe dilated cardiomyopathy and ventricular arrhythmia in a patient with Emery‐Dreifuss muscular dystrophy harboring a novel frameshift mutation in EMD 査読

Akihiko Mitsutake, Atsushi Unuma, Mizuho Kawai, Akatsuki Kubota, Hiroyuki Ishiura, Kaori Sakuishi, Jun Shimizu, Hisataka Maki, Eisuke Amiya, Masaru Hatano, Issei Komuro, Shoji Tsuji, Tatsushi Toda

Neurology and Clinical Neuroscience 9 ( 6 ) 490 - 493 2021年10月

掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley

Abstract

We report a case of a 55‐year‐old man with dilated cardiomyopathy and ventricular tachycardia/ventricular fibrillation (VT/VF). He had contracture of neck and ankle flexion from infancy and was found to have dilated cardiomyopathy at the age of 24 years. Intensive cardiac treatment including medication and the use of a defibrillator failed to improve his cardiac function, and heart transplantation was indicated at the age of 55 years. Joint contractures and proximal dominant muscle atrophy with mild weakness suggested Emery‐Dreifuss muscular dystrophy (EDMD). The diagnosis of EDMD1 was made based on genetic analysis of EMD and muscle biopsy showing the absence of emerin. The patient was listed as a candidate for heart transplantation, but he died 3 months later due to sustained VT/VF. The present case emphasizes the necessity of considering timely heart transplantation even when a defibrillator is implanted in patients with EDMD.

DOI： 10.1111/ncn3.12552

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ncn3.12552

Clinical Impact of Copy Number Variation on the Genetic Diagnosis of Syndromic Aortopathies. 国際誌

Norifumi Takeda, Ryo Inuzuka, Hiroki Yagi, Hiroyuki Morita, Masahiko Ando, Haruo Yamauchi, Yuki Taniguchi, Kristine Joyce Porto, Tsubasa Kanaya, Hiroyuki Ishiura, Jun Mitsui, Shoji Tsuji, Tatsushi Toda, Minoru Ono, Issei Komuro

Circulation. Genomic and precision medicine 14 ( 4 ) CIRCGEN121003458 2021年7月

A Role of Aging in the Progression of Cortical Excitability in Benign Adult Familial Myoclonus Epilepsy type 1 Patients. 国際誌

Shuichiro Neshige, Takefumi Hitomi, Maya Tojima, Kazuki Oi, Katsuya Kobayashi, Masao Matsuhashi, Akihiro Shimotake, Riki Matsumoto, Masutaro Kanda, Hirofumi Maruyama, Hiroyuki Ishiura, Shoji Tsuji, Ryosuke Takahashi, Akio Ikeda

Movement disorders : official journal of the Movement Disorder Society 36 ( 10 ) 2446 - 2448 2021年7月

Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis. 国際誌

Hitoshi Aizawa, Haruhisa Kato, Koji Oba, Takuya Kawahara, Yoshihiko Okubo, Tomoko Saito, Makiko Naito, Makoto Urushitani, Akira Tamaoka, Kiyotaka Nakamagoe, Kazuhiro Ishii, Takashi Kanda, Masahisa Katsuno, Naoki Atsuta, Yasushi Maeda, Makiko Nagai, Kazutoshi Nishiyama, Hiroyuki Ishiura, Tatsushi Toda, Akihiro Kawata, Koji Abe, Ichiro Yabe, Ikuko Takahashi-Iwata, Hidenao Sasaki, Hitoshi Warita, Masashi Aoki, Gen Sobue, Hidehiro Mizusawa, Yutaka Matsuyama, Tomohiro Haga, Shin Kwak

Journal of neurology 269 ( 2 ) 885 - 896 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS). METHODS: This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment. RESULTS: One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [- 8.4 (95% CI - 13.9 to - 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483). CONCLUSIONS: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.

DOI： 10.1007/s00415-021-10670-y

A Case of Irreversible Corneal Edema Associated with Dentatorubropallidoluysian Atrophy Following Corneal Endothelial Transplantation

Yumi Hashimoto, Jun Mitsui, Hiroyuki Ishiura, Takashi Matsukawa, Tatsushi Toda, Koji Kakisu, Yuichi Hori, Suguru Nakagawa, Tetsuya Toyono, Junko Yoshida, Tomohiko Usui, Satoru Yamagami, Makoto Aihara, Takashi Miyai

SN Comprehensive Clinical Medicine 2021年6月

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia. 国際誌

Manuela Wiessner, Reza Maroofian, Meng-Yuan Ni, Andrea Pedroni, Juliane S Müller, Rolf Stucka, Christian Beetz, Stephanie Efthymiou, Filippo M Santorelli, Ahmed A Alfares, Changlian Zhu, Anna Uhrova Meszarosova, Elham Alehabib, Somayeh Bakhtiari, Andreas R Janecke, Maria Gabriela Otero, Jin Yun Helen Chen, James T Peterson, Tim M Strom, Peter De Jonghe, Tine Deconinck, Willem De Ridder, Jonathan De Winter, Rossella Pasquariello, Ivana Ricca, Majid Alfadhel, Bart P van de Warrenburg, Ruben Portier, Carsten Bergmann, Saghar Ghasemi Firouzabadi, Sheng Chih Jin, Kaya Bilguvar, Sherifa Hamed, Mohammed Abdelhameed, Nourelhoda A Haridy, Shazia Maqbool, Fatima Rahman, Najwa Anwar, Jenny Carmichael, Alistair Pagnamenta, Nick W Wood, Frederic Tran Mau-Them, Tobias Haack, Maja Di Rocco, Isabella Ceccherini, Michele Iacomino, Federico Zara, Vincenzo Salpietro, Marcello Scala, Marta Rusmini, Yiran Xu, Yinghong Wang, Yasuhiro Suzuki, Kishin Koh, Haitian Nan, Hiroyuki Ishiura, Shoji Tsuji, Laëtitia Lambert, Emmanuelle Schmitt, Elodie Lacaze, Hanna Küpper, David Dredge, Cara Skraban, Amy Goldstein, Mary J H Willis, Katheryn Grand, John M Graham, Richard A Lewis, Francisca Millan, Özgür Duman, Nihal Dündar, Gökhan Uyanik, Ludger Schöls, Peter Nürnberg, Gudrun Nürnberg, Andrea Catala Bordes, Pavel Seeman, Martin Kuchar, Hossein Darvish, Adriana Rebelo, Filipa Bouçanova, Jean-Jacques Medard, Roman Chrast, Michaela Auer-Grumbach, Fowzan S Alkuraya, Hanan Shamseldin, Saeed Al Tala, Jamileh Rezazadeh Varaghchi, Maryam Najafi, Selina Deschner, Dieter Gläser, Wolfgang Hüttel, Michael C Kruer, Erik-Jan Kamsteeg, Yoshihisa Takiyama, Stephan Züchner, Jonathan Baets, Matthis Synofzik, Rebecca Schüle, Rita Horvath, Henry Houlden, Luca Bartesaghi, Hwei-Jen Lee, Konstantinos Ampatzis, Tyler Mark Pierson, Jan Senderek

Brain : a journal of neurology 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

DOI： 10.1093/brain/awab041

Adrenoleukodystrophy siblings with a novel ABCD1 missense variant presenting with phenotypic differences: a case report and literature review. 国際誌

Yuka Shibata, Masaaki Matsushima, Takashi Matsukawa, Hiroyuki Ishiura, Shoji Tsuji, Ichiro Yabe

Journal of human genetics 66 ( 5 ) 535 - 537 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Adrenoleukodystrophy (ALD) is an X-linked disease that affects primarily the white matter of the central nervous system and adrenal cortex. A correlation between genotypes and phenotypes has not been observed. Here, we present two Japanese siblings with a novel missense variant (c.1887T > G) in the ABCD1 gene who presented with different clinical phenotypes, i.e., adolescent cerebral and cerebello-brainstem types. We also review the literature focusing on the variation in the clinical phenotypes within ALD families. In our review, 61.9% of sibling pairs presented with the same clinical type of ALD and 59.1% of sibling pairs presented with a similar age of onset. Conversely, 15.4% of sibling pairs had a similar age of onset, but different clinical types of ALD. To observe the correlation between genotypes and phenotypes, it is important to diagnose early and to accumulate reports describing age of onset, first onset symptom, and progression of the symptom.

DOI： 10.1038/s10038-020-00866-x

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