Case Study 緩徐進行性の舌萎縮と四肢の運動・感覚障害、起立性低血圧を呈する68歳男性 (成人発症Triple A 症候群), すべてがわかるALS (筋萎縮性側索硬化症)・運動ニューロン疾患 中山書店 2013 Author:中村勝哉
論文 Long-term Observation of a Japanese Patient with a Multiple-system Neurodegenerative Disorder with a Uniallelic de novo Missense Variant in KIF1A. Internal medicine (Tokyo, Japan),62(20):3047-3051 2023(Oct. 15) Author:Katsuya Nakamura; Tsuneaki Yoshinaga; Minori Kodaira; Emiko Kise; Tomoki Kosho; Yoshiki Sekijima Abstract:We encountered a 37-year-old Japanese man with KIF1A-associated neurological disorder (KAND) who exhibited motor developmental delay, intellectual disability, and slowly progressive cerebellar ataxia, hypotonia, and optic neuropathy. Pyramidal tract signs were evident late in this case. At 30 years old, the patient developed a neurogenic bladder. A molecular diagnosis revealed a uniallelic missense de novo variant (p.L278P) of KIF1A. Serial neuroradiological studies revealed atrophy of the cerebellum at an early age, and cerebral hemisphere atrophy progressed slowly over a 22-year observation period. Our study suggests that the primary etiology of KAND may be acquired, long-standing neurodegeneration rather than congenital hypoplasia.
Clinical Features and Neuroimaging Findings of Neuropil Antibody-Positive Idiopathic Sporadic Ataxia of Unknown Etiology. Cerebellum (London, England),22(5):915-924 2023(Oct.) Author:Akira Takekoshi; Akio Kimura; Nobuaki Yoshikura; Isamu Yamakawa; Makoto Urushitani; Katsuya Nakamura; Kunihiro Yoshida; Takayoshi Shimohata Abstract:Idiopathic sporadic ataxia (ISA) is the clinical term for nonfamilial ataxia with adult-onset and a slowly progressive course. However, immune-mediated cerebellar ataxia cannot be completely excluded from ISA. The current study investigated the neuropil antibodies against cell-surface antigens and clarified the clinical features and neuroimaging findings of patients with these antibodies. Using tissue-based immunofluorescence assays (TBAs), we examined antibodies against the cerebellum in serum samples from 67 patients who met the ISA diagnostic criteria, including 30 patients with multiple system atrophy with predominant cerebellar features (MSA-C) and 20 patients with hereditary ataxia (HA), and 18 healthy control subjects. According to the TBA results, we divided subjects into three groups: subjects positive for neuropil antibodies, subjects positive for intracellular antibodies only, and subjects negative for antibodies. We compared clinical features and neuroimaging findings in ISA patients among these three groups. The prevalence of neuropil antibodies in ISA (17.9%) was significantly higher than that in MSA-C (3.3%), HA (0%), or healthy subjects (0%). The neuropil antibody-positive ISA patients showed pure cerebellar ataxia more frequently than the other ISA patients. Two neuropil antibody-positive patients showed significant improvement of cerebellar ataxia after immunotherapy. We detected neuropil antibodies in 17.9% of ISA patients. Characteristic clinical features of neuropil antibody-positive ISA patients were pure cerebellar ataxia. Some cases of neuropil antibody-positive ISA responded to immunotherapy.
Tongue Hemiatrophy in Multifocal Motor Neuropathy. Internal medicine (Tokyo, Japan),62(18):2759-2760 2023(Sep. 15) Author:Masateru Tajiri; Minori Kodaira; Katsuya Nakamura; Yoshiki Sekijima
Lysinuric protein intolerance exhibiting renal tubular acidosis/Fanconi syndrome in a Japanese woman JIMD Reports 2023(Sep. 07) Author:Hiroaki Hanafusa; Katsuya Nakamura; Yuji Kamijo; Masashi Kitahara; Takashi Ehara; Tsuneaki Yoshinaga; Kaoru Aoki; Nagaaki Katoh; Tomomi Yamaguchi; Tomoki Kosho; Yoshiki Sekijima Abstract:Abstract
Lysinuric protein intolerance (LPI), caused by pathogenic variants of SLC7A7, is characterized by protein aversion, failure to thrive, hyperammonemia, and hepatomegaly. Recent studies have reported that LPI can cause multiple organ dysfunctions, including kidney disease, autoimmune deficiency, pulmonary alveolar proteinosis, and osteoporosis. We report the case of a 47‐year‐old Japanese woman who was initially diagnosed with renal tubular acidosis (RTA), Fanconi syndrome, and rickets. At the age of 3 years, she demonstrated a failure to thrive. Urinary amino acid analysis revealed elevated lysine and arginine levels, which were masked by pan‐amino aciduria. She was subsequently diagnosed with rickets at 5 years of age and RTA/Fanconi syndrome at 15 years of age. She was continuously treated with supplementation of vitamin D3, phosphate, and bicarbonate. A renal biopsy at 18 years of age demonstrated diffuse proximal and distal tubular damage with endocytosis‐lysosome pathway abnormalities. Distinctive symptoms of LPI, such as protein aversion and postprandial hyperammonemia were not observed throughout the patient's clinical course. The patient underwent a panel‐based comprehensive genetic testing and was diagnosed with LPI. As the complications of LPI involve many organs, patients lacking distinctive symptoms may develop various diseases, including RTA/Fanconi syndrome. Our case indicates that proximal and distal tubular damages are notable findings in patients with LPI. The possibility of LPI should be carefully considered in the management of RTA/Fanconi syndrome and/or incomprehensible pathological tubular damage, even in the absence of distinctive symptoms; furthermore, a comprehensive genetic analysis is useful for diagnosing LPI.
Clinical utility of urinary mulberry bodies/cells testing in the diagnosis of Fabry disease. Molecular genetics and metabolism reports,36:100983-100983 2023(Sep.) Author:Katsuya Nakamura; Saki Mukai; Yuka Takezawa; Yuika Natori; Akari Miyazaki; Yuichiro Ide; Mayu Takebuchi; Kana Nanato; Mizuki Katoh; Harue Suzuki; Akiko Sakyu; Tomomi Kojima; Emiko Kise; Hiroaki Hanafusa; Tomoki Kosho; Koichiro Kuwahara; Yoshiki Sekijima Abstract:INTRODUCTION: Variants in the galactosidase alpha (GLA) gene cause Fabry disease (FD), an X-linked lysosomal storage disorder caused by α-galactosidase A (α-GAL) deficiency. Recently, disease-modifying therapies have been developed, and simple diagnostic biomarkers for FD are required to initiate these therapies in the early stages of the disease. Detection of urinary mulberry bodies and cells (MBs/MCs) is beneficial for diagnosing FD. However, few studies have evaluated the diagnostic accuracy of urinary MBs/MCs in FD. Herein, we retrospectively evaluated the diagnostic ability of urinary MBs/MCs for FD. METHODS: We analyzed the medical records of 189 consecutive patients (125 males and 64 females) who underwent MBs/MCs testing. Out of these, two female patients had already been diagnosed with FD at the time of testing, and the remaining 187 patients were suspected of having FD and underwent both GLA gene sequencing and/or α-GalA enzymatic testing. RESULTS: Genetic testing did not confirm the diagnosis in 50 females (26.5%); hence, they were excluded from the evaluation. Two patients were previously diagnosed with FD, and sixteen were newly diagnosed. Among these 18 patients, 15, including two who had already developed HCM at diagnosis, remained undiagnosed until targeted genetic screening of at-risk family members of patients with FD was performed. The accuracy of urinary MBs/MCs testing exhibited a sensitivity of 0.944, specificity of 1, positive predictive value of 1, and negative predictive value of 0.992. CONCLUSIONS: MBs/MCs testing is highly accurate in diagnosing FD and should be considered during the initial evaluation prior to genetic testing, particularly in female patients.
Auditory Neuropathy Spectrum Disorder Progressing with Motor and Sensory Neuropathy Caused by an ATP1A1 Variant. Internal medicine (Tokyo, Japan) 2023(Aug. 09) Author:Gaku Okumura; Katsuya Nakamura; Rie Seyama; Yuri Uchiyama; Jun Shinagawa; Shinya Nishio; Junji Ikeda; Shohei Takayama; Minori Kodaira; Tomoki Kosho; Yutaka Takumi; Naomichi Matsumoto; Yoshiki Sekijima Abstract:We encountered a 27-year-old Japanese woman with sensorineural deafness progressing to motor and sensory neuropathy. At 16 years old, she had developed weakness in her lower extremities and hearing impairment, which gradually deteriorated. At 22 years old, combined audiological, electrophysiological, and radiological examination results were consistent with auditory neuropathy spectrum disorder (ANSD). Genetic analyses identified a previously reported missense variant in the ATP1A1 gene (NM_000701.8:c.1799C>G, p.Pro600Arg). Although sensorineural deafness has been reported as a clinical manifestation of ATP1A1-related disorders, our case suggested that ANSD may underlie the pathogenesis of deafness in ATP1A1-related disorders. This case report broadens the genotype-phenotype spectrum of ATP1A1-related disorders.
Severe Cerebral Small Vessel Disease Caused by the Uniallelic p.A252T Variant of HTRA1. Neurology. Genetics,9(1):e200047 2023(Feb.) Author:Yasufumi Kondo; Tsuneaki Yoshinaga; Katsuya Nakamura; Tomomi Yamaguchi; Masumi Ishikawa; Tomoki Kosho; Yoshiki Sekijima Abstract:OBJECTIVE: To investigate the clinical effect of a heterozygous missense variant of HTRA1 on cerebral small vessel disease (CSVD) in a large Japanese family with a p.A252T variant. METHODS: We performed clinical, laboratory, radiologic, and genetic evaluations of members of a previously reported family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). RESULTS: Two family members were previously reported patients with CARASIL. Among 6 uniallelic p.A252T carriers, 2 had neurologic symptoms with brain MRI abnormalities, 2 showed CSVD on the MRI only, and the other 2 were unaffected. Clinical phenotypes of 2 heterozygous patients were comparable with those of patients with CARASIL, whereas the other 3 heterozygous patients had developed milder and later-onset CSVD. One heterozygous carrier was asymptomatic. DISCUSSION: Previous studies have suggested that uniallelic p.A252T causes disease. However, our study revealed that patients with uniallelic p.A252T can have severe and young-onset CSVD. The clinical manifestations of uniallelic variant carriers were highly variable, even within the same family. Male and atherosclerotic risk factors were considered to be additional factors in the severity of neurologic symptoms in uniallelic p.A252T carriers, suggesting that strict control of vascular risk factors can prevent vascular events in uniallelic HTRA1 carriers.
Moyamoya Disease-like Cerebrovascular Stenotic Lesions Are an Important Phenotype of POEMS Syndrome-associated Vasculopathy. Internal medicine (Tokyo, Japan),61(10):1603-1608 2022(May 15) Author:Yusuke Takahashi; Yusuke Mochizuki; Katsuya Nakamura; Nagaaki Katoh; Yoshiki Sekijima Abstract:A 41-year-old woman was diagnosed with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome based on polyneuropathy, hepatosplenomegaly, sclerotic bone lesions, IgA-λ M-protein, and an elevated level of serum vascular endothelial growth factor. One month after the initiation of lenalidomide-dexamethasone with prophylactic aspirin, she developed facial paralysis, dysarthria, and left hemiplegia. Multiple cerebral infarctions and internal carotid artery stenosis were detected. Five months after switching to pomalidomide-dexamethasone, she again developed cerebral infarction. Progressed stenotic lesions in the bilateral internal carotid artery terminal portions were detected, showing a moyamoya disease-like appearance. Quasi-moyamoya disease can be an important phenotype of systemic vasculopathies of POEMS syndrome.
Heterozygous missense variant in TRPC6 in a boy with rapidly progressive infantile nephrotic syndrome associated with diffuse mesangial sclerosis. American journal of medical genetics. Part A,185(7):2175-2179 2021(Apr. 21) Author:Hiroaki Hanafusa; Yoshihiko Hidaka; Tomomi Yamaguchi; Hisashi Shimojo; Takanori Tsukahara; Tsubasa Murase; Daisuke Matsuoka; Nao Chiba; Shun Shimada; Hirokazu Morokawa; Norio Omori; Hironori Minoura; China Nagano; Kyoko Takano; Katsuya Nakamura; Keiko Wakui; Yoshimitsu Fukushima; Takeshi Uehara; Yozo Nakazawa; Kazumoto Iijima; Kandai Nozu; Tomoki Kosho Abstract:Transient receptor potential channel C6 encoded by TRPC6 is involved in slit diaphragm formation in podocytes, and abnormalities of the TRPC6 protein cause various glomerular diseases. The first identified pathogenic variant of TRPC6 was found to cause steroid-resistant nephrotic syndrome that typically developed in adulthood and then slowly led to end-stage renal disease, along with a renal pathology of focal segmental glomerulosclerosis. Here, we report a patient with rapidly progressing infantile nephrotic syndrome and a heterozygous missense TRPC6 variant. The patient, a 2-year-old Japanese boy, developed steroid-resistant nephrotic syndrome at age 11 months. His renal function deteriorated rapidly, and peritoneal dialysis was introduced at age 1 year and 6 months. His renal pathology, obtained at age 1 year and 1 month, was consistent with diffuse mesangial sclerosis (DMS). Clinical exome analysis and custom panel analysis for hereditary renal diseases revealed a reported heterozygous missense variant in TRPC6 (NM_004621.5:c.523C > T:p.Arg175Trp). This is the first report of a patient with a TRPC6-related renal disorder associated with DMS.
Late-onset Hereditary ATTR Amyloidosis with a Novel p.P63S (P43S) Transthyretin Variant. Internal medicine (Tokyo, Japan),60(4):557-561 2021(Feb. 15) Author:Yuya Aono; Yasuhiro Hamatani; Nagaaki Katoh; Mayuko Nakagawa; Katsuya Nakamura; Masahide Yazaki; Fuyuki Kametani; Moritake Iguchi; Ikuko Murakami; Hisashi Ogawa; Mitsuru Abe; Masaharu Akao; Yoshiki Sekijima Abstract:The patient was an 82-year-old Japanese man with no family history suggestive of amyloidosis. He developed bilateral leg edema and shortness of breath and was referred to our hospital. An electrocardiogram showed atrial fibrillation with right bundle branch block. Echocardiography showed concentric LV hypertrophy. An endomyocardial biopsy showed severe ATTR amyloid deposits. A genetic analysis of the transthyretin (TTR) gene revealed a heterozygous c.187C>T missense variant resulting in p.P63S (P43S). In silico analyses predicted that this variant only modestly altered the structure and function of the TTR protein. The p.P63S variant might be associated with an elderly-onset cardiac-dominant ATTRv phenotype.
A novel frameshift mutation of SYNE1 in a Japanese family with autosomal recessive cerebellar ataxia type 8 Human Genome Variation,4:17052 2017(Oct. 26) Author:Tsuneaki Yoshinaga; Katsuya Nakamura; Masumi Ishikawa; Tomomi Yamaguchi; Kyoko Takano; Keiko Wakui; Tomoki Kosho; Kunihiro Yoshida; Yoshimitsu Fukushima; Yoshiki Sekijima Abstract:A Japanese family with autosomal recessive cerebellar ataxia type 8 (SCAR8, MIM 610743) is described. We identified a novel SYNE1 frameshift deletion (c.6843del, p.Q2282Sfs∗3). This family shared similar clinical manifestations characterized by adult-onset, relatively pure cerebellar ataxia with mild eye movement abnormality. Intelligence and bulbar and respiratory functions were unaffected. This study suggests the clinical utility of using panel-based exome sequencing for genetic diagnosis in hereditary ataxias in a cost-efficient manner.
A case report of WEBINO syndrome with convergence impairment J. Neurol. Neurophysiol.,6:1 2015 Author:Yoshinaga T; Nakamura K; Kaneko K; Nakamura A
Autosomal-recessive complicated spastic paraplegia with a novel lysosomal trafficking regulator gene mutation Journal of Neurology, Neurosurgery and Psychiatry,85(9):1024-1028 2014(Sep.) Author:Haruo Shimazaki; Junko Honda; Tametou Naoi; Michito Namekawa; Imaharu Nakano; Masahide Yazaki; Katsuya Nakamura; Kunihiro Yoshida; Shu Ichi Ikeda; Hiroyuki Ishiura; Yoko Fukuda; Yuji Takahashi; Jun Goto; Shoji Tsuji; Yoshihisa Takiyama Abstract:Background: Autosomal-recessive hereditary spastic paraplegias (AR-HSP) consist of a genetically diverse group of neurodegenerative diseases characterised by pyramidal tracts dysfunction. The causative genes for many types of AR-HSP remain elusive. We tried to identify the gene mutation for AR-HSP with cerebellar ataxia and neuropathy. Methods: This study included two patients in a Japanese family with their parents who are first cousins. Neurological examination and gene analysis were conducted in the two patients and two normal family members. We undertook genome-wide linkage analysis employing single nucleotide polymorphism arrays using the two patients' DNAs and exome sequencing using one patient's sample. Results: We detected a homozygous missense mutation (c.4189T>G, p.F1397V) in the lysosomal trafficking regulator (LYST) gene, which is described as the causative gene for Chédiak-Higashi syndrome (CHS). CHS is a rare autosomal-recessive syndrome characterised by hypopigmentation, severe immune deficiency, a bleeding tendency and progressive neurological dysfunction. This mutation was co-segregated with the disease in the family and was located at well-conserved amino acid. This LYST mutation was not found in 200 Japanese control DNAs. Microscopic observation of peripheral blood in the two patients disclosed large peroxidase-positive granules in both patients' granulocytes, although they had no symptoms of immune deficiency or bleeding tendency. Conclusions: We diagnosed these patients as having adult CHS presenting spastic paraplegia with cerebellar ataxia and neuropathy. The clinical spectrum of CHS is broader than previously recognised. Adult CHS must be considered in the differential diagnosis of AR-HSP.
Response to satomura et al. European Journal of Neurology,21(8):e63 2014(Aug.) Author:K. Nakamura; Y. Sekijima
Clinical and serial MRI findings of a sialidosis type I patient with a novel missense mutation in the NEU1 gene Internal Medicine,52(1):119-124 2013 Author:Yoshiki Sekijima; Katsuya Nakamura; Dai Kishida; Aya Narita; Kaori Adachi; Kosaku Ohno; Eiji Nanba; Shu ichi Ikeda Abstract:The case of a Japanese sialidosis type I patient with a novel NEU1 gene mutation is described. The patient developed an unsteady gait at age 14 and was referred to our hospital at age 16. On admission, subnormal intelligence, dysarthria, myoclonus, intentional tremors, limb and gait ataxia, hyperreflexia and macular cherry-red spots were observed. An enzymological analysis revealed a primary deficiency of neuraminidase. An NEU1 gene analysis identified two heterozygous missense mutations: p.P80L and p.D135N. The p.D135N mutation is a novel mutation that is considered to be associated with the mild clinical phenotype of sialidosis. Serial brain MRI showed diffuse brain atrophy progressing rapidly over the 41-month observation period.
講演・口頭発表等 Clinical features of KIF1A-Related Disorders: A Japanese patient with a novel missense variant and literature review The ASHG 2019 Annual Meeting 2019(Oct. 17) Presenter:Katsuya Nakamura, Emiko Kise, Tomomi Yamaguchi, Tsuneaki Yoshinaga, Minori Kodaira, Yoshiki Sekijima, Tomoki Kosho
Targeting ran proteins improves phenotypes in C9orf72 BAC ALS/FTD mice 2019(Jul. 27) Presenter:L Ranum, L Nguyen, F Montrasio, O Bardhi, S Guo, SK Tusi, K Nakamura, MB Coronel, N Sonenberg, J Grimm, T Zu
Identification of novel variants in spectrin, beta, non-erythrocytic 2 (SPTBN2) in a large cohort of ataxia patients 7th Ataxia Investigators Meeting AIM 2018 2018(Apr. 02) Presenter:Katsuya Nakamura, Tyisha J. Hathorn, Karen Armbrust, Damaris N. Lorenzo, John D.Cleary, Tammy Reid, David A. Ostrov, Eleonora Di Gregorio, Olga Calabrese, Alfredo Brusco, Christopher M. Gomez, Rebekah Jobling, Grace Yoon, S.H. Subramony, Tetsuo Ashizawa1, and Laura P.W. Ranum
Next Generation Sequencing as a Clinical Diagnostic Tool for Hereditary Spinocerebellar Degeneration The 13th International Congress of Human Genetics 2016(Apr.) Presenter:NAKAMURA Katsuya, YOSHIDA Kunihiro, KOSHO Tomoki, TAKANO Kyoko, WAKUI Keiko, SATOH Shunichi, SEKIJIMA Yoshiki, MAKISHITA Hideo, OHARA Shinji, ISHIKAWA Masumi, IKEDA Shu‐ichi, FUKUSHIMA Yoshimitsu, FUKUSHIMA Yoshimitsu
p.E66Q Mutation in the GLA Gene Is an Important Genetic Risk Factor for Stroke in Elderly Japanese Men NEUROLOGY 76 9 A9-A10 2011(Mar.) Presenter:Nakamura Katsuya, Sekijima Yoshiki, Nakamura Kimitoshi, Hattori Kiyoko, Endo Fumio, Nagamatsu Kiyoshiro, Shimizu Yusaku, Ikeda Shu-ichi
Clinical features of KIF1A-Related Disorders: A Japanese patient with a novel missense variant and literature review The American Society of Human Genetics 2019 Annual Meeting 2019(Oct. 17) Author:Katsuya Nakamura; Emiko Kise; Tomomi Yamaguchi; Tsuneaki Yoshinaga; Minori Kodaira; Yoshiki Sekijima; Tomoki Kosho
Targeting ran proteins improves phenotypes in C9orf72 BAC ALS/FTD mice Neuro2019 2019(Jul. 27) Author:L Ranum; L Nguyen; F Montrasio; O Bardhi; S Guo; SK Tusi; K Nakamura; MB Coronel; N Sonenberg; J Grimm; T Zu
Identification of novel variants in spectrin, beta, non-erythrocytic 2 (SPTBN2) in a large cohort of ataxia patients 7th Ataxia Investigators Meeting AIM 2018 2018(Apr. 02) Author:Katsuya Nakamura; Tyisha J. Hathorn; Karen Armbrus; Damaris N. Lorenzo; John D.Cleary; Tammy Reid; David A. Ostrov; Eleonora Di Gregorio; Olga Calabrese; Alfredo Brusco; Christopher M. Gomez; Rebekah Jobling; Grace Yoon; S.H. Subramony; Tetsuo Ashizawa; d Laura; P.W. Ranum
Next Generation Sequencing as a Clinical Diagnostic Tool for Hereditary Spinocerebellar Degeneration The 13th International Congress of Human Genetics 2016(Apr.) Author:NAKAMURA Katsuya; YOSHIDA Kunihiro; KOSHO Tomoki; TAKANO Kyoko; WAKUI Keiko; SATOH Shunichi; SEKIJIMA Yoshiki; MAKISHITA Hideo; OHARA Shinji; ISHIKAWA Masumi; IKEDA Shu‐ichi; FUKUSHIMA Yoshimitsu; FUKUSHIMA Yoshimitsu
p.E66Q Mutation in the GLA Gene Is an Important Genetic Risk Factor for Stroke in Elderly Japanese Men The 63th American Academy of Neurology Annual Meeting 2011(Apr.) Author:Katsuya Nakamura; Yoshiki Sekijima; Kimitoshi Nakamura; Kiyoko Hattori; Fumio Endo; Kiyoshiro Nagamatsu; Yusaku Shimizu; Shu-ichi Ikeda
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