Publications by authors named "Jun Mitsui"

98 Publications

Associations of pathological diagnosis and genetic abnormalities in meningiomas with the embryological origins of the meninges.

Sci Rep 2021 Mar 26;11(1):6987. Epub 2021 Mar 26.

Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.

Certain driver mutations and pathological diagnoses are associated with the anatomical site of meningioma, based on which the meninges have different embryological origins. We hypothesized that mutations and pathological diagnoses of meningiomas are associated with different embryological origins. We comprehensively evaluated associations among tumor location, pathological diagnosis (histological type), and genetic alterations including AKT1, KLF4, SMO, POLR2A, and NF2 mutations and 22q deletion in 269 meningioma cases. Based on the embryological origin of meninges, the tumor locations were as follows: neural crest, paraxial mesodermal, and dorsal mesodermal origins. Tumors originating from the dura of certain embryologic origin displayed a significantly different pathological diagnoses and genetic abnormality ratio. For instance, driver genetic mutations with AKT1, KLF4, SMO, and POLR2A, were significantly associated with the paraxial mesodermal origin (p = 1.7 × 10). However, meningiomas with NF2-associated mutations were significantly associated with neural crest origin (p = 3.9 × 10). On analysis of recurrence, no difference was observed in embryological origin. However, POLR2A mutation was a risk factor for the tumor recurrence (p = 1.7 × 10, Hazard Ratio 4.08, 95% Confidence Interval 1.28-13.0). Assessment of the embryological origin of the meninges may provide novel insights into the pathomechanism of meningiomas.
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http://dx.doi.org/10.1038/s41598-021-86298-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998008PMC
March 2021

Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Japan.

Clin Genet 2021 Mar 27;99(3):359-375. Epub 2020 Nov 27.

Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

We aimed to reveal the genetic features associated with MPZ variants in Japan. From April 2007 to August 2017, 64 patients with 23 reported MPZ variants and 21 patients with 17 novel MPZ variants were investigated retrospectively. Variation in MPZ variants and the pathogenicity of novel variants was examined according to the American College of Medical Genetics standards and guidelines. Age of onset, cranial nerve involvement, serum creatine kinase (CK), and cerebrospinal fluid (CSF) protein were also analyzed. We identified 64 CMT patients with reported MPZ variants. The common variants observed in Japan were different from those observed in other countries. We identified 11 novel pathogenic variants from 13 patients. Six novel MPZ variants in eight patients were classified as likely benign or uncertain significance. Cranial nerve involvement was confirmed in 20 patients. Of 30 patients in whom serum CK levels were evaluated, eight had elevated levels. Most of the patients had age of onset >20 years. In another subset of 30 patients, 18 had elevated CSF protein levels; four of these patients had spinal diseases and two had enlarged nerve root or cauda equina. Our results suggest genetic diversity across patients with MPZ variants.
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http://dx.doi.org/10.1111/cge.13881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898366PMC
March 2021

Targeted deep sequencing of DNA from multiple tissue types improves the diagnostic rate and reveals a highly diverse phenotype of mosaic neurofibromatosis type 2.

J Med Genet 2020 Oct 16. Epub 2020 Oct 16.

Department of Neurosurgery, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

Background: Although 60% of patients with de novo neurofibromatosis type 2 (NF2) are presumed to have mosaic NF2, the actual diagnostic rate of this condition remains low at around 20% because of the existing difficulties in detecting variants with low variant allele frequency (VAF). Here, we examined the correlation between the genotype and phenotype of mosaic NF2 after improving the diagnostic rate of mosaic NF2.

Methods: We performed targeted deep sequencing of 36 genes including using DNA samples from multiple tissues (blood, buccal mucosa, hair follicle and tumour) of 53 patients with de novo NF2 and elucidated their genotype-phenotype correlation.

Results: Twenty-four patients (45.2%) had the germline variant, and 20 patients with NF2 (37.7%) had mosaic NF2. The mosaic NF2 phenotype was significantly different from that in patients with germline variant in terms of distribution of NF2-related disease, tumour growth rate and hearing outcome. The behaviour of schwannoma correlated to the extent of VAF with variant in normal tissues unlike meningioma.

Conclusion: We have improved the diagnostic rate of mosaic NF2 compared with that of previous studies by targeted deep sequencing of DNA from multiple tissues. Many atypical patients with NF2 diagnosed with 'unilateral vestibular schwannoma' or 'multiple meningiomas' presumably have mosaic NF2. Finally, we suggest that the highly diverse phenotype of NF2 could result not only from the type and location of variant but also the extent of VAF in the variant within normal tissue DNA.
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http://dx.doi.org/10.1136/jmedgenet-2020-106973DOI Listing
October 2020

Familial dementia with Lewy bodies with VPS13C mutations.

Parkinsonism Relat Disord 2020 12 7;81:31-33. Epub 2020 Oct 7.

Department of Psychiatry, Yamagata University School of Medicine, Yamagata, Japan.

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http://dx.doi.org/10.1016/j.parkreldis.2020.10.008DOI Listing
December 2020

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy.

Brain Commun 2020 14;2(1):fcz048. Epub 2020 Jan 14.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2-125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0-104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation ( = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.
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http://dx.doi.org/10.1093/braincomms/fcz048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425345PMC
January 2020

Loss-of-function variants in NEK1 are associated with an increased risk of sporadic ALS in the Japanese population.

J Hum Genet 2021 Mar 12;66(3):237-241. Epub 2020 Sep 12.

Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Loss-of-function (LoF) variants in NEK1 have recently been reported to be associated with amyotrophic lateral sclerosis (ALS). In this study, we investigated the association of NEK1 LoF variants with an increased risk of sporadic ALS (SALS) and the clinical characteristics of patients with SALS carrying LoF variants in a Japanese case series. Whole-exome sequencing analysis was performed for a series of 446 SALS patients in whom pathogenic variants in familial ALS-causative genes have not been identified and 1163 healthy control subjects in our Japanese series. We evaluated LoF variants, defined as nonsense, splice-site disrupting single-nucleotide variants (SNVs), or short insertion/deletion (indel) variants predicted to cause frameshifts in NEK1. We identified seven NEK1 LoF variants in patients with SALS (1.57%), whereas only one was identified in control subjects (0.086%) (P = 0.00073, Fisher's exact test). This finding is consistent with those in recent reports from other regions in the world. In conclusion, we demonstrated that NEK1 LoF variants are also associated with an increased risk of SALS in the Japanese population.
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http://dx.doi.org/10.1038/s10038-020-00830-9DOI Listing
March 2021

Juvenile amyotrophic lateral sclerosis with complex phenotypes associated with novel mutations.

Amyotroph Lateral Scler Frontotemporal Degener 2020 Sep 1:1-3. Epub 2020 Sep 1.

Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Mutations in have been originally described to cause a slowly progressive, pure cerebellar ataxia (spinocerebellar ataxia, autosomal-recessive 8; SCAR8). Notably, recent studies revealed that affected patients with -associated ataxia can present with complex phenotypes rather than pure cerebellar ataxia, including motor neuron and brainstem dysfunctions. We herein report a Japanese patient diagnosed with juvenile amyotrophic lateral sclerosis (ALS) with a complex phenotype, who carried compound heterozygous pathogenic variants in . Of the variants, one was a novel frameshift variant and the other was a nonsense variant previously reported as pathogenic for SCAR8. The patient showed an early age at onset with a relatively slow but progressive course of ALS, accompanied by cognitive decline. Our findings suggest that the clinical spectrum of patients carrying pathogenic variants is broader than expected, and variants should be considered in patients diagnosed with juvenile ALS, even without prominent cerebellar ataxia.
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http://dx.doi.org/10.1080/21678421.2020.1813312DOI Listing
September 2020

Splice-site mutations in KIF5A in the Japanese case series of amyotrophic lateral sclerosis.

Neurogenetics 2021 03 19;22(1):11-17. Epub 2020 Aug 19.

Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan.

Our objective was to investigate the frequency of KIF5A variants in amyotrophic lateral sclerosis (ALS) and the clinical characteristics of familial ALS (FALS) associated with variants in KIF5A. Whole-exome sequence analysis was performed for a Japanese series of 43 families with FALS and 444 patients with sporadic ALS (SALS), in whom causative variants had not been identified. We compared the frequencies of rare variants (MAF < 0.01) in KIF5A, including missense and loss of function (LoF) variants, between ALS and control subjects (n = 1163). Clinical characteristics of patients with FALS carrying pathogenic variants in KIF5A were also described. LoF variants were identified only in the probands of two families with FALS, both of which were 3' splice-site variants leading to exon skipping and an altered C-terminal domain, located in the mutational hotspot causing FALS, and were considered to be pathogenic for FALS. Rare missense variants in KIF5A were identified in five patients with SALS (1.13%) and 11 control subjects (0.95%, carrier frequency), which were not significantly different. Consequently, the pathogenic LoF variants in KIF5A accounted for 2.1% of all FALS families in this study. These patients suffered from ALS characteristically associated with the predominant involvement of upper motor neuron. In conclusion, we identified two pathogenic splice-site variants in KIF5A in the probands in two Japanese families with FALS, which altered the C-terminal region of KIF5A. Our findings broaden the phenotype spectrum of ALS associated with variants in KIF5A in the Japanese series.
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http://dx.doi.org/10.1007/s10048-020-00626-1DOI Listing
March 2021

Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis.

Sci Rep 2020 07 20;10(1):11942. Epub 2020 Jul 20.

Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Intracranial artery stenosis (ICAS) is the most common cause of ischemic stroke worldwide. RNF213 single nucleotide variant c.14429G > A (p.Arg4810Lys, rs112735431) was recently reported to be associated with ICAS in East Asians. However, the disease susceptibility of other RNF213 variants has not been clarified. This study comprehensively investigated ICAS-associated RNF213 variants in a pool of 168 Japanese ICAS patients and 1,194 control subjects. We found 138 nonsynonymous germline variants by target resequencing of all coding exons in RNF213. Association study between ICAS patients and control subjects revealed that only p.Arg4810Lys had significant association with ICAS (P = 1.5 × 10, odds ratio = 29.3, 95% confidence interval 15.31-56.2 [dominant model]). Fourteen of 138 variants were rare variants detected in ICAS patients not harboring p.Arg4810Lys variant. Two of these rare variants (p.Cys118Arg and p.Leu2356Phe) consistent with variants previously reported in moyamoya disease patients characterized by stenosis of intracranial artery and association with RNF213, and three rare variants (p.Ser193Gly, p.Val1817Leu, and p.Asp3329Tyr) were found neither in control subjects and Single Nucleotide Polymorphism Database. The present findings may improve our understanding of the genetic background of intracranial artery stenosis.
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http://dx.doi.org/10.1038/s41598-020-68888-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371676PMC
July 2020

Esophageal Dysmotility is Common in Patients With Multiple System Atrophy.

Laryngoscope 2021 04 4;131(4):832-838. Epub 2020 Jul 4.

Department of Otolaryngology and Head and Neck Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Objectives: Esophageal dysmotility (ED) in patients with multiple system atrophy (MSA) are poorly understood. This study aimed to investigate the prevalence of ED in patients with MSA and to assess the relationship of esophageal abnormalities with other clinical findings and characteristics in these patients.

Methods: A retrospective chart review was conducted to identify patients with MSA and to compare them to the elderly controls without MSA (65+ years) who underwent a videofluorographic esophagram from 2014 to 2019. Disease type, disease severity, vocal fold mobility impairment, abnormal deglutitive proximal esophageal contraction (ADPEC), and intra-esophageal stasis (IES) were reviewed and compared between groups.

Results: Thirty-seven patients with MSA were identified. The median age was 63 and 26 (70%) were male. These patients were matched to 22 elderly adults with presbylarynx but not MSA (median age 77, 68% male). In MSA patients, cerebellar variant type was predominant (59%), and ADPEC was recognized in 18 patients (49%). Disease severity level (P = 0.028) and existence of IES (P = 0.046) were associated with higher risks of developing ADPEC. The prevalence of IES was significantly higher in patients with MSA (95%) compared to controls without MSA (46%) (P < 0.001). Disease severity level and the existence of IES were significantly associated with the presence of ADPEC (p < 0.05).

Conclusion: ADPEC and IES were significantly more common in MSA than in elderly subjects without MSA. MSA severity is associated with the development of ADPEC. The data suggest that esophageal motility is predominantly affected in MSA.

Level Of Evidence: 3 Laryngoscope, 131:832-838, 2021.
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http://dx.doi.org/10.1002/lary.28852DOI Listing
April 2021

Germline MICA Polymorphism Is Associated with the Long-Term Outcomes in Patients Undergoing Hepatectomy for Colorectal Liver Metastases.

J Gastrointest Surg 2020 09 10;24(9):2137-2139. Epub 2020 Jun 10.

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8654, Japan.

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http://dx.doi.org/10.1007/s11605-020-04659-7DOI Listing
September 2020

Clinical and molecular genetic characterization of two female patients harboring the Xq27.3q28 deletion with different ratios of X chromosome inactivation.

Hum Mutat 2020 08 19;41(8):1447-1460. Epub 2020 Jun 19.

Department of Genetics, Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai, Aichi, Japan.

A heterozygous deletion at Xq27.3q28 including FMR1, AFF2, and IDS causing intellectual disability and characteristic facial features is very rare in females, with only 10 patients having been reported. Here, we examined two female patients with different clinical features harboring the Xq27.3q28 deletion and determined the chromosomal breakpoints. Moreover, we assessed the X chromosome inactivation (XCI) in peripheral blood from both patients. Both patients had an almost overlapping deletion at Xq27.3q28, however, the more severe patient (Patient 1) showed skewed XCI of the normal X chromosome (79:21) whereas the milder patient (Patient 2) showed random XCI. Therefore, deletion at Xq27.3q28 critically affected brain development, and the ratio of XCI of the normal X chromosome greatly affected the clinical characteristics of patients with deletion at Xq27.3q28. As the chromosomal breakpoints were determined, we analyzed a change in chromatin domains termed topologically associated domains (TADs) using published Hi-C data on the Xq27.3q28 region, and found that only patient 1 had a possibility of a drastic change in TADs. The altered chromatin topologies on the Xq27.3q28 region might affect the clinical features of patient 1 by changing the expression of genes just outside the deletion and/or the XCI establishment during embryogenesis resulting in skewed XCI.
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http://dx.doi.org/10.1002/humu.24058DOI Listing
August 2020

An autopsy case of G gangliosidosis type II in a patient who survived a long duration with artificial respiratory support.

Neuropathology 2020 Aug 27;40(4):379-388. Epub 2020 Mar 27.

Department of Neurology, Kitasato University School of Medicine, Sagamihara-shi, Japan.

G gangliosidosis is a storage disorder with autosomal recessive inheritance caused by deficiency of β-galactosidase (GLB1), which is a lysosomal hydrolase, due to mutations in GLB1. We describe here an autopsy case of G gangliosidosis in a female patient who survived for 38 years with a long period of artificial respiratory support (ARS). She was born after a normal pregnancy and delivery. Although development was normal until one year old, she was unable to walk at two years old and started having seizures by nine years old. At 21 years old, she became unable to communicate and was bed-ridden. At 36 years old, she suffered from pneumonia and required ARS. She died of pneumonia at 40 years old. Neuropathological examination revealed severe atrophy, predominantly found in the frontal lobes. Microscopically, severe gliosis and neuronal loss were observed in the cerebral cortex, putamen, cerebellum, the latter including Purkinje cell and granule cell layers. The hippocampus was relatively preserved. Severe neuronal swelling was observed in the limbic regions and stored a material in these neurons negative for periodic acid-Schiff (PAS). A PAS-positive granular storage material in neurons and macrophages was mainly observed in the brainstem and limbic regions. Exome analysis showed a known c.152T>C (p.I51T) variant that has been described in type III patients and a novel c.1348-2A>G variant in GLB1. Detailed analysis of reverse transcription-polymerase chain reaction products of GLB1 mRNA revealed that these variants were present in a compound heterozygous state. In our case, clinical features and neuropathological findings were most consistent with type II, although the entire course was longer than any previously reported cases. This may be explained by the residual enzyme activity in this patient whose severity lay between types II and III. Our finding of relative preservation of the limbic regions suggests that neuronal loss in G gangliosidosis has regional selectivity.
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http://dx.doi.org/10.1111/neup.12651DOI Listing
August 2020

Clinical features of inherited neuropathy with BSCL2 mutations in Japan.

J Peripher Nerv Syst 2020 06 12;25(2):125-131. Epub 2020 Mar 12.

Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene have been reported with different clinical phenotypes including Silver syndrome (SS)/spastic paraplegia 17 (SPG17), distal hereditary motor neuropathy type V (dHMN-V), and Charcot-Marie-Tooth (CMT) disease type 2. We screened 407 Japanese patients who were clinically suspected of having CMT by exome sequencing and searched mutations in BSCL2. As a result, we identified five patients with heterozygous mutations in BSCL2. We confirmed three cases of known mutations (p.N88S and p.S90L) and two cases of novel mutations (p.N88T and p.S141A). The clinical features of the cases with known mutations in Japan were similar to those previously reported in other countries. In particular, there were many cases with sensory disturbance. The case with p.N88T mutation showed severe phenotype such as early onset age and prominent vocal cord paresis. The case with p.S141A mutation showed characteristics of demyelinating neuropathy such as CMT disease type 1 by electrophysiological examination. In this article, we report the clinical features and spread of cases with BSCL2 mutation in a Japanese cohort.
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http://dx.doi.org/10.1111/jns.12369DOI Listing
June 2020

A Novel de novo KIF1A Mutation in a Patient with Autism, Hyperactivity, Epilepsy, Sensory Disturbance, and Spastic Paraplegia.

Intern Med 2020 Mar 6;59(6):839-842. Epub 2019 Dec 6.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, Japan.

Heterozygous mutations in KIF1A have been reported to cause syndromic intellectual disability or pure spastic paraplegia. However, their genotype-phenotype correlations have not been fully elucidated. We herein report a man with autism and hyperactivity along with sensory disturbance and spastic paraplegia, carrying a novel de novo mutation in KIF1A [c.37C>T (p.R13C)]. Autism and hyperactivity have only previously been reported in a patient with c.38 G>A (R13H) mutation. This case suggests that alterations in this arginine at codon 13 might lead to a common clinical spectrum and further expand the genetic and clinical spectra associated with KIF1A mutations.
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http://dx.doi.org/10.2169/internalmedicine.3661-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118386PMC
March 2020

UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias (SPG80) and impair UBAP1 targeting to endosomes.

J Hum Genet 2019 Nov 12;64(11):1055-1065. Epub 2019 Sep 12.

Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.

We aimed to find a new causative gene and elucidate the molecular mechanisms underlying a new type of hereditary spastic paraplegia (HSP). Patients with HSP were recruited from the Japan Spastic Paraplegia Research Consortium (JASPAC). Exome sequencing of genomic DNA from patients in four families was carried out, followed by Sanger sequencing of the UBAP1 gene. A mouse homolog of one UBAP1 frameshift mutation carried by one of the patients was created as a disease model. Functional properties of the UBAP1 wild type and UBAP1-mutant in mouse hippocampus neurons were examined. We identified three novel heterozygous loss of function mutations (c.425_426delAG, c.312delC, and c.535G>T) in the UBAP1 gene as the genetic cause of a new type of HSP (SPG80). All the patients presented identical clinical features of a pure type of juvenile-onset HSP. Functional studies on mouse hippocampal neurons revealed that the C-terminal deletion UBAP1-mutant of our disease model had lost its ability to bind ubiquitin in vitro. Overexpression of the UBAP1 wild type interacts directly with ubiquitin on enlarged endosomes, while the UBAP1-mutant cannot be recruited to endosome membranes. Our study demonstrated that mutations in the UBAP1 gene cause a new type of HSP and elucidated its pathogenesis. The full-length UBAP1 protein is involved in endosomal dynamics in neurons, while loss of UBAP1 function may perturb endosomal fusion and sorting of ubiquitinated cargos. These effects could be more prominent in neurons, thereby giving rise to the phenotype of a neurodegenerative disease such as HSP.
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http://dx.doi.org/10.1038/s10038-019-0670-9DOI Listing
November 2019

Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease.

Nat Genet 2019 08 22;51(8):1222-1232. Epub 2019 Jul 22.

Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan.

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.
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http://dx.doi.org/10.1038/s41588-019-0458-zDOI Listing
August 2019

Atypical Familial Amyotrophic Lateral Sclerosis with Slowly Progressing Lower Extremities-predominant Late-onset Muscular Weakness and Atrophy.

Intern Med 2019 1;58(13):1851-1858. Epub 2019 Jul 1.

Department of Neurology, The University of Tokyo Hospital, Japan.

Objective Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the progressive loss of the upper and lower motor neurons that progresses to paralysis of almost all skeletal muscles of the extremities, bulbar, and respiratory system. Although most ALS cases are sporadic, about 10% are dominantly inherited. We herein report an atypical phenotype of familial ALS (fALS). To elucidate the phenotype-genotype correlation of this atypical phenotype of fALS, clinical and genetic investigations were performed. Methods and Patients Five sibling patients (three men, two women) from a Japanese family and one healthy sibling (a woman) were clinically interviewed and examined. Genetic analyses, including genome-wide linkage analyses and whole-exome sequencing, were performed using genomic DNA extracted from the peripheral blood samples of these siblings. Results The clinical features of fALS are characterized by slow progression (mean duration of the disease±standard deviation [SD]: 19.6±3.9 years) and lower extremities-predominant late-onset muscular weakness (mean onset of muscular weakness±SD: 52.8±2.6 years). Genetic analyses revealed novel heterozygous missense mutations of c.2668C>T, p.R890C in the PLEC gene and c.421G>C, p.V141L in the ST3GAL6 gene in all affected siblings. Conclusion A new atypical fALS family with a benign clinical course is herein reported. We identified two candidate gene mutations of PLEC and ST3GAL6 linked to this phenotype.
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http://dx.doi.org/10.2169/internalmedicine.2222-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663526PMC
October 2019

Ataxic phenotype with altered Ca3.1 channel property in a mouse model for spinocerebellar ataxia 42.

Neurobiol Dis 2019 10 20;130:104516. Epub 2019 Jun 20.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel Ca3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of Ca3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His Ca3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.
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http://dx.doi.org/10.1016/j.nbd.2019.104516DOI Listing
October 2019

Prominent Spasticity and Hyperreflexia of the Legs in a Nepalese Patient with Friedreich Ataxia.

Intern Med 2019 Oct 7;58(19):2865-2869. Epub 2019 Jun 7.

Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Japan.

Friedreich ataxia (FRDA) is an autosomal recessive spinocerebellar ataxia caused by mutations of FXN. Hypotonus and hyporeflexia of the lower extremities are observed in most FRDA patients. Patients with hyperreflexia, called Friedreich ataxia with retained reflexes (FARR), have also been identified. We herein report the case of a 16-year-old Nepalese boy presenting with early-onset ataxia with prominent spasticity and hyperreflexia of the legs. Mutational analyses established the diagnosis of FRDA presenting as FARR. A haplotype analysis revealed that expanded alleles of the patient shared a common haplotype with Indian and European FRDA patients, suggesting that the mutation descended from a common founder.
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http://dx.doi.org/10.2169/internalmedicine.2953-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815894PMC
October 2019

Functional evaluation of PDGFB-variants in idiopathic basal ganglia calcification, using patient-derived iPS cells.

Sci Rep 2019 04 5;9(1):5698. Epub 2019 Apr 5.

Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu, Japan.

Causative genes in patients with idiopathic basal ganglia calcification (IBGC) (also called primary familial brain calcification (PFBC)) have been reported in the past several years. In this study, we surveyed the clinical and neuroimaging data of 70 sporadic patients and 16 families (86 unrelated probands in total) in Japan, and studied variants of PDGFB gene in the patients. Variant analyses of PDGFB showed four novel pathogenic variants, namely, two splice site variants (c.160 + 2T > A and c.457-1G > T), one deletion variant (c.33_34delCT), and one insertion variant (c.342_343insG). Moreover, we developed iPS cells (iPSCs) from three patients with PDGFB variants (c.160 + 2T > A, c.457-1G > T, and c.33_34 delCT) and induced endothelial cells. Enzyme-linked immunoassay analysis showed that the levels of PDGF-BB, a homodimer of PDGF-B, in the blood sera of patients with PDGFB variants were significantly decreased to 34.0% of that of the control levels. Those in the culture media of the endothelial cells derived from iPSCs of patients also significantly decreased to 58.6% of the control levels. As the endothelial cells developed from iPSCs of the patients showed a phenotype of the disease, further studies using IBGC-specific iPSCs will give us more information on the pathophysiology and the therapy of IBGC in the future.
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http://dx.doi.org/10.1038/s41598-019-42115-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450963PMC
April 2019

Whole-exome sequencing in a Japanese pedigree implicates a rare non-synonymous single-nucleotide variant in BEST3 as a candidate for mandibular prognathism.

Bone 2019 05 5;122:193-198. Epub 2019 Mar 5.

Department of Orthodontics, Division of Oral Functional Science, Graduate School of Dental Medicine, Hokkaido University, Kita 13 Nishi 7, Kita-ku, Sapporo 060-8586, Japan.

Mandibular prognathism is a phenotype of facial deformity seen in populations around the world, but with higher incidence among East Asian populations. Five genome-wide nonparametric linkage analyses and a genome-wide association study to identify susceptibility loci of the phenotype have shown inconsistent results. To explore variants related to mandibular prognathism, we undertook whole-exome sequencing in a Japanese pedigree. The pedigree was ascertained as mandibular prognathism. The pedigree comprised 15 individuals from 4 generations. Four affected individuals across 2 generations and 5 unaffected individuals were chosen for whole-exome sequencing. Five non-synonymous single-nucleotide variants (SNVs) of UBASH3B, OR6M1, OR8D4, OR8B4, and BEST3 genes were detected in all 4 affected individuals, but in none of the 5 unaffected individuals. A non-synonymous SNV of the BEST3 gene, Chr12(GRCh37):g.70048878G>T, NM_032735.2:c.1816C>A, p.(L606I), was identified as rare missense variant. BEST3 is located on chromosome 12q15 and encodes bestrophin 3 from the bestrophin family of anion channels. The 4 other non-synonymous SNVs of UBASH3B, OR6M1, OR8D4, and OR8B4 were not considered plausible candidates for mandibular prognathism. Our whole-exome sequencing implicates a rare non-synonymous SNV of BEST3 as a candidate for mandibular prognathism in the Japanese pedigree.
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http://dx.doi.org/10.1016/j.bone.2019.03.004DOI Listing
May 2019

Association of ATXN2 intermediate-length CAG repeats with amyotrophic lateral sclerosis correlates with the distributions of normal CAG repeat alleles among individual ethnic populations.

Neurogenetics 2019 05 7;20(2):65-71. Epub 2019 Mar 7.

Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan.

Intermediate-length CAG repeats in ATXN2 have been widely shown to be a risk factor for sporadic amyotrophic lateral sclerosis (SALS). To evaluate the association of ATXN2 intermediate-length CAG repeat alleles with an increased risk of SALS, we investigated distributions of CAG repeat alleles in 394 patients with SALS and 490 control individuals in the Japanese population. In the intermediate-length repeat units of 29 or more, we identified one SALS patient with 31 repeat units and two control individuals with 30 repeat units. Thus, no significant differences in the carrier frequency of intermediate-length CAG repeat alleles were detected between patients with SALS and control individuals. When we investigated the distribution of "large normal alleles" defined as ATXN2 CAG repeats ranging from 24 up to 33 in the Japanese population compared with those in other populations in previous studies, the frequency of large normal alleles was significantly higher in the European and North American series than in the Japanese series. Moreover, these frequencies in the Turkish, Chinese, Korean, and Brazilian (Latin American) series were also higher than that in the Japanese series. These results raise the possibility that the frequencies of large normal alleles in individual populations underlie the frequencies of ALS risk alleles in the corresponding populations.
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http://dx.doi.org/10.1007/s10048-019-00570-9DOI Listing
May 2019

Oxygen consumption rate for evaluation of COQ2 variants associated with multiple system atrophy.

Neurogenetics 2019 03 7;20(1):51-52. Epub 2019 Jan 7.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

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http://dx.doi.org/10.1007/s10048-018-0563-7DOI Listing
March 2019

CNV analysis using whole exome sequencing identified biallelic CNVs of VPS13B in siblings with intellectual disability.

Eur J Med Genet 2020 Jan 30;63(1):103610. Epub 2018 Dec 30.

Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan; Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan. Electronic address:

Cohen syndrome is an autosomal recessive disease characterized by myopia, retinal dystrophy, neutropenia, short stature, microcephaly, persistent hypotonia, intellectual disability (ID), and a distinct facial appearance. Cohen syndrome is caused by mutations, such as single nucleotide variants (SNVs) and small insertions/deletions, and copy number variations (CNVs) in vacuolar protein sorting 13 homolog B (VPS13B). Here, we report Japanese siblings with ID, who were subsequently diagnosed with Cohen syndrome by whole exome sequencing (WES). The older sister had hypotonia and mild to moderate ID. The younger sister had short stature, postnatal onset microcephaly, and developmental delay. No pathogenic mutations, including SNVs or small insertions/deletions, were found by WES. Comparative genomic hybridization (CGH)-array did not detect pathogenic copy-number variations. However, using log2-ratio values calculated from WES depth data, we detected pathogenic biallelic heterozygous CNVs in VPS13B in both sisters: a maternally-derived exons 8-15 deletion and a paternally-derived exons 32-33 deletion. Interestingly, the sisters did not show obvious clinical features suggestive of Cohen syndrome, including the distinct facial appearance. These results support the idea that the typical facial features of Cohen syndrome do not appear in early childhood, and that the late appearance of distinctive clinical features results in delayed diagnosis. Furthermore, these results show the possibility that CNV analysis using log2-ratio values calculated from WES depth data is a useful and effective method to detect CNVs, such as the deletion of multiple exons.
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http://dx.doi.org/10.1016/j.ejmg.2018.12.015DOI Listing
January 2020

Neuroimaging, genetic, and enzymatic study in a Japanese family with a GBA gross deletion.

Parkinsonism Relat Disord 2019 04 2;61:57-63. Epub 2018 Dec 2.

Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan. Electronic address:

Introduction: Glucocerebrosidase gene (GBA) variants are associated with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The molecular mechanisms underlying these diseases with GBA variants, however, are not well understood. In order to determine the effect of a deletion mutation in GBA, we performed a neuroimaging, genetic, and enzymatic study in a Japanese family with a gross deletion of exons 3 to 11 in GBA.

Methods: We performed [I] FP-CIT SPECT and [I] N-isopropyl-p-iodoamphetamine SPECT (IMP-SPECT), and determined GBA expression and glucocerebrosidase (GCase) activity in leukocytes in two GBA-associated PD patients and nine unaffected individuals (including four mutation carriers) in a Japanese family with a heterozygous gross deletion mutation in the GBA gene.

Results: The two PD patients and two of the four clinically unaffected carriers showed decreased [I] FP-CIT uptake. IMP-SPECT showed a pattern like that in DLB in one patient. When we compared PD patients with GBA mutations with clinically unaffected carriers, there was a poor correlation between the development of PD and the expression level of GBA or GCase activity.

Conclusion: We confirmed the gross deletion mutation in the GBA gene, which appeared to be associated with the PD or reduced [I] FP-CIT in this family. However, since we cannot conclude whether a reduction of GCase activity is directly correlated with the pathogenesis of PD or not, longitudinal follow-up of this family is needed.
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http://dx.doi.org/10.1016/j.parkreldis.2018.11.028DOI Listing
April 2019

Simultaneous detection of reduced and oxidized forms of coenzyme Q10 in human cerebral spinal fluid as a potential marker of oxidative stress.

J Clin Biochem Nutr 2018 Nov 8;63(3):205-210. Epub 2018 Jun 8.

Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan.

The redox balance of coenzyme Q10 in human plasma is a good marker of oxidative stress because the reduced form of coenzyme Q10 (ubiquinol-10) is very sensitive to oxidation and is quantitatively converted to its oxidized form (ubiquinone-10). Here we describe an HPLC method for simultaneous detection of ubiquinol-10 and ubiquinone-10 in human cerebral spinal fluid to meet a recent demand for measuring local oxidative stress. Since the levels of coenzyme Q10 in human cerebral spinal fluid are less than 1/500 of those in human plasma, cerebral spinal fluid extracted with 2-propanol requires concentration for electrochemical detection. Using human plasma diluted 500-fold with physiological saline as a pseudo-cerebral spinal fluid, we found that addition of -butylhydroquinone was effective in preventing the oxidation of ubiquinol-10. The optimized -butylhydroquinone concentration in the extraction solvent was 20 µM. The addition of 20 µM ascorbic acid or co-addition of -butylhydroquinone and ascorbic acid (20 µM each) were also effective in preventing the oxidation of ubiquinol-10, but ascorbic acid alone gave poor reproducibility. Good within day reproducibility was observed, and day-to-day analytical variance was excellent.
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http://dx.doi.org/10.3164/jcbn.17-131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252302PMC
November 2018

Correction: PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia.

J Hum Genet 2019 01;64(1):61-63

Department of Neurology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.

The originally published version of this article contained an error in Fig. 1 and Table 2. The correct figure and table of this article should have read as below. This has now been corrected in the PDF and HTML versions of the article. The authors apologize for any inconvenience caused.
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http://dx.doi.org/10.1038/s10038-018-0533-9DOI Listing
January 2019

Burden of rare variants in causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS.

J Neurol Neurosurg Psychiatry 2019 05 24;90(5):537-542. Epub 2018 Oct 24.

Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Objectives: To evaluate the burden of rare variants in the causative genes for amyotrophic lateral sclerosis (ALS) on the age at onset of ALS in a Japanese case series.

Methods: We conducted whole-exome sequencing analysis of 89 families with familial ALS (FALS) and 410 patients with sporadic ALS (SALS) to identify known pathogenic mutations or rare functionally predicted deleterious variants in the causative genes for ALS. Rare variants (minor allele frequency <1%) with scaled Combined Annotation-Dependent Depletion score >20 were defined as rare functionally predicted deleterious variants. The patients with ALS were classified on the basis of the number of pathogenic and/or rare functionally predicted deleterious variants, and the age at onset was compared among the classified groups.

Results: Whole-exome sequencing analysis revealed known pathogenic mutations or rare functionally predicted deleterious variants in causative genes for ALS in 56 families with FALS (62.9%) and 87 patients with SALS (21.2%). Such variants in multiple genes were identified in seven probands with FALS and eight patients with SALS. The ages at onset in the patients with ALS with multiple variants were significantly earlier than those in other patients with ALS. Even when the patients with known pathogenic mutations were excluded, a significantly earlier onset of the disease was still observed in patients with multiple rare functionally predicted deleterious variants.

Conclusions: A substantial number of patients carried rare variants in multiple genes, and the burden of rare variants in the known causative genes for ALS affects the age at onset in the Japanese ALS series.
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http://dx.doi.org/10.1136/jnnp-2018-318568DOI Listing
May 2019

PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia.

J Hum Genet 2019 Jan 9;64(1):55-59. Epub 2018 Oct 9.

Department of Neurology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.

PLA2G6-associated neurodegeneration (PLAN) comprises heterogeneous neurodegenerative disorders, including infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation 2B, and Parkinson disease 14 (PARK14). In addition, very recently, PLA2G6 mutations have been reported to represent a phenotype of hereditary spastic paraplegia (HSP). In this study, we screened 383 HSP families to clarify the frequency of PLA2G6 mutations in the Japan Spastic Paraplegia Research Consortium, and revealed the clinical characteristics of HSP with PLA2G6 mutations. We found three families with compound heterozygous mutations of the PLA2G6 gene, c.517 C > T/c.1634A > G, c.662 T > C/c.991 G > T, and c.1187-2 A > G/c.1933C > T, and one family with a homozygous mutation of the PLA2G6 gene, c.1904G > A/c.1904G > A. All three families with compound heterozygous mutations presented a uniform phenotype of a complicated form of HSP with infantile/child-onset spastic paraplegia, cerebellar ataxia, and mental retardation. On the other hand, the family with a homozygous mutation presented a late-onset complicated form of HSP with parkinsonism. This study may extend the clinical and genetic findings for PLAN.
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http://dx.doi.org/10.1038/s10038-018-0519-7DOI Listing
January 2019