Noriko Miyake

Yokohama City University, Yokohama, Kanagawa, Japan

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Publications (189)762.87 Total impact

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    ABSTRACT: KCNT1 mutations have been found in epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies (EOEEs). We performed KCNT1-targeted next-generation sequencing (207 samples) and/or whole-exome sequencing (229 samples) in a total of 362 patients with Ohtahara syndrome, West syndrome, EIMFS, or unclassified EOEEs. We identified nine heterozygous KCNT1 mutations in 11 patients: nine of 18 EIMFS cases (50%) in whom migrating foci were observed, one of 180 West syndrome cases (0.56%), and one of 66 unclassified EOEE cases (1.52%). KCNT1 mutations occurred de novo in 10 patients, and one was transmitted from the patient's mother who carried a somatic mosaic mutation. The mutations accumulated in transmembrane segment 5 (2/9, 22.2%) and regulators of K(+) conductance domains (7/9, 77.8%). Five of nine mutations were recurrent. Onset ages ranged from the neonatal period (<1 month) in five patients (5/11, 45.5%) to 1-4 months in six patients (6/11, 54.5%). A generalized attenuation of background activity on electroencephalography was seen in six patients (6/11, 54.5%). Our study demonstrates that the phenotypic spectrum of de novo KCNT1 mutations is largely restricted to EIMFS. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.
    Epilepsia 07/2015; DOI:10.1111/epi.13072 · 4.58 Impact Factor
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    ABSTRACT: Glycine encephalopathy (GCE) is a rare autosomal recessive disorder caused by defects in the glycine cleavage complex. Here we report a patient with GCE and elevated level of glycine in both the serum and the cerebrospinal fluid. Trio-based whole-exome sequencing identified novel compound heterozygous mutations (c.738-2A>G and c.929T>C (p.Met310Thr)) in LIAS. To date, three homozygous mutations have been reported in LIAS. All previously reported GCE patients also show elevated level of serum glycine. Our data further supports LIAS mutations as a genetic cause for GCE.Journal of Human Genetics advance online publication, 25 June 2015; doi:10.1038/jhg.2015.72.
    Journal of Human Genetics 06/2015; DOI:10.1038/jhg.2015.72 · 2.53 Impact Factor
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    ABSTRACT: Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder associated with mitochondrial dysfunction. LS is characterised by elevated lactate and pyruvate and bilateral symmetric hyperintense lesions in the basal ganglia, thalamus, brainstem, cerebral white matter or spinal cord on T2-weighted MRI. LS is a genetically heterogeneous disease, and to date mutations in approximately 40 genes related to mitochondrial function have been linked to the disorder. We investigated a pair of female monozygotic twins diagnosed with LS from consanguineous healthy parents of Indian origin. Their common clinical features included optic atrophy, ophthalmoplegia, spastic paraparesis and mild intellectual disability. High-blood lactate and high-intensity signal in the brainstem on T2-weighted MRI were consistent with a clinical diagnosis of LS. To identify the genetic cause of their condition, we performed whole exome sequencing. We identified a homozygous nonsense mutation in C12orf65 (NM_001143905; c.346delG, p.V116*) in the affected twins. Interestingly, the identical mutation was previously reported in an Indian family with Charcot-Marie Tooth disease type 6, which displayed some overlapping clinical features with the twins. We demonstrate that the identical nonsense mutation in C12orf65 can result in different clinical features, suggesting the involvement of unknown modifiers. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Journal of neurology, neurosurgery, and psychiatry 05/2015; DOI:10.1136/jnnp-2014-310084 · 5.58 Impact Factor
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    ABSTRACT: De novo GNAO1 variants have been found in four patients including three patients with Ohtahara syndrome and one patient with childhood epilepsy. In addition, two patients showed involuntary movements, suggesting that GNAO1 variants can cause various neurological phenotypes. Here we report an additional four patients with de novo missense GNAO1 variants, one of which was identical to that of the previously reported. All the three novel variants were predicted to impair Gαo function by structural evaluation. Two patients showed early-onset epileptic encephalopathy, presenting with migrating or multifocal partial seizures in their clinical course, but the remaining two patients showed no or a few seizures. All the four patients showed severe intellectual disability, motor developmental delay, and involuntary movements. Progressive cerebral atrophy and thin corpus callosum were common features in brain images. Our study demonstrated that GNAO1 variants can cause involuntary movements and severe developmental delay with/without seizures, including various types of early-onset epileptic encephalopathy.European Journal of Human Genetics advance online publication, 13 May 2015; doi:10.1038/ejhg.2015.92.
    European journal of human genetics: EJHG 05/2015; DOI:10.1038/ejhg.2015.92 · 4.23 Impact Factor
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    ABSTRACT: Generalized hypertrichosis is a feature of several genetic disorders, and the nosology of these entities is still provisional. Recent studies have implicated chromosome 17q24.2-q24.3 microdeletion and the reciprocal microduplication in a very rare form of congenital generalized hypertrichosis terminalis (CGHT) with or without gingival hyperplasia. Here, we report on a 5-year-old Egyptian girl born to consanguineous parents. The girl presented with CGHT and gingival hyperplasia for whom we performed detailed clinical, pathological, and molecular studies. The girl had coarse facies characterized by bilateral epicanthic folds, thick and abundant eyelashes, a broad nose, full cheeks, and lips that constituted the distinctive facial features for this syndrome. Biopsy of the gingiva showed epithelial marked acanthosis and hyperkeratosis with hyperplastic thick collagen bundles and dense fibrosis in the underlying tissues. Array analysis indicated a 17q24.2-q24.3 chromosomal microdeletion. We validated this microdeletion by real-time quantitative PCR and confirmed a perfect co-segregation of the disease phenotype within the family. In summary, this study indicates that 17q24.2-q24.3 microdeletion caused CGHT with gingival hyperplasia and distinctive facies, which should be differentiated from the autosomal recessive type that lacks the distinctive facies. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 05/2015; DOI:10.1002/ajmg.a.37185 · 2.05 Impact Factor
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    ABSTRACT: Focal cortical dysplasia (FCD) Type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD Type IIb. We collected a total of 24 blood-brain paired samples with FCD, including 13 individuals with FCD Type IIb, five with Type IIa, and six with Type I. We performed whole exome sequencing using paired samples from nine of the FCD Type IIb subjects. Somatic MTOR mutations were identified and further investigated using all 24 paired samples by deep sequencing of the entire gene's coding region. Somatic MTOR mutations were confirmed by droplet digital PCR. The effect of MTOR mutations on mTOR kinase signaling was evaluated by immunohistochemistry and western blot analyses of brain samples and by in vitro transfection experiments. We identified four lesion-specific somatic MTOR mutations in six of 13 (46%) individuals with FCD Type IIb showing mutant allele rates of 1.11-9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD Type IIb brain tissues with MTOR mutations was clearly elevated compared with control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase. We found low-prevalence somatic mutations in MTOR in FCD Type IIb, indicating that activating somatic mutations in MTOR cause FCD Type IIb. This article is protected by copyright. All rights reserved. © 2015 American Neurological Association.
    Annals of Neurology 05/2015; DOI:10.1002/ana.24444 · 11.91 Impact Factor
  • European Journal of Paediatric Neurology 05/2015; 19:S76. DOI:10.1016/S1090-3798(15)30252-X · 1.93 Impact Factor
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    ABSTRACT: We encountered a 5-year-old girl who had short-lasting, severe, unilateral temporal headaches with ipsilateral lacrimation, nasal congestion and rhinorrhoea, and facial flushing after severe attacks. Family history revealed similar short-lasting, severe headaches in an older brother, younger sister, mother, maternal aunt, and maternal grandfather's brother. We performed routine laboratory examinations and electrophysiological and radiological studies for three children, and whole-exome sequencing to determine the genetic causality in this family. Focal hyperperfusion of the right trigeminal root entry zone was seen during a right-sided attack in one child, while left-sided temporal headache attacks were provoked by bilateral electrical stimulation of the upper extremities in another. We identified a novel SCN9A mutation (NM_002977: c.5218G>C, p.Val1740Leu) in all affected family members, but not in any of the unaffected members. SCN9A encodes the voltage-gated sodium-channel type IX alpha subunit known as Nav1.7. Gain-of-function mutations in Nav1.7 are well known to cause paroxysmal extreme pain disorder (PEPD), a painful Na-channelopathy characterized by attacks of excruciating deep burning pain in the rectal, ocular, or jaw areas. The SCN9A mutation suggests that our patients had a phenotype of PEPD with a predominant symptom of short-lasting, severe, unilateral headache.
    The Journal of Headache and Pain 04/2015; 16(1):35. DOI:10.1186/s10194-015-0519-3 · 3.28 Impact Factor
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    ABSTRACT: Using whole exome sequencing, we confirmed a diagnosis of biotin-responsive basal ganglia disease (BBGD) accompanied by possible Kawasaki Disease. BBGD is an autosomal-recessive disease arising from a mutation of the SLC19A3 gene encoding the human thiamine transporter 2 protein, and usually manifests as subacute to acute encephalopathy. In this case, compound heterozygous mutations of SLC19A3, including a de novo mutation in one allele, was the cause of disease. Although a large number of genetic neural diseases have no efficient therapy, there are several treatable genetic diseases, including BBGD. However, to achieve better outcome and accurate diagnosis, therapeutic analysis and examination for disease confirmation should be done simultaneously. We encountered a case of possible Kawasaki disease, which had progressed to BBGD caused by an extremely rare genetic condition. Although the prevalence of BBGD is low, early recognition of this disease is important because effective improvement can be achieved by early biotin and thiamine supplementation.Journal of Human Genetics advance online publication, 16 April 2015; doi:10.1038/jhg.2015.35.
    Journal of Human Genetics 04/2015; DOI:10.1038/jhg.2015.35 · 2.53 Impact Factor
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    ABSTRACT: Objective Recently, de novo mutations in GRIN1 have been identified in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Whole exome sequencing (WES) analysis of patients with genetically unsolved epileptic encephalopathies identified four patients with GRIN1 mutations, allowing us to investigate the phenotypic spectrum of GRIN1 mutations.Methods Eighty-eight patients with unclassified early onset epileptic encephalopathies (EOEEs) with an age of onset <1 year were analyzed by WES. The effect of mutations on N-methyl-d-aspartate (NMDA) receptors was examined by mapping altered amino acids onto three-dimensional models.ResultsWe identified four de novo missense GRIN1 mutations in 4 of 88 patients with unclassified EOEEs. In these four patients, initial symptoms appeared within 3 months of birth, including hyperkinetic movements in two patients (2/4, 50%), and seizures in two patients (2/4, 50%). Involuntary movements, severe developmental delay, and intellectual disability were recognized in all four patients. In addition, abnormal eye movements resembling oculogyric crises and stereotypic hand movements were observed in two and three patients, respectively. All the four patients exhibited only nonspecific focal and diffuse epileptiform abnormality, and never showed suppression-burst or hypsarrhythmia during infancy. A de novo mosaic mutation (c.1923G>A) with a mutant allele frequency of 16% (in DNA of blood leukocytes) was detected in one patient. Three mutations were located in the transmembrane domain (3/4, 75%), and one in the extracellular loop near transmembrane helix 1. All the mutations were predicted to impair the function of the NMDA receptor.SignificanceClinical features of de novo GRIN1 mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that GRIN1 mutations cause encephalopathy resulting in seizures and movement disorders.
    Epilepsia 04/2015; 56(6). DOI:10.1111/epi.12987 · 4.58 Impact Factor
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    ABSTRACT: Myoclonus-dystonia syndrome (MDS) is a rare autosomal-dominant movement disorder characterized by brief, frequently alcohol-responsive myoclonic jerks that begin in childhood or early adolescence, caused by mutations in the ε-sarcoglycan gene (SGCE). The patient was a 6-year-old boy. At 2 years 8 months, he had abnormal movement when he ran due to dystonia of his left leg. At 3 years 5 months, he exhibited dystonia and myoclonic movement of his arms when eating. Myoclonus was likely to develop when he felt anxiety or exhaustion. Genomic DNA showed a heterozygous mutation in SGCE (c.109 + 1 G > T). His father and uncle with the same mutation also experienced milder dystonia or myoclonic movements. SGCE mutation can cause a broad range of clinical symptoms between and within families. We should consider MDS as a differential diagnosis for patients with paroxysmal walking abnormalities and/or myoclonic movements. © 2015 Japan Pediatric Society.
    Pediatrics International 04/2015; 57(2):324-6. DOI:10.1111/ped.12613 · 0.73 Impact Factor
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    ABSTRACT: Wiedemann-Steiner syndrome (WSS) is an autosomal dominant congenital anomaly syndrome characterized by hairy elbows, dysmorphic facial appearances (hypertelorism, thick eyebrows, downslanted and vertically narrow palpebral fissures), pre- and post-natal growth deficiency, and psychomotor delay. WSS is caused by heterozygous mutations in KMT2A (also known as MLL), a gene encoding a histone methyltransferase. Here, we identify six novel KMT2A mutations in six WSS patients, with four mutations occurring de novo. Interestingly, some of the patients were initially diagnosed with atypical Kabuki syndrome, which is caused by mutations in KMT2D or KDM6A, genes also involved in histone methylation. KMT2A mutations and clinical features are summarized in our six patients together with eight previously reported patients. Furthermore, clinical comparison of the two syndromes is discussed in detail. This article is protected by copyright. All rights reserved.
    Clinical Genetics 03/2015; DOI:10.1111/cge.12586 · 3.65 Impact Factor
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    ABSTRACT: 6p duplication syndrome is a rare chromosomal disorder that frequently manifests renal complications, including proteinuria, hypoplastic kidney, and hydronephrosis. We report a girl with the syndrome, manifesting left hydronephrosis, proteinuria/hematuria, and focal segmental glomerular sclerosis (FSGS) resulting in chronic end-stage renal failure, successfully treated with renal transplantation. Microarray comparative genomic hybridization showed the derivative chromosome 6 to have a 6.4-Mb duplication at 6p25.3-p25.1 with 32 protein-coding genes and a 220-Kb deletion at 6p25.3 with two genes of no possible relation to the renal pathology. Review of the literature shows that variation of renal complications in the syndrome is compatible with congenital anomalies of the kidney and urinary tract (CAKUT). FSGS, observed in another patient with 6p duplication syndrome, could be a non-coincidental complication. FOXC1, located within the 6.4-Mb duplicated region at 6p25.3-p25.2, could be a candidate gene for CAKUT, but its single gene duplication effect would not be sufficient. FSGS would be a primary defect associated with duplicated gene(s) albeit no candidate could be proposed, or might occur in association with CAKUT. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 03/2015; 167(3):592-601. DOI:10.1002/ajmg.a.36942 · 2.05 Impact Factor
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    ABSTRACT: Distal arthrogryposis (DA) encompasses a heterogeneous group of hereditary disorders with multiple congenital contractures predominant in the distal extremities. A total of 10 subtypes are proposed based on the pattern of contractures and association with extraarticular symptoms. DA5 is defined as a subtype with ptosis/oculomotor limitation. However, affected individuals have a variety of non-ocular features as well. We report on a two-generation family, including four affected individuals who all had congenital contractures of the distal joints, ptosis, restricted ocular movements, distinct facial appearance with deep-set eyes, and shortening of the 1st and 5th toes. The proband and her affected mother had restrictive lung disease, a recently recognized syndromic component of DA5, while younger patients did not. The proband had metacarpal and metatarsal synostosis, and the mother showed excavation of the optic disk. Whole-exome sequencing revealed a novel heterozygous mutation c.4456G>C (p.A1486P) of PIEZO2. PIEZO2 encodes a mechanosensitive ion channel, malfunction of which provides pleiotropic effects on joints, ocular muscles, lung function, and bone development. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 02/2015; 167(5). DOI:10.1002/ajmg.a.36881 · 2.05 Impact Factor
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    ABSTRACT: Autism spectrum disorder (ASD) is a clinically heterogeneous psychiatric disorder with various genetic backgrounds. Here, we report a novel mutation in the pogo transposable element-derived protein with zinc finger domain gene (POGZ) identified by trio-based whole exome sequencing. To date, a total of seven de novo POGZ mutations in ASD have been reported. POGZ contains a total of five functional domains, and this study reports the first de novo missense mutation in the centromere protein B-like DNA-binding domain. POGZ is highly expressed in the human fetal brain and is involved in mitosis and the regulation of neuronal proliferation. Therefore its loss-of-function or pathogenic missense mutations are likely to be causative of ASD.Journal of Human Genetics advance online publication, 19 February 2015; doi:10.1038/jhg.2015.13.
    Journal of Human Genetics 02/2015; 60(5). DOI:10.1038/jhg.2015.13 · 2.53 Impact Factor
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    ABSTRACT: Context: Ciliopathies are a group of rare conditions that present through a wide range of manifestations. Given the relative common occurrence of defects of the GH/IGF-1 axis in children with short stature and growth retardation, the association between ciliopathies and these defects needs further attention. Case: Our patient is a boy who was born at term and noted to have early growth retardation and weight gain within the first 18 months of life. Biochemical tests demonstrated low IGF-1 but a normal peak GH on stimulation and an adequate rise in IGF-1 on administration of rhGH. An MRI scan revealed pituitary hypoplasia and an ectopic posterior pituitary. His growth responded well to rhGH therapy. Subsequently he also developed a retinopathy of his rods and cones, metaphyseal dysplasia and hypertension with renal failure requiring renal replacement therapy. Whole exome sequencing demonstrated compound heterozygous mutations of IFT172, thus consistent with a ciliopathy. Conclusions: This is the first reported case of a child with a mutation in IFT172 who presented with growth retardation in early childhood and was initially managed as a case of functional GH deficiency that responded to rhGH therapy. This case highlights the importance of ciliary function in pituitary development and the link between early onset growth failure and ciliopathies.
    Journal of Clinical Endocrinology &amp Metabolism 02/2015; 100(4):jc20143852. DOI:10.1210/jc.2014-3852 · 6.31 Impact Factor
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    ABSTRACT: Mitochondrial complex III (CIII) deficiency comprises a group of complex and heterogeneous genetic disorders. TTC19 mutations constitute a rare cause of CIII deficiency and are associated with neurological disorders in childhood and adulthood. Herein, we describe a 27-year-old Japanese man with cerebellar ataxia, spastic paraparesis, loss of deep sensation, mild frontal lobe dysfunction and transient psychiatric symptoms. Brain magnetic resonance imaging showed cerebellar atrophy and bilateral high-intensity signals in the inferior olives and regions adjacent to periaqueductal gray matter, on T2-weighted images. On whole-exome sequencing, we detected a novel homozygous frameshift mutation c.157_158dup [p.Pro54Alafs*48] in TTC19. Mitochondrial enzyme assays confirmed mild impairment of CIII enzymatic activity in lymphoblasts, which was consistent with TTC19-related CIII deficiency. His symptoms and radiological findings demonstrated an early stage or mild form of this disease, and further clarify the characteristics of patients with rare TTC19 mutations.Journal of Human Genetics advance online publication, 5 February 2015; doi:10.1038/jhg.2015.7.
    Journal of Human Genetics 02/2015; 60(4). DOI:10.1038/jhg.2015.7 · 2.53 Impact Factor
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    ABSTRACT: Whole-exome sequencing (WES) is becoming a standard tool for detecting nucleotide changes, and determining whether WES data can be used for the detection of copy-number variations (CNVs) is of interest. To date, several algorithms have been developed for such analyses, although verification is needed to establish if they fit well for the appropriate purpose, depending on the characteristics of each algorithm. Here, we performed WES CNV analysis using the eXome Hidden Markov Model (XHMM). We validated its performance using 27 rare CNVs previously identified by microarray as positive controls, finding that the detection rate was 59%, or higher (89%) with three or more targets. XHMM can be effectively used, especially for the detection of >200 kb CNVs. XHMM may be useful for deletion breakpoint detection. Next, we applied XHMM to genetically unsolved patients, demonstrating successful identification of pathogenic CNVs: 1.5-1.9-Mb deletions involving NSD1 in patients with unknown overgrowth syndrome leading to the diagnosis of Sotos syndrome, and 6.4-Mb duplication involving MECP2 in affected brothers with late-onset spasm and progressive cerebral/cerebellar atrophy confirming the clinical suspect of MECP2 duplication syndrome. The possibility of an 'exome-first' approach for clinical genetic investigation may be considered to save the cost of multiple investigations.Journal of Human Genetics advance online publication, 22 January 2015; doi:10.1038/jhg.2014.124.
    Journal of Human Genetics 01/2015; 60(4). DOI:10.1038/jhg.2014.124 · 2.53 Impact Factor
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    ABSTRACT: Aminoacylation is the process of attaching amino acids to their cognate tRNA, and thus is essential for the translation of mRNA into protein. This direct interaction of tRNA with amino acids is catalyzed by aminoacyl-tRNA synthetases. Using whole-exome sequencing, we identified compound heterozygous mutations [c.169T>C (p.Tyr57His) and c.1485dup (p.Lys496*)] in QARS, which encodes glutaminyl-tRNA synthetase, in two siblings with early-onset epileptic encephalopathy (EOEE). Recessive mutations in QARS, including the loss-of-function missense mutation p.Tyr57His, have been reported to cause intractable seizures with progressive microcephaly. The p.Lys496* mutation is novel and causes truncation of the QARS protein, leading to a deletion of part of the catalytic domain and the entire anticodon-binding domain. Transient expression of the p.Lys496* mutant in neuroblastoma 2A cells revealed diminished and aberrantly aggregated expression, indicating the loss-of-function nature of this mutant. Together with the previous report, our data suggest that abnormal aminoacylation is one of the underlying pathologies of EOEE.Journal of Human Genetics advance online publication, 4 December 2014; doi:10.1038/jhg.2014.103.
    Journal of Human Genetics 12/2014; 60(2). DOI:10.1038/jhg.2014.103 · 2.53 Impact Factor
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    ABSTRACT: Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias (ARHSPs) are clinically and genetically heterogeneous neurological disorders. Herein we describe Japanese siblings with a midlife-onset, slowly progressive type of cerebellar ataxia and spastic paraplegia, without intellectual disability. Using whole exome sequencing, we identified a homozygous missense mutation in DDHD2, whose mutations were recently identified as the cause of early-onset ARHSP with intellectual disability. Brain MRI of the patient showed a thin corpus callosum. Cerebral proton magnetic resonance spectroscopy revealed an abnormal lipid peak in the basal ganglia, which has been reported as the hallmark of DDHD2-related ARHSP (SPG 54). The mutation caused a marked reduction of phospholipase A1 activity, supporting that this mutation is the cause of SPG54. Our cases indicate that the possibility of SPG54 should also be considered when patients show a combination of adult-onset spastic ataxia and a thin corpus callosum. Magnetic resonance spectroscopy may be helpful in the differential diagnosis of patients with spastic ataxia phenotype.
    Scientific Reports 11/2014; 4:7132. DOI:10.1038/srep07132 · 5.58 Impact Factor

Publication Stats

2k Citations
762.87 Total Impact Points

Institutions

  • 2006–2015
    • Yokohama City University
      Yokohama, Kanagawa, Japan
    • Lund University
      • Department of Molecular Medicine and Gene Therapy
      Lund, Skåne, Sweden
  • 2005–2014
    • Nippon Medical School
      • Department of Biochemistry and Molecular Biology
      Edo, Tōkyō, Japan
    • Nagasaki University Hospital
      Nagasaki, Nagasaki, Japan
  • 2011
    • Nippon Veterinary and Life Science University
      Edo, Tōkyō, Japan
  • 2010
    • RIKEN
      • Laboratory for Bone and Joint Diseases
      Wako, Saitama-ken, Japan
  • 2001–2010
    • Juntendo University
      • • Department of Clinical Laboratory
      • • Department of Medicine
      • • Department of Clinical Pathology
      Edo, Tōkyō, Japan
  • 2008
    • Health Sciences University of Hokkaido
      Tōbetsu, Hokkaidō, Japan
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 2005–2008
    • Nagasaki University
      • • Department of Pediatrics
      • • Graduate School of Biomedical Sciences
      Nagasaki, Nagasaki, Japan
  • 2003
    • University of Helsinki
      • Department of Pediatrics
      Helsinki, Uusimaa, Finland