Yoichi Matsubara

National Research Institute for Child Health and Development, Tokyo, Edo, Tōkyō, Japan

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Publications (166)856.41 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: GNE myopathy is an autosomal recessive muscular disorder caused by mutations in the gene encoding the key enzyme in sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK). Here, we report two siblings with myopathy with rimmed vacuoles and congenital thrombocytopenia who harbored two compound heterozygous GNE mutations, p.V603L and p.G739S. Thrombocytopenia, which is characterized by shortened platelet lifetime rather than ineffective thrombopoiesis, has been observed since infancy. We performed exome sequencing and array CGH to identify the underlying genetic etiology of thrombocytopenia. No pathogenic variants were detected among the known causative genes of recessively inherited thrombocytopenia; yet, candidate variants in two genes that followed an autosomal recessive mode of inheritance, including previously identified GNE mutations, were detected. Alternatively, it is possible that the decreased activity of GNE/MNK itself, which would lead to decreased sialic content in platelets, is associated with thrombocytopenia in these patients. Further investigations are required to clarify the association between GNE myopathy and the pathogenesis of thrombocytopenia.
    Neuromuscular Disorders 08/2014; · 3.46 Impact Factor
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    ABSTRACT: Cardio-facio-cutaneous (CFC) syndrome is one of the 'RASopathies', a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS-MAPK pathway. Germline mutations in BRAF cause CFC syndrome, which is characterized by heart defects, distinctive facial features and ectodermal abnormalities. To define the pathogenesis and to develop a potential therapeutic approach in CFC syndrome, we here generated new knock-in mice (here Braf(Q241R/+)) expressing the BrafQ241R mutation, which corresponds to the most frequent mutation in CFC syndrome, Q257R. Braf(Q241R/+) mice manifested embryonic/neonatal lethality, showing liver necrosis, edema and craniofacial abnormalities. Histological analysis revealed multiple heart defects, including cardiomegaly, enlarged cardiac valves, ventricular noncompaction and ventricular septal defects. Braf(Q241R/+) embryos also showed massively distended jugular lymphatic sacs and subcutaneous lymphatic vessels, demonstrating lymphatic defects in RASopathy knock-in mice for the first time. Prenatal treatment with a MEK inhibitor, PD0325901, rescued the embryonic lethality with amelioration of craniofacial abnormalities and edema in Braf(Q241R/+) embryos. Unexpectedly, one surviving pup was obtained after treatment with a histone 3 demethylase inhibitor, GSK-J4, or NCDM-32b. Combination treatment with PD0325901 and GSK-J4 further increased the rescue from embryonic lethality, ameliorating enlarged cardiac valves. These results suggest that our new BRAF knock-in mice recapitulate major features of RASopathies and that epigenetic modulation as well as the inhibition of the ERK pathway will be a potential therapeutic strategy for the treatment of CFC syndrome.
    Human Molecular Genetics 07/2014; · 7.69 Impact Factor
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    ABSTRACT: Acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP) are caused by mutations in the hydroxymethylbilane synthase (HMBS), protoporphyrinogen oxidase (PPOX), and coproporphyrinogen oxidase (CPOX) genes, respectively. This study aimed to identify mutations in seven Bulgarian families with AIP, six with VP, and one with HCP. A total of 33 subjects, both symptomatic (n = 21) and asymptomatic (n = 12), were included in this study. The identification of mutations was performed by direct sequencing of all the coding exons of the corresponding enzymes in the probands. The available relatives were screened for the possible mutations. A total of six different mutations in HMBS were detected in all seven families with AIP, three of which were previously described: c.76C>T [p.R26C] in exon 3, c.287C>T [p.S96F] in exon 7, and c.445C>T [p.R149X] in exon 9. The following three novel HMBS mutations were found: c.345-2A>C in intron 7-8, c.279-280insAT in exon 7, and c.887delC in exon 15. A total of three different novel mutations were identified in the PPOX gene in the VP families: c.441-442delCA in exon 5, c.917T>C [p.L306P] in exon 9, and c.1252T>C [p.C418R] in exon 12. A novel nonsense mutation, c.364G>T [p.E122X], in exon 1 of the CPOX gene was identified in the HCP family. This study, which identified mutations in Bulgarian families with AHP for the first time, established seven novel mutation sites. Seven latent carriers were also diagnosed and, therefore, were able to receive crucial counseling to prevent attacks.
    JIMD reports. 07/2014;
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    ABSTRACT: Although TBX1 mutations have been identified in patients with 22q11.2 deletion syndrome (22q11.2DS)-like phenotypes including characteristic craniofacial features, cardiovascular anomalies, hypoparathyroidism, and thymic hypoplasia, the frequency of TBX1 mutations remains rare in deletion-negative patients. Thus, it would be reasonable to perform a comprehensive genetic analysis in deletion-negative patients with 22q11.2DS-like phenotypes. We studied three subjects with craniofacial features and hypocalcemia (group 1), two subjects with craniofacial features alone (group 2), and three subjects with normal phenotype within a single Japanese family. Fluorescence in situ hybridization analysis excluded chromosome 22q11.2 deletion, and genomewide array comparative genomic hybridization analysis revealed no copy number change specific to group 1 or groups 1+2. However, exome sequencing identified a heterozygous TBX1 frameshift mutation (c.1253delA, p.Y418fsX459) specific to groups 1+2, as well as six missense variants and two in-frame microdeletions specific to groups 1+2 and two missense variants specific to group 1. The TBX1 mutation resided at exon 9C and was predicted to produce a non-functional truncated protein missing the nuclear localization signal and most of the transactivation domain. Clinical features in groups 1+2 are well explained by the TBX1 mutation, while the clinical effects of the remaining variants are largely unknown. Thus, the results exemplify the usefulness of exome sequencing in the identification of disease-causing mutations in familial disorders. Furthermore, the results, in conjunction with the previous data, imply that TBX1 isoform C is the biologically essential variant and that TBX1 mutations are associated with a wide phenotypic spectrum, including most of 22q11.2DS phenotypes.
    PLoS ONE 01/2014; 9(3):e91598. · 3.53 Impact Factor
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    ABSTRACT: A male infant, born at 32 weeks gestation by cesarean because of hydrops fetalis, presented with multiple anomalies, such as sparse and curly scalp hair, absent eyebrows, frontal bossing, an atrial septal defect, pulmonary artery stenosis, and whole myocardial thickening. He was clinically diagnosed with cardio-facio-cutaneous (CFC) syndrome, and was confirmed to have a germline V-raf murine sarcoma viral oncogene homologue B1 (BRAF) c.721 A>C mutation. At 1 month of age, he presented with a transient myelodysplastic/myeloproliferative neoplasm (MDS/MPN), which improved within a month without the administration of antineoplastic agents. This is the first report of CFC syndrome with MDS/MPN. The coexistence of MDS/MPN may be related to this BRAF c.721 A>C mutation. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 08/2013; · 2.30 Impact Factor
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    ABSTRACT: Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 08/2013; · 2.30 Impact Factor
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    ABSTRACT: RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.
    The American Journal of Human Genetics 06/2013; · 11.20 Impact Factor
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    ABSTRACT: Taking nucleos(t)ide analogues is a major antiviral therapy for chronic hepatitis B infection. The problem with this treatment is the selection for drug-resistant mutants. Currently, identification of genotypic drug-resistance is conducted by molecular cloning sequenced by the Sanger method. However, this methodology is complicated and time-consuming. These limitations can be overcome by deep sequencing technology. Therefore, we performed sequential analysis of the frequency of drug-resistance in one individual, who was treated with lamivudine on-and-off therapy for two years, by deep sequencing. The lamivudine resistance mutations at rtL180M and rtM204V and the entecavir resistance mutation at rtT184L were detected in the first subject. The lamivudine and entecavir resistant strain was still detected in the last subject. However, in the deep sequencing analysis, rt180 of the first subject showed a mixture in 76.9% of the methionine and in 23.1% of the leucine and rt204 also showed a mixture in 69.0% of the valine and 29.8% of the isoleucine. During the treatment, the ratio of resistant mutations increased. At rt184, the resistant variants were detectable in 58.7% of the sequence, with the replacement of leucine by the wild type threonine in the first subject. Gradually, entecavir resistant variants increased in 82.3% of the leucine in the last subject. In conclusion, we demonstrated the amino acid substitutions of the serial nucleos(t)ide analogues resistants. We revealed that drug-resistant mutants appear unchanged at first glance actually there are low-abundant mutations that might develop drug resistance against nucleos(t)ide analogues through the selection of dominant mutations.
    Hepatology Research 05/2013; · 2.07 Impact Factor
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    ABSTRACT: Myofibrillar myopathy (MFM) is a group of chronic muscular disorders that show the focal dissolution of myofibrils and accumulation of degradation products. The major genetic basis of MFMs is unknown. In 1993, our group reported a Japanese family with dominantly inherited cytoplasmic body myopathy, which is now included in MFM, characterized by late-onset chronic progressive distal muscle weakness and early respiratory failure. In this study, we performed linkage analysis and exome sequencing on these patients and identified a novel c.90263G>T mutation in the TTN gene (NM_001256850). During the course of our study, another groups reported three mutations in TTN in patients with hereditary myopathy with early respiratory failure (HMERF, MIM #603689), which is characterized by overlapping pathologic findings with MFMs. Our patients were clinically compatible with HMERF. The mutation identified in this study and the three mutations in patients with HMERF were located on the A-band domain of titin, suggesting a strong relationship between mutations in the A-band domain of titin and HMERF. Mutation screening of TTN has been rarely carried out because of its huge size, consisting of 363 exons. It is possible that focused analysis of TTN may detect more mutations in patients with MFMs, especially in those with early respiratory failure.Journal of Human Genetics advance online publication, 28 February 2013; doi:10.1038/jhg.2013.9.
    Journal of Human Genetics 02/2013; · 2.37 Impact Factor
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    Yoko Aoki, Yoichi Matsubara
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    ABSTRACT: Noonan syndrome (NS) is an autosomal-dominant disease characterized by distinctive facial features, webbed neck, cardiac anomalies, short stature and cryptorchidism. NS exhibits phenotypic overlap with Costello syndrome and cardio-facio-cutaneous (CFC) syndrome. Germline mutations of genes encoding proteins in the RAS/mitogen-activated protein kinase (MAPK) pathway cause NS and related disorders. Germline mutations in PTPN11, KRAS, SOS1, RAF1, and NRAS have been identified in 60-80 % of NS patients. Germline mutations in HRAS have been identified in patients with Costello syndrome and mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) have been identified in patients with CFC syndrome. Recently, mutations in SHOC2 and CBL have been identified in patients with Noonan-like syndrome. It has been suggested that these syndromes be comprehensively termed RAS/MAPK syndromes, or RASopathies. Molecular analysis is beneficial for the confirmation of clinical diagnoses and follow-up with patients using a tumor-screening protocol, as patients with NS and related disorders have an increased risk of developing tumors. In this review, we summarize the genetic mutations, clinical manifestations, associations with malignant tumors, and possible therapeutic approaches for these disorders.
    International journal of hematology 12/2012; · 1.17 Impact Factor
  • Neurology 08/2012; 79(7):e63-8. · 8.30 Impact Factor
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    ABSTRACT: Abstract is missing (Letter).
    Acta Dermato-Venereologica 06/2012;
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    ABSTRACT: Somatic CBL mutations have been reported in a variety of myeloid neoplasms but are rare in acute lymphoblastic leukemia (ALL). We analyzed 77 samples from hematologic malignancies, identifying a somatic mutation in CBL (p.C381R) in one patient with T-ALL that was associated with a uniparental disomy at the CBL locus and a germline heterozygous mutation in one patient with JMML. Two NOTCH1 mutations and homozygous deletions in LEF1 and CDKN2A were identified in T-ALL cells. The activation of the RAS pathway was enhanced, and activation of the NOTCH1 pathway was inhibited in NIH 3T3 cells that expressed p.C381R. This study appears to be the first to identify a CBL mutation in T-ALL.
    Leukemia research 05/2012; 36(8):1009-15. · 2.36 Impact Factor
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    ABSTRACT: Costello syndrome and cardio-facio-cutaneous (CFC) syndrome are congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, and intellectual disability. Germline mutations in HRAS cause Costello syndrome, and mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) cause CFC syndrome. Since the discovery of the causative genes, approximately 150 new patients with each syndrome have been reported. However, the clinico-epidemiological features of these disorders remain to be identified. In order to assess the prevalence, natural history, prognosis, and tumor incidence associated with these diseases, we conducted a nationwide prevalence study of patients with Costello and CFC syndromes in Japan. Based on the result of our survey, we estimated a total number of patients with either Costello syndrome or CFC syndrome in Japan of 99 (95% confidence interval, 77-120) and 157 (95% confidence interval, 86-229), respectively. The prevalences of Costello and CFC syndromes are estimated to be 1 in 1,290,000 and 1 in 810,000 individuals, respectively. An evaluation of 15 adult patients 18-32 years of age revealed that 12 had moderate to severe intellectual disability and most live at home without constant medical care. These results suggested that the number of adult patients is likely underestimated and our results represent a minimum prevalence. This is the first epidemiological study of Costello syndrome and CFC syndrome. Identifying patients older than 32 years of age and following up on the patients reported here is important to estimate the precise prevalence and the natural history of these disorders.
    American Journal of Medical Genetics Part A 04/2012; 158A(5):1083-94. · 2.30 Impact Factor
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    ABSTRACT: RNF213 was recently reported as a susceptibility gene for moyamoya disease (MMD). Our aim was to clarify the correlation between the RNF213 genotype and MMD phenotype. The entire coding region of the RNF213 gene was sequenced in 204 patients with MMD, and corresponding variants were checked in 62 pairs of parents, 13 mothers and 4 fathers of the patients, and 283 normal controls. Clinical information was collected. Genotype-phenotype correlations were statistically analyzed. The c.14576G>A variant was identified in 95.1% of patients with familial MMD, 79.2% of patients with sporadic MMD, and 1.8% of controls, thus confirming its association with MMD, with an odds ratio of 259 and p < 0.001 for either heterozygotes or homozygotes. Homozygous c.14576G>A was observed in 15 patients but not in the controls and unaffected parents. The incidence rate for homozygotes was calculated to be >78%. Homozygotes had a significantly earlier age at onset compared with heterozygotes or wild types (median age at onset 3, 7, and 8 years, respectively). Of homozygotes, 60% were diagnosed with MMD before age 4, and all had infarctions as the first symptom. Infarctions at initial presentation and involvement of posterior cerebral arteries, both known as poor prognostic factors for MMD, were of significantly higher frequency in homozygotes than in heterozygotes and wild types. Variants other than c.14576G>A were not associated with clinical phenotypes. The homozygous c.14576G>A variant in RNF213 could be a good DNA biomarker for predicting the severe type of MMD, for which early medical/surgical intervention is recommended, and may provide a better monitoring and prevention strategy.
    Neurology 02/2012; 78(11):803-10. · 8.30 Impact Factor
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    ABSTRACT: Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene and has two disease outcomes: adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency. The clinical appearance of these diseases is variable, ranging from almost no symptoms to coma, brain edema, and severe liver failure. Genetic testing for SLC25A13 mutations is essential for the diagnosis of citrin deficiency because chemical diagnoses are prohibitively difficult. Eleven SLC25A13 mutations account for 95% of the mutant alleles in Japanese patients with citrin deficiency. Therefore, a simple test for these mutations is desirable. We established a 1-hour, closed-tube assay for the 11 SLC25A13 mutations using real-time PCR. Each mutation site was amplified by PCR followed by a melting-curve analysis with adjacent hybridization probes (HybProbe, Roche). The 11 prevalent mutations were detected in seven PCR reactions. Six reactions were used to detect a single mutation each, and one reaction was used to detect five mutations that are clustered in a 21-bp region in exon 17. To test the reliability, we used this method to genotype blind DNA samples from 50 patients with citrin deficiency. Our results were in complete agreement those obtained using previously established methods. Furthermore, the mutations could be detected without difficulty using dried blood samples collected on filter paper. Therefore, this assay could be used for newborn screening and for facilitating the genetic diagnosis of citrin deficiency, especially in East Asian populations.
    Molecular Genetics and Metabolism 01/2012; 105(4):553-8. · 2.83 Impact Factor
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    ABSTRACT: Neural tube defects (NTDs), including spina bifida and anencephaly, are common birth defects of the central nervous system. The complex multigenic causation of human NTDs, together with the large number of possible candidate genes, has hampered efforts to delineate their molecular basis. Function of folate one-carbon metabolism (FOCM) has been implicated as a key determinant of susceptibility to NTDs. The glycine cleavage system (GCS) is a multi-enzyme component of mitochondrial folate metabolism, and GCS-encoding genes therefore represent candidates for involvement in NTDs. To investigate this possibility, we sequenced the coding regions of the GCS genes: AMT, GCSH and GLDC in NTD patients and controls. Two unique non-synonymous changes were identified in the AMT gene that were absent from controls. We also identified a splice acceptor site mutation and five different non-synonymous variants in GLDC, which were found to significantly impair enzymatic activity and represent putative causative mutations. In order to functionally test the requirement for GCS activity in neural tube closure, we generated mice that lack GCS activity, through mutation of AMT. Homozygous Amt(-/-) mice developed NTDs at high frequency. Although these NTDs were not preventable by supplemental folic acid, there was a partial rescue by methionine. Overall, our findings suggest that loss-of-function mutations in GCS genes predispose to NTDs in mice and humans. These data highlight the importance of adequate function of mitochondrial folate metabolism in neural tube closure.
    Human Molecular Genetics 12/2011; 21(7):1496-503. · 7.69 Impact Factor
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    ABSTRACT: Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by a distinctive facial appearance, ectodermal abnormalities, and heart defects. Clinically, it overlaps with both Noonan syndrome and Costello syndrome. Mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) have been identified in patients with CFC syndrome. BRAF mutations are involved in more than 80% of CFC syndrome patients, and we have reported earlier that 2 CFC patients with BRAF mutations developed acute lymphoblastic leukemia. Here we report a boy with CFC syndrome who developed non-Hodgkin lymphoma. At 2 months of age, he developed pneumonia with pleurisy and was diagnosed as having non-Hodgkin lymphoma (precursor T-cell lymphoblastic lymphoma) by cytopathologic examination of the pleural fluid. He was suspected of having Noonan syndrome because of his facial appearance, webbed neck, and cubitus valgus. Precursor T-cell lymphoblastic lymphoma was treated by the TCCSG NHL 94-04 protocol. At 9 years of age, he was clinically reevaluated and diagnosed as having CFC syndrome because of his distinctive facial appearance, multiple nevi, and moderate mental retardation. Sequencing analysis showed a germline p.A246P (c.736G>C) mutation in BRAF reported earlier in CFC syndrome. Molecular diagnosis and careful observation should be considered in children with CFC syndrome.
    Journal of Pediatric Hematology/Oncology 12/2011; 33(8):e342-6. · 0.97 Impact Factor
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    ABSTRACT: LEOPARD syndrome (LS), generally caused by heterozygous mutations in the PTPN11 gene, is a rare autosomal-dominant multiple congenital anomaly condition, characterized by skin, facial, and cardiac abnormalities. Prognosis appears to be related to the type of structural, myocardial, and arrhythmogenic cardiac disease, especially hypertrophic cardiomyopathy (HCM). We report on a woman with LS and a novel Gln510His mutation in PTPN11, who had progressive HCM with congestive heart failure and nonsustained ventricular tachycardia, successfully treated with implantable cardioverter defibrillator (ICD). Comparing our patient to the literature suggests that specific mutations at codon 510 in PTPN11 (Gln510Glu, Gln510His, but not Gln510Pro) might be a predictor of fatal cardiac events in LS. Molecular risk stratification and careful evaluations for an indication of ICD implantation are likely to be beneficial in managing patients with LS and HCM.
    American Journal of Medical Genetics Part A 09/2011; 155A(10):2529-33. · 2.30 Impact Factor
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    Masao Adachi, Yu Abe, Yoko Aoki, Yoichi Matsubara
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    ABSTRACT: We report two individual cases of cardio-facio-cutaneous (CFC) syndrome with severe neurological impairment consisting of infantile spasms with hypsarrhythmia and refractory epilepsy with multifocal epileptic paroxysms such as modified hypsarrhythmia. Both cases shared diffuse brain atrophy and severely delayed myelination on neuroimaging. Genetic analysis revealed individual heterozygous mutations in the KRAS (phenotype of CFC/Noonan syndrome) and BRAF genes (phenotype of CFC syndrome). Neurological impairment in cases with mutations in the RAS/MAPK (mitogen activated protein kinase) signal pathway may be more severe, and could be linked to some forms of refractory epilepsy, especially epileptic encephalopathy that includes infantile spasms.
    Seizure 08/2011; 21(1):55-60. · 2.00 Impact Factor

Publication Stats

4k Citations
856.41 Total Impact Points

Institutions

  • 2014
    • National Research Institute for Child Health and Development, Tokyo
      Edo, Tōkyō, Japan
  • 2012
    • University Hospital Medical Information Network
      Edo, Tōkyō, Japan
  • 1992–2012
    • Tohoku University
      • • Department of Medical Genetics
      • • Graduate School of Pharmaceutical Sciences
      • • Department of Pediatrics
      Sendai, Kagoshima, Japan
  • 2011
    • Saitama Medical University
      • Department of Pediatrics
      Saitama, Saitama-ken, Japan
    • National Center of Neurology and Psychiatry
      • Department of Child Neurology
      Tokyo, Tokyo-to, Japan
  • 2010
    • Ochanomizu University
      Tōkyō, Japan
  • 2005
    • Hebrew University of Jerusalem
      • Human Genetics Center
      Jerusalem, Jerusalem District, Israel
    • Cincinnati Children's Hospital Medical Center
      • Division of Neurology
      Cincinnati, OH, United States
  • 1997
    • St. Vincent's Hospital Melbourne
      Melbourne, Victoria, Australia
  • 1994
    • Showa University
      • Division of Pharmaceutical Sciences
      Shinagawa, Tōkyō, Japan
  • 1987–1989
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States