Assuntos
Análise Mutacional de DNA , Hiperparatireoidismo Primário/genética , Doenças do Recém-Nascido/genética , Receptores de Detecção de Cálcio/genética , Cálcio/sangue , Aberrações Cromossômicas , Consanguinidade , Genes Dominantes/genética , Triagem de Portadores Genéticos , Homozigoto , Humanos , Hiperparatireoidismo Primário/diagnóstico , Lactente , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Masculino , Hormônio Paratireóideo/sangue , Mutação Puntual/genéticaRESUMO
The autosomal recessive demyelinating form of Charcot-Marie-Tooth can be due to SH3TC2 gene pathogenic variants (CMT4C, AR-CMTde-SH3TC2). We report on a series of 13 patients with AR-CMTde-SH3TC2 among a French cohort of 350 patients suffering from all type of inheritance peripheral neuropathy. The SH3TC2 gene appeared to be the most frequently mutated gene for demyelinating neuropathy in this series by NGS. Four new pathogenic variants have been identified: two nonsense variants (p.(Tyr970*), p.(Trp1199*)) and two missense variants (p.(Leu1126Pro), p.(Ala1206Asp)). The recurrent variant p.Arg954* was present in 62%, and seems to be a founder mutation. The phenotype is fairly homogeneous, as all these patients, except the youngest ones, presented scoliosis and/or hearing loss.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Surdez/genética , Variação Genética/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Escoliose/genética , Adulto , Idoso , Doença de Charcot-Marie-Tooth/epidemiologia , Criança , Estudos de Coortes , Surdez/epidemiologia , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Escoliose/epidemiologia , Adulto JovemRESUMO
Oculo-dento-digital dysplasia (ODDD) is an autosomal dominant disorder with complete penetrance and high intra- and interfamilial phenotypic variability. The key features in this syndrome are microphthalmia, enamel hypoplasia and syndactyly of the 4th-5th fingers. ODDD is caused by mutations in the connexin 43 gene (GJA1). We report here four patients from three families with GJA1 mutations, one of them diagnosed prenatally. The three mutations (c.52T > C/p.Ser18Pro, c.689_690delTA/p.Tyr230CysfsX6, c.442C > G/p.Arg148Gly) have been reported once before. Two patients had white matter hypersignal anomalies, associated in one case with mental retardation, but asymptomatic in the other one, an observation that leads us to discuss systematic neuroradiological imaging for ODDD. One case has optic atrophy, another has hypospadias. The patient carrying a truncating mutation of Cx43 did not have palmoplantar keratoderma, in contradiction with the previously suggested genotype-phenotype correlation between truncating mutation and skin involvement.
Assuntos
Conexina 43/genética , Diagnóstico por Imagem , Anormalidades do Olho/genética , Sindactilia/genética , Anormalidades Dentárias/genética , Adulto , Sequência de Aminoácidos , Pré-Escolar , Hipoplasia do Esmalte Dentário/genética , Feminino , Dedos/anormalidades , Genótipo , Humanos , Hipospadia/genética , Deficiência Intelectual/genética , Masculino , Mutação , Linhagem , Fenótipo , Análise de Sequência de DNA , Adulto JovemRESUMO
OBJECTIVE: Severe early-onset axonal neuropathy (SEOAN) is a heterogeneous phenotype first delineated by Ouvrier et al., characterized by progressive axonal degeneration with gait problems often progressing to wheelchair requirement and later respiratory involvement. Most cases are sporadic single cases. Some have heterozygous mitofusin 2 (MFN2) mutations, many of which are de novo dominant mutations. The aim of this study was to investigate the mode of inheritance in three individuals with severe early-onset axonal neuropathy and homozygous or compound heterozygous MFN2 mutations. METHODS: The clinical and molecular findings in the parents of three individuals with SEOAN with homozygous or compound heterozygous MFN2 mutations were examined. RESULTS: All parents were asymptomatic or mildly symptomatic with some signs of peripheral neuropathy indicating a minimal phenotype. Two had hearing problems. All parents carried the relevant single base (heterozygous) MFN2 variations. CONCLUSION: Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism.
Assuntos
Axônios/metabolismo , Predisposição Genética para Doença/genética , Heterozigoto , Homozigoto , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Mutação/genética , Doenças do Sistema Nervoso Periférico/genética , Adulto , Idade de Início , Axônios/patologia , Análise Mutacional de DNA , Feminino , GTP Fosfo-Hidrolases , Genes Dominantes/genética , Marcadores Genéticos/genética , Testes Genéticos , Genótipo , Perda Auditiva Neurossensorial/genética , Humanos , Padrões de Herança/genética , Masculino , Nervos Periféricos/metabolismo , Nervos Periféricos/patologia , Nervos Periféricos/fisiopatologia , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/fisiopatologia , Degeneração Walleriana/genética , Degeneração Walleriana/metabolismo , Degeneração Walleriana/fisiopatologiaRESUMO
In some countries with a high prevalence of consanguineous marriages, autosomal recessive inheritance is likely to account for the great majority of all forms of Charcot-Marie-Tooth (CMT) disease. As with the dominant forms, it is usual to differentiate the demyelinating forms (autosomal recessive -CMT1 or AR-CMT4) from the axonal forms (AR-CMT2). Genetic analysis of large families with recessive transmission has proved to be an efficient mean of discovering novel CMT genotypes (eg, the genes GDAP1, MTMR2, MTMR13, KIAA1985, NDGR1, periaxin, and lamin). Because of the clinical, electrophysiologic, and histologic heterogeneity of these patients, it is likely that there are numerous genes that remain to be discovered, which will probably make classification even more complex. Clinical, and especially histologic, phenotypes often lead to a suspicion that a specific gene is implicated. There is, therefore, an indication for nerve biopsy to orient diagnostic research in molecular biology, which is presently very time consuming and can only be performed in highly specialized laboratories.