RESUMO
Mutations in the GJB1 gene are the second most frequent cause of Charcot-Marie-Tooth disease (CMT), accounting for approximately 10% of CMT cases worldwide. We retrospectively analyzed detailed clinical and neurophysiological data on four Brazilian families carrying novel mutations of the GJB1 gene. Mutations were identified by bidirectional Sanger sequence analysis on the GJB1 coding region. We identified a total of 12 subjects from four different kindred. There was no male-to-male transmission, and their clinical pictures were within the expected spectrum for GJB1-related neuropathy. Males were more severely affected than females. Five out of the eight females only had subclinical neuropathy. Nerve conduction velocities were in the intermediate range in the male patients and higher in the females affected. These mutations increase the genotypic variability associated with GJB1.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Conexinas/genética , Genótipo , Mutação , Adolescente , Adulto , Idoso , Brasil , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Condução Nervosa/genética , Linhagem , Fenótipo , Estudos Retrospectivos , Adulto Jovem , Proteína beta-1 de Junções ComunicantesRESUMO
We report a new transthyretin (ATTR) gene c.272C>G mutation and variant protein, p.Leu32Val, in a kindred of Bolivian origin with a rapid progressive peripheral neuropathy and cardiomyopathy. Three individuals from a kindred with peripheral nerve and cardiac amyloidosis were examined. Analysis of the TTR gene was performed by Sanger direct sequencing. Neuropathologic examination was obtained on the index patient with mass spectrometry study of the ATTR deposition. Direct DNA sequence analysis of exons 2, 3, and 4 of the TTR gene demonstrated a c.272 C>G mutation in exon 2 (p.L32V). Sural nerve biopsy revealed massive amyloid deposition in the perineurium, endoneurium and vasa nervorum. Mass spectrometric analyses of ATTR immunoprecipitated from nerve biopsy showed the presence of both wild-type and variant proteins. The observed mass results for the wild-type and variant proteins were consistent with the predicted values calculated from the genetic analysis data. The ATTR L32V is associated with a severe course. This has implications for treatment of affected individuals and counseling of family members.
Assuntos
Neuropatias Amiloides Familiares/genética , Saúde da Família , Leucina/genética , Mutação/genética , Pré-Albumina/genética , Valina/genética , Neuropatias Amiloides Familiares/fisiopatologia , Bolívia , Análise Mutacional de DNA , Feminino , Humanos , Pessoa de Meia-Idade , Condução Nervosa/genética , Pré-Albumina/metabolismoRESUMO
INTRODUCTION: Understanding the natural history of dysferlinopathy is essential to design and quantify novel therapeutic protocols. Our aim in this study was to assess, clinically and functionally, a cohort of patients with dysferlinopathy, using validated scales. METHODS: Thirty-one patients with genetically confirmed dysferlinopathy were assessed using the motor function measure (MFM), Modified Rankin Scale (MRS), Muscle Research Council (MRC) scale, serum creatine kinase (CK) assessment, baseline spirometry data, and echocardiographic and electrophysiologic studies. RESULTS: MFM and MRC scores showed a significant negative correlation with disease duration and inverse correlation with MRS, but not with onset age, clinical phenotype, or CK levels. Percent forced vital capacity (%FVC) correlated negatively with disease duration and onset age. Eight known pathogenic mutations were identified recurrently, 4 of which accounted for 79% of the total. CONCLUSIONS: The results suggest that MFM is a reliable outcome measure that may be useful for longitudinal follow-up in dysferlinopathy. Recurrent mutations suggest a founder effect in the Chilean population.
Assuntos
Avaliação da Deficiência , Pessoas com Deficiência , Proteínas de Membrana/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Adolescente , Adulto , Estudos de Coortes , Creatina Quinase/sangue , Disferlina , Eletromiografia , Potencial Evocado Motor/fisiologia , Extremidades/fisiopatologia , Feminino , Humanos , Masculino , Proteínas de Membrana/sangue , Proteínas Musculares/sangue , Músculo Esquelético/fisiopatologia , Distrofia Muscular do Cíngulo dos Membros/sangue , Condução Nervosa/genética , Respiração , Espirometria , Estatísticas não Paramétricas , Capacidade Vital/fisiologia , Adulto JovemRESUMO
Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral neuropathies in which the neuropathy is the sole or primary component of the disorder, as opposed to diseases in which the neuropathy is part of a more generalized neurologic or multisystem syndrome. Because of the great genetic heterogeneity of this condition, it can be challenging for the general neurologist to diagnose patients with specific types of CMT. This article reviews the biology of the inherited peripheral neuropathies, delineates major phenotypic features of the CMT subtypes, and suggest strategies for focusing genetic testing.
Assuntos
Heterogeneidade Genética , Proteínas de Membrana/genética , Mutação/genética , Doenças do Sistema Nervoso Periférico/genética , Adulto , Testes Genéticos , Humanos , Masculino , Condução Nervosa/genética , Doenças do Sistema Nervoso Periférico/fisiopatologiaRESUMO
We describe a large Brazilian consanguineous kindred with 3 clinically affected patients with a Thomsen myotonia phenotype. They carry a novel homozygous nonsense mutation in the CLCN1 gene (K248X). None of the 6 heterozygote carriers show any sign of myotonia on clinical evaluation or electromyography. These findings confirm the autosomal recessive inheritance of the novel mutation in this family, as well as the occurrence of phenotypic variability in the autosomal recessive forms of myotonia.
Assuntos
Canais de Cloreto/genética , Códon sem Sentido/genética , Miotonia Congênita/genética , Miotonia/genética , Adenosina Trifosfatases/metabolismo , Adolescente , Brasil , Criança , Consanguinidade , Ecocardiografia , Éxons/genética , Saúde da Família , Feminino , Humanos , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Miotonia/patologia , Miotonia/fisiopatologia , Miotonia Congênita/patologia , Miotonia Congênita/fisiopatologia , Condução Nervosa/genética , FenótipoRESUMO
Nerve conduction is profoundly affected in Spinocerebellar ataxia 2 (SCA2) even before the onset of the disease, but there is no information regarding its progression to the final stage of SCA2. In order to study the progression patterns of nerve conduction abnormalities in SCA2 we performed a prospective follow up evaluation of sensory and motor conduction in 21 SCA2 mutation carriers-initially presymptomatics- and 19 non-SCA2 mutation carriers during 20years. The earliest electrophysiological alterations were the reduction of sensory amplitudes in median and sural nerves, which could be found 8 to 5years prior disease onset and in the last 4years of the preclinical stage respectively. These abnormalities were followed by the increase of sensory latencies and decrease of conduction velocities. Sensory amplitudes progressively decreased during the follow-up clinical stage, rendering almost all patients with abnormal amplitudes and lack of sensory potentials, with faster progression rates in patients with larger CAG repeat lengths. Peripheral motor nerves showed the later involvement. These findings were used to define three distinct stages that describe the progression of the peripheral neuropathy. We suggest that sensory amplitudes could be useful biomarkers to assess the progression of peripheral nerve involvement and therefore to evaluate future clinical trials of therapeutic agents.