RESUMO
BACKGROUND: Mutations in the LMNA gene, encoding human lamin A/C, have been associated with an increasing number of disorders often involving skeletal and cardiac muscle, but no clear genotype/phenotype correlation could be established to date. METHODS: We analyzed the LMNA gene in a large cohort of patients mainly affected by neuromuscular or cardiac disease and clustered mutated patients in two groups to unravel possible correlations. RESULTS: We identified 28 variants, 9 of which reported for the first time. The two groups of patients were characterized by clinical and genetic differences: 1) patients with childhood onset displayed skeletal muscle involvement with predominant scapuloperoneal and facial weakness associated with missense mutations; 2) patients with adult onset mainly showed cardiac disorders or myopathy with limb girdle distribution, often associated with frameshift mutations presumably leading to a truncated protein. CONCLUSIONS: Our findings, supported by meta-analysis of previous literature, suggest the presence of two different pathogenetic mechanisms: late onset phenotypes may arise through loss of function secondary to haploinsufficiency, while dominant negative or toxic gain of function mechanisms may explain the severity of early phenotypes. This model of patient stratification may help patient management and facilitate future studies aimed at deciphering lamin A/C pathogenesis.
Assuntos
Predisposição Genética para Doença/genética , Cardiopatias/genética , Laminas/genética , Mutação/genética , Doenças Neuromusculares/genética , Adulto , Idade de Início , Criança , Pré-Escolar , Análise por Conglomerados , Estudos de Coortes , Análise Mutacional de DNA , Progressão da Doença , Mutação da Fase de Leitura/genética , Marcadores Genéticos/genética , Haplótipos/genética , Cardiopatias/metabolismo , Cardiopatias/fisiopatologia , Humanos , Lamina Tipo A/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Mutação de Sentido Incorreto/genética , Miocárdio/metabolismo , Miocárdio/patologia , Doenças Neuromusculares/metabolismo , Doenças Neuromusculares/fisiopatologia , FenótipoRESUMO
Mutations in the lamin A/C gene (LMNA) have been associated with neuromuscular diseases and more complex syndromes, involving bone and adipose tissue. We report on a case of early onset myopathy due to a heterozygous LMNA mutation in exon 9, characterized by the presence of a marked number of cytoplasmic bodies with extensive myofibrillar abnormalities and Z-disk disruption in skeletal muscle. This case suggests there is a need to increase the list of genes to be screened in patients with myofibrillar myopathy.
Assuntos
Lamina Tipo A/genética , Doenças Musculares/genética , Mutação de Sentido Incorreto/genética , Miofibrilas/patologia , Criança , Análise Mutacional de DNA/métodos , Desmina/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Éxons , Feminino , Humanos , Imuno-Histoquímica/métodos , Doenças Musculares/metabolismo , Miofibrilas/metabolismo , Miofibrilas/ultraestruturaRESUMO
Dropped head syndrome is characterized by severe weakness of neck extensor muscles with sparing of the flexors. It is a prominent sign in several neuromuscular conditions, but it may also be an isolated feature with uncertain aetiology. We report two children in whom prominent weakness of neck extensor muscles is associated with mutations in lamin A/C (LMNA) and selenoprotein N1 (SEPN1) genes, respectively. This report expands the underlying causes of the dropped head syndrome which may be the presenting feature of a congenital muscular dystrophy.
