RESUMO
BACKGROUND: Autosomal dominant (AD) central core disease (CCD) is a congenital myopathy characterised by the presence of cores in the muscle fibres which correspond to broad areas of myofibrils disorganisation, Z-line streaming and lack of mitochondria. Heterozygous mutations in the RYR1 gene were observed in the large majority of AD-CCD families; however, this gene was excluded in some of AD-CCD families. OBJECTIVE: To enlarge the genetic spectrum of AD-CCD demonstrating mutations in an additional gene. PATIENTS AND METHODS: Four affected AD family members over three generations, three of whom were alive and participate in the study: the mother and two of three siblings. The symptoms began during the early childhood with mild delayed motor development. Later they developed mainly tibialis anterior weakness, hypertrophy of calves and significant weakness (amyotrophic) of quadriceps. No cardiac or ocular involvement was noted. RESULTS: The muscle biopsies sections showed a particular pattern: eccentric cores in type 1 fibres, associated with type 1 predominance. Most cores have abrupt borders. Electron microscopy confirmed the presence of both unstructured and structured cores. Exome sequencing analysis identified a novel heterozygous missense mutation p.Leu1723Pro in MYH7 segregating with the disease and affecting a conserved residue in the myosin tail domain. CONCLUSIONS: We describe MYH7 as an additional causative gene for AD-CCD. These findings have important implications for diagnosis and future investigations of AD-congenital myopathies with cores, without cardiomyopathy, but presenting a particular involvement of distal and quadriceps muscles.
Assuntos
Miosinas Cardíacas/genética , Predisposição Genética para Doença/genética , Mutação de Sentido Incorreto/genética , Miopatia da Parte Central/genética , Cadeias Pesadas de Miosina/genética , Adulto , Idoso , Feminino , Heterozigoto , Humanos , Masculino , Fibras Musculares de Contração Lenta/diagnóstico por imagem , Fibras Musculares de Contração Lenta/patologia , Fibras Musculares de Contração Lenta/ultraestrutura , Miopatia da Parte Central/diagnóstico por imagem , Miopatia da Parte Central/patologia , Linhagem , RadiografiaRESUMO
BACKGROUND: Congenital myopathies (CM) are a group of rare inherited muscle disorders characterized by particular histopathological alterations on muscle biopsy. Core-rod myopathy is a CM presenting with cores and rods as distinctive muscle morphological features. METHODS/RESULTS: We describe 3 young patients presenting congenital core-rod myopathy with bilateral foot-drop associated with autosomal recessive nebulin gene (NEB) mutations detected by exome sequencing. CONCLUSIONS: This report illustrates that core-rod congenital myopathy with foot-drop is frequently associated with NEB gene mutations and should be considered in the differential diagnosis of early onset distal myopathies.
Assuntos
Transtornos Neurológicos da Marcha/genética , Proteínas Musculares/genética , Miopatias Congênitas Estruturais/diagnóstico , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Criança , Exoma , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Miopatias Congênitas Estruturais/genética , Adulto JovemRESUMO
The slow α-tropomyosin gene (TPM3) has been associated with three distinct histological entities: nemaline myopathy (NM, NEM1), congenital fibre-type disproportion (CFTD), and cap disease (CD). Here we describe a patient presenting an early-onset congenital myopathy associated with a combination of well separated cap structures and nemaline bodies in his muscle biopsy. Exome sequencing analysis allowed us to identify a de novo missense mutation in the TPM3 gene. Our study confirms the extreme variability of morphological findings in TPM3-related myopathies, and proves that cap and nemaline bodies are two sides of the same 'coin'.