Nemaline myopathy is a rare neuromuscular disorder, showing striking clinical and genetic heterogeneity. Patients can show a spectrum of disease ranging from severe congenital to an adult-onset mild form. Disease-causing mutations have been reported in five genes encoding sarcomeric thin filament proteins, and inheritance can be either autosomal recessive or dominant. No phenotype-genotype correlation is apparent at the moment. α-actin gene mutations are responsible for about 20% of cases. We have collected 18 patients from 17 families. Our patients exhibit an overall marked clinical variability, but 10 out of 18 show typical features of nemaline myopathy (slowly progressive congenital form). We have identified disease-causing mutations in the α-actin gene in 5 out of 17 families, through direct sequencing of its whole coding sequence. One patient carried two mutations, thus we describe a total of 6 mutations, all arising de novo. We also describe some intronic polymorphisms which constitute two common α-actin gene haplotypes; we show that haplotype characterisation may have a strong impact in mutation detection due to preferential amplification of a chromosome in subjects carrying both haplotypes. Screening of the α-actin gene coding sequence may account for the identification of disease-causing mutations in 20-30% of nemaline myopathy patients. Since the chance to identify mutations is indipendent of the clinical picture, we suggest that it is appropriate to check for mutations in all patients. Demonstration of a de novo origin of the mutation is of great relevance for families seeking genetic counselling.

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