Cardiomyopathy: Genetics in muscular dystrophies

Dilated cardiomyopathy (DC) presents high mortality and morbidity and is a leading indication to heart transplantation; among etiopathological hypotheses the existence of genetic defects has recently become consistent. However, genetic studies are complicated by the genetic heterogeneity of the disease. A skeletal muscle involvement (by definition subclinical) was present in 18% of our cases belonging to families with X-linked DC (XLDC) or autosomal dominant inheritance (MDDC). Different mutations/deletions of the gene codifying for dystrophin, a protein that plays a critical role in membrane stability, force transduction, and organizing membrane specialization, have been identified in XLDC. The absence of clinical signs of skeletal muscle involvement in patients with XLDC could be explained by the compensatory production of the brain and Purkinje isoforms in the muscles, which assures a lower but still sufficient expression of dystrophin and a clinically normal phenotype. In the MDDC form, no disease gene has been identified so far, however, genes codifying for cytoskeletal proteins, such as the components of the DAG complex, appear to be excellent candidates. This hypothesis is supported by the recent findings of involvement of these genes in muscular dystrophies associated with cardiomyopathy as well as in DC in animal models and humans. In conclusion, DC is frequently inherited and heterogeneous. Among the different subgroups of patients with FDC, skeletal muscle involvement can be present even if subclinical and, therefore, should always be carefully investigated.