Cardiomyopathy in patients with ACTA1-myopathy

Mutations in ACTA1, encoding for skeletal muscle α-actin, cause a spectrum of myopathies with a range of characteristic findings such as nemaline rods or fiber type disproportion on biopsy and with variable clinical expressivity ranging from a lack of spontaneous movement and respiratory failure at birth, via intermediate phenotypes, to adult-onset myopathy. Cardiac involvement is rarely seen in ACTA1-myopathy and has been reported in less than ten patients at this time. We add to this the largest single series to date of six unrelated patients with skeletal weakness and variable degrees of cardiomyopathy, caused by four different previously unreported ACTA1 mutations. Four patients presented with rapid-onset cardiac failure in childhood requiring transplantation. Interestingly, these patients had only relatively mild skeletal muscle involvement prior to cardiac failure. In addition, we present data on two patients with ACTA1-myopathy with cardiomyopathy identified on cardiac imaging but who have not progressed to cardiac failure. Biopsy review did not observe typical nemaline rod pathology; however four out of six biopsies showed fiber type disproportion. This series expands the cardiac manifestations of ACTA1-myopathy, indicating that cardiac screening is important in this patient population. This is the first series to report successful cardiac transplantation in ACTA1-myopathy. In addition, as cardiac failure can precede skeletal muscle involvement, neuromuscular screening may be considered in patients presenting with cardiomyopathy. Additional studies are necessary to establish genotype-phenotype correlation and to understand the underlying pathophysiological mechanism, including the relative balance between skeletal muscle and cardiac actin in the heart.