595P ACTA1-related cardiomyopathy: emerging genotypic and phenotypic patterns among patients with ACTA1-related myopathy with cardiac involvement

• Published in: Neuromuscular disorders : NMD 2024-10, Vol.43, p.104441, Article 104441.350
• Main Authors: McAnally, M., Potticary, A., Hayes, L., Clayton, J., Haliloğlu, G., Donkervoort, S., Yang, M., Gibbons, M., Gross, B., Foley, A., Guglieri, M., Lee, T., Munot, P., Sarkozy, A., Muntoni, F., Straub, V., Laing, N., Beggs, A., Bönnemann, C.
• Format: Article
• Language: English
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.359

ACTA1 encodes skeletal muscle α‐actin, the principal muscle actin isoform and the central component of sarcomeric thin filaments necessary for producing skeletal muscle contraction. Heterozygous pathogenic variants in ACTA1 cause myopathy with histopathologic features ranging from nemaline rods or actin aggregates to non-specific myopathic findings and a clinical spectrum ranging from severe congenital weakness and respiratory failure to a milder childhood or adult-onset myopathy. Cardiac involvement is not a commonly recognized feature of ACTA1-related disease as the predominant cardiac actin isoform is encoded by ACTC1, separate from skeletal actin. Nonetheless, there have been rare reports in the literature of cardiomyopathy related to ACTA1. To add to these observations and establish ACTA1 as a causative cardiac disease gene, we present the clinical, genetic, and histopathologic data collected for 25 patients with ACTA1-related cardiomyopathy (CM), representing the largest single cohort to date. This series includes four novel ACTA1 variants not previously reported in either skeletal or cardiac myopathy and 13 novel cardiac variants with previously reported ACTA1-myopathy without any associated cardiac phenotype. The present study comprises 18 dilated cardiomyopathy (DCM), four hypertrophic cardiomyopathy (HCM), one mixed DCM/HCM, and two other classified CM. There is also emergence of isolated congenital fiber type disproportion (CFTD) as the predominant histopathologic feature in patients with ACTA1-CM. Among patients in this series, we have identified two emerging groups with seemingly dichotomous phenotypes, namely those with neonatal-onset profoundly severe congenital myopathy with associated early-onset HCM and those with childhood or adult-onset mild skeletal myopathy with rigid spine and severe, rapidly progressive DCM often necessitating transplantation. Recognizing the possibility of ACTA1-related cardiac involvement is critical to promoting investigation into the pathophysiologic underpinnings of this disease.