ACTA1-related cardiomyopathy: cardiac involvement as an unrecognized critical clinical manifestation of ACTA1-related myopathy

Topic:

Other

Poster Number: P362

Author(s):

Meghan McAnally, MD, MPH, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Abigail Potticary, BS, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, Leslie Hayes, MD, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Joshua Clayton, PhD, Centre for Medical Research University of Western Australia, Harry Perkins Institute, Göknur Haliloğlu, MD, Division of Pediatric Neurology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Sandra Donkervoort, MS, CGC, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Michele Yang, MD, University of Colorado School of Medicine, Children's Hospital, Melissa Gibbons, MS, CGC, University of Colorado School of Medicine, Children's Hospital Colorado, Brianna Gross, MS, LCGC, Children’s Hospital of Philadelphia, Susan Matesanz, MD, Children's Hospital of Philadelphia, Livija Medne, MS, LCGC, CGC, Children's Hospital of Philadelphia, Sabrina Yum, MD, Children's Hospital of Philadelphia, Pomi Yun, Johns Hopkins University, Roula Ghaoui, BSc, BMBS, PhD, Central Adelaide Local Health Network/Royal Adelaide Hospital, Adelaide, Jana Haberlová, MD, PhD, Second Faculty of Medicine Charles University and University Hos, Colin Quinn, MD, Department of Neurology, University of Pennsylvania, Robert Dilley, MD, PhD, Massachusetts General Hospital, Meganne Leach, MSN, PNP, Oregon Health and Science University, Kathryn Chatfield, MD, University of Colorado School of Medicine, Children's Hospital Colorado, Michela Guglieri, MD, Newcastle University, Newcastle upon Tyne, England, UK, Teresa Lee, MD, Columbia University Medical Center, Pinki Munot, MD, John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS, Giovanni Baranello, MD, Great Ormond Street Institute of Child Health University College London, London, UK, Anna Sarkozy, MD, Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, GOSH, NHS Trust, Francesco Muntoni, MD, University College London, Volker Straub, PhD, Newcastle University, JWMDRC, Nigel Laing, PhD, Centre for Medical Research University of Western Australia, Harry Perkins Institute, PathWest Lab, Alan Beggs, PhD, Boston Children's Hospital, Carsten G Bönnemann, National Institute of Neurological Disorders and Stroke

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 five novel ACTA1 variants not previously reported in either skeletal or cardiac myopathy and 14 novel cardiac variants with previously reported ACTA1-myopathy without any associated cardiac phenotype. The present study comprises 20 dilated cardiomyopathy (DCM), four hypertrophic cardiomyopathy (HCM), one restrictive cardiomyopathy (RCM). 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-onset mild skeletal myopathy with rigid spine and severe, rapidly progressive DCM necessitating transplantation. Recognizing the possibility of ACTA1-related cardiac involvement is critical to promoting investigation into the pathophysiologic underpinnings of this disease. We speculate that there is a relative increase in ACTA1 expression in the heart, with abnormal skeletal actin polymerizing with cardiac actin, exerting a dominant negative effect leading to cardiomyocyte dysfunction.