Recurring homozygous ACTN2 variant (p.Arg506Gly) cause a recessive adult-onset myopathy

Topic:

Other

Poster Number: 195

Author(s):

Sandra Donkervoort, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Payam Mohassel, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Melanie O’Leary, Broad Institute of MIT and Harvard, Talia Hartley, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Nicole Acquaye, National Institute of Neurological Disorders and Stroke, Tahseen Mozaffar, MD, University of California Irvine, Sandra Donkervoort, Genetic Counselor, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, David Dyment, Children's Hospital of Eastern Ontario Research Institute, Christina Austin-Tse, Broad Institute of MIT and Harvard, Kyle Hurth, Department of Pathology, University of Southern California, Julie Cohen, Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Kirsty McWalter, Genedx, A. Reghan Foley, MD, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Jodi Warman-Chardon, MD, Department of Medicine, The Ottawa Hospital, University of Ottawa, Anne O'Donnell-Luria, MD, PhD, Center for Mendelian Genomics, Broad Institute of MIT, Carsten Bönnemann, MD, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH

ACTN2, encoding alpha-actinin-2, is essential for sarcomeric function in cardiac and skeletal muscle. Pathogenic ACTN2 variants are a known cause for cardiomyopathies without muscle manifestations. Recently specific dominant variants have been reported as a rare cause of core myopathy, although the precise pathomechanism remains to be elucidated. A tentative recessive ACTN2 manifestation has also been proposed previously. Here we report six patients from four families with a recurring biallelic c.1516A>G (p.Arg506Gly) ACTN2 variant manifesting with adult-onset, asymmetric, progressive, proximal and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant. Muscle biopsy findings were consistent with an underlying myopathic process with disruption of the intermyofibrillar architecture and type I fiber hypotrophy. MRI of the lower extremities revealed a distinct pattern of surprisingly asymmetric muscle involvement with selective involvement of the hamstrings in the thigh and anterior tibial group and soleus in the lower leg. Additional mechanistic studies are ongoing to evaluate the molecular and functional consequences of the c.1516A>G (p.Arg506Gly) ACTN2 variant on myofibrillar structure and function. Our series further establishes ACTN2 as a muscle disease gene, to now also include recessively acting variants, and expands the actininopathy clinical spectrum to adult-onset progressive muscle disease.