Expanding the cardiac phenotype of homozygous PPA2 variants: insights from a large Finnish family

Abstract

Abstract Background Cardiomyopathies in children associate with significant morbidity and mortality. PPA2 deficiency is a rare mitochondrial disorder linked to sudden cardiac death in children and adolescents. Most reported cases are post-mortem, with limited data on surviving individuals. To expand the phenotypic understanding of PPA2 -related disease, we describe the cardiac features of nine previously unreported homozygous carriers of the PPA2 c.380G > T, p.(Arg127Leu) variant. Methods This study included 23 individuals (22 living, one deceased) from a large Finnish family. All participants underwent genetic testing. Twenty individuals were interviewed by telephone, 16 underwent cardiac evaluation, and hospital records were reviewed for six participants. Results Nine individuals homozygous for the PPA2 p.(Arg127Leu) variant were identified. Two 15-year-old males experienced severe cardiac events following alcohol exposure: one suffered sudden cardiac death, while the other developed fulminant myocarditis. In the deceased male, a recent respiratory infection also preceded the fatal event. The remaining seven homozygotes, aged 24 to 81 years, reported no cardiac symptoms, had limited alcohol exposure restricted to communion, and showed no pathological findings on cardiac evaluation. No participants displayed neurological symptoms attributable to PPA2 -related disease. All 14 heterozygous carriers were asymptomatic. Conclusions PPA2 deficiency represents a rare but potentially fatal cause of sudden cardiac death or fulminant myocarditis, particularly in the setting of alcohol exposure. Our findings indicate that individuals homozygous for the PPA2 c.380G > T, p.(Arg127Leu) variant may remain asymptomatic into adulthood.