Acute Heart Failure in Adulthood is the First Manifestation of a Homozygous Pyrophosphatase 2 Variant, Expanding the Phenotypic Spectrum: A Case Report

Background PPA2 encodes the mitochondrial inorganic pyrophosphatase 2 enzyme, essential for energy metabolism. Biallelic loss-of-function variants have been associated with early-onset sudden cardiac death and cardiomyopathy, typically in infants or adolescents following minimal alcohol intake. Adult-onset presentations are extremely rare. Case summary We report a 58-year-old woman presenting with acute heart failure following a febrile viral infection. Echocardiography revealed severe left ventricular systolic dysfunction. Cardiac MRI showed diffuse myocardial fibrosis. Genetic testing identified a homozygous pathogenic variant in PPA2 (p.Arg127Leu). Family history included two brothers who died suddenly in adolescence, one after minimal alcohol intake. Our patient after six months of follow-up with treatment for heart failure, her systolic function normalized. However an implantable cardioverter-defibrillator was placed due to extensive fibrosis and non-sustained ventricular tachycardia and the high risk of sudden death associated with the desease. Conclusion This is the first known case of PPA2-related cardiomyopathy presenting with reversible heart failure in adulthood, highlighting an expanded phenotypic spectrum. Recognizing adult-onset cases is crucial, as it provides an opportunity to manage these patients in a personalized manner and to prevent complications, decompensation or fatal outcomes.