Acute heart failure in adulthood as the first manifestation of a homozygous pyrophosphatase 2 variant, expanding the phenotypic spectrum: a case report

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.

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 6 months of follow-up with treatment for heart failure, had 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 disease.

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.