PPA2 gene is involved in neonatal fatal acute dilated cardiomyopathy

Introduction Inherited inborn errors of metabolism can cause premature severe dilated cardiomyopathy in infants and cause sudden unexpected death (SUDI). PPA2 gene encoding the mitochondrial pyrophosphatase is involved in many reactions for energy metabolism of the cell. Biallelic mutations induce a mitochondrial disease with a particularly serious cardiac phenotype. Methods In an international consortium, we identified recently 11 new cases from 5 unrelated families, with homozygous or compound heterozygous hypomorphic PPA2 variations. We reviewed the clinical features and outcomes from both our patients and those previously described in the literature [1] , [2] . Results All of the cases ( n  = 28) suffered from cardiac defects. MRI, when performed, showed dilated left ventricle while histology of cardiac muscle documented typical diffuse myocardial fibrosis or necrosis. Twenty-four patients (86%) died suddenly from cardiogenic shock at a median age of 11.5 months (range, 11 days to 20 years) even in case of active resuscitation attempt. Ventricular fibrillation was sometimes noted just before the cardiac arrest. Acute myocarditis was basically suspected. Interestingly, three times, very low alcohol consummation was reported as trigger before the death while 5 children had a proved viral disease. Alcohol metabolism and viral illness likely increase the stress of the cells already deprived of adequate ATP. The survivor cases underwent defibrillator implantation. Moreover, two of them expressed mild neurological features such as cerebellar syndrome. Conclusions PPA2 gene plays a significant role in inherited infant dilated cardiomyopathies. According to the genotype, sudden death can happen very early in the childhood or might be triggered with alcohol absorption or common viral illness. PPA2 should be systematically added in the currently used cardiomyopathy genes panels but also in SUDI's since cardiac manifestations can be extremely acute especially in neonates.