eP029: Response of an infant with presumed type II multiple Acyl-CoA dehydrogenase deficiency to ketone supplementation


      Multiple acyl-CoA dehydrogenase deficiency (MADD) type II has neonatal onset without congenital anomalies. In those who survive the neonatal period, recurrent metabolic decompensation and hypertrophic cardiomyopathy can occur. Deficiency of the electron transfer flavoprotein (ETF alpha and beta subunits, ETFA and ETFB) or the ETF flavin adenine dinucleotide (FAD)-dependent dehydrogenase (ETFDH) negatively impacts electron transfer in the mitochondria which subsequently affects fatty acid oxidation (FAO) and the metabolism of some amino acids. The diagnosis of MADD is established via detection of a characteristic pattern of metabolite derangements on newborn screen (NBS), acylcarnitine profiles (ACP), and urine organic acids (UOA) and/or identification of biallelic pathogenic variants in ETFA, ETFB, or ETFDH. Here we report a patient who presented with a biochemical phenotype consistent with MADD who developed cardiomyopathy that responded to ketone supplementation therapy but whole genome sequencing (WGS) failed to identify the molecular cause of his phenotypes.

      Case presentation

      Consent was obtained from the family to present this case. The patient presented with repeated NBS showing elevated C5, C16, C18:2, C18:1, C18, C16:1, and C16-OH. ACP results paralleled the NBS results and revealed additional elevations of C4, C5DC, C8, C10, C12, C14, and C14:1. UOA revealed elevations in lactic, glutaric, 2-hydroxyglutaric, ethylmalonic, adipic, suberic, and sebacic acids (among other elevations). All were characteristic of MADD but DNA testing including WGS failed to detect variants in the ETF genes or other genes that could explain his phenotype. He was treated with riboflavin (150mg daily) and levocarnitine (adequately supplemented with 150mg daily). At three months of age, he developed severe cardiomyopathy (EF as low as 20%) and a pericardial effusion in the context of a presumed viral infection. We initiated a low-fat, modified-protein, high-carbohydrate diet and, following the addition of ketone supplementation (max dose of 3g/kg/day), he rapidly improved clinically. His EF increased to 45% and the elevated metabolites on ACP and UOA decreased. Complications including emesis, electrolyte abnormalities, and nephrocalcinosis resulted from the high calcium content in the high doses of ketone supplementation necessitating decreasing his dose; there was a corresponding decrease in EF to 32%.


      The patient’s biochemical phenotype and presentation are consistent with MADD type II which is associated with fatal hypertrophic cardiomyopathy. His biochemical phenotypes and EF quickly responded to high dose ketone supplementation. Ongoing work to optimize his ketone supplementation without causing electrolyte derangements and to identify the underlying molecular cause of this MADD clinical and biochemical phenotype is in progress.