Response of an Infant With Presumed Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) to Ketone Supplementation

Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is an autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in one of three known genes: ETFA, ETFB, and ETFDH. It can cause multisystem dysfunction, including cardiomyopathy in severe cases. Ketone supplementation has been reported to be beneficial in a few case reports, but its long-term effectiveness remains unclear. We report an infant with a clinical and biochemical diagnosis of MADD who showed a favorable response to ketone supplementation, with marked improvement in severe cardiac dysfunction and sustained near-normal cardiac function and biochemical profiles over 3.5 years. Although genome sequencing did not identify causative variants, RNA sequencing revealed reduced ETFB transcript levels, and western blot analysis showed decreased ETFB protein levels. This case report illustrates MADD without an identified molecular diagnosis and provides evidence that near-absent ETFB expression is likely responsible for his presentation. These observations can guide further studies investigating the transcriptional regulation of ETFB, thereby elucidating an underappreciated molecular mechanism underlying MADD. Initiating metabolic therapy in patients with clinically suspected MADD, even in the absence of a confirmed molecular diagnosis, can be beneficial as suggested by the clinical and biochemical responses to our therapeutic trial.