A Case of Multiple Mitochondrial Dysfunctions Syndrome 1 and Review of the Literature

Multiple mitochondrial dysfunctions syndrome 1 (MMDS1, MIM #605711) due to NFU1 gene defects is an ultra-rare autosomal recessive inborn error of metabolism associated with reduced function of NFU1 iron-sulfur cluster (ISC) scaffold protein. This disorder demonstrates variable clinical features including hypotonia, epileptic encephalopathy, respiratory failure, lactic acidosis, hyperglycinemia, and hemodynamic instability. One unique feature of this mitochondrial disorder is the common manifestation of pulmonary arterial hypertension (PAH), for which the pathophysiologic mechanism is not well defined to date. Here, we report a case of infantile-onset lactic acidosis, refractory epilepsy with encephalopathy, hyperglycinemia, and severe PAH in a patient who underwent rapid genome sequencing (GS) which identified compound heterozygous variants in NFU1 consistent with a diagnosis of MMDS1. We additionally review the literature on published cases of MMDS1 including developments in the understanding of the intracellular impact of defective ISC proteins. Recent studies delineate a multifactorial pathogenesis including globally dysregulated energy metabolism, specific deficiencies in oxidative phosphorylation, and excess reactive oxygen species (ROS) production. A key difference between established animal models of this disorder and human cases published to date is that the previously described sex-based phenotype discrepancy in rats was not recapitulated in this review. Identification of the clinical combination of lactic acidosis, PAH, and hyperglycinemia during diagnostic evaluation should raise suspicion for a defect of the ISC pathway, and further investigations of the cellular pathophysiology of this disorder may provide insight into the phenotypic spectrum of human disease and potential therapeutic targets.