Malate dehydrogenases (MDH) serve a critical role in maintaining equilibrium of the NAD+/NADH ratio between the mitochondria and cytosol through the catalysis of the oxidation of L-malate to oxaloacetate in a reversible, NADH-dependent manner. MDH2 encodes the mitochondrial isoform, which is integral to the tricarboxylic acid cycle and thus energy homeostasis. Recently, five patients harboring compound heterozygous MDH2 variants have been described, three with early-onset epileptic encephalopathy, one with a stroke-like episode, and one with dilated cardiomyopathy. Here, we describe an additional seven patients with biallelic variants in MDH2, the largest and most neurodevelopmentally and ethnically diverse cohort to-date, including homozygous variants, a sibling pair, non-European patients, and an adult. From these patients, we learn that MDH2 deficiency results in a biochemical signature including elevations of plasma lactate and the lactate:pyruvate ratio with urinary excretion of malate. It also results in a recognizable constellation of neuroimaging findings of anterior-predominant cerebral atrophy, subependymal cysts with ventricular septations. We also recognize MDH2 deficiency as a cause of Leigh syndrome. Taken with existing patient reports, we conclude that MDH2 deficiency is an emerging and likely under-recognized cause of infantile epileptic encephalopathy and provide a framework for medical evaluation of patients identified with biallelic MDH2 variants.

Pulmonary hemorrhage is a rare, life-threatening condition affecting premature infants. There is no single etiological explanation for it but some common denominators include the presence of extreme prematurity, respiratory distress syndrome, surfactant use, birth asphyxia, etc. Although the incidence of pulmonary hemorrhage in neonates may be small, it is associated with a high risk of mortality. Congenital bleeding disorders such as hemophilia are rare coagulation disorders that have been known to present in the early neonatal period with an increased tendency for bleeding after blood draws, circumcision, surgical interventions, intracranial hemorrhage, oral or mucosal bleeding, and very rarely as gastrointestinal hemorrhage. There are no reports so far in the published literature of hemophilia presenting as pulmonary hemorrhage in early life. We report an unusual primary presentation of hemophilia B in a premature, monochorionic-diamniotic twin with acute life-threatening pulmonary hemorrhage with no family history of bleeding disorders.