Malate dehydrogenase 2 deficiency is an emerging cause of pediatric epileptic encephalopathy with a recognizable biochemical signature

• Published in: Molecular genetics and metabolism reports 2022-12, Vol.33, p.100931-100931, Article 100931
• Main Authors: Priestley, Jessica R.C., Pace, Lisa M., Sen, Kuntal, Aggarwal, Anjali, Alves, Cesar Augusto P.F., Campbell, Ian M., Cuddapah, Sanmati R., Engelhardt, Nicole M., Eskandar, Marina, Jolín García, Paloma C., Gropman, Andrea, Helbig, Ingo, Hong, Xinying, Gowda, Vykuntaraju K., Lusk, Laina, Trapane, Pamela, Srinivasan, Varunvenkat M., Suwannarat, Pim, Ganetzky, Rebecca D.
• Format: Article
• Language: English
• Subjects: Epileptic encephalopathy; Leigh syndrome; Malate dehydrogenase; MDH2; Mitochondrial malate dehydrogenase; Research Paper; TCA cycle
• ISSN: 2214-4269; 2214-4269
• DOI: 10.1016/j.ymgmr.2022.100931

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. •MDH2 deficiency results from biallelic variants in the MDH2 gene and causes an early-onset epileptic encephalopathy.•The biochemical signature of MDH2 is high plasma lactate, high plasma lactate:pyruvate ratio, and high urinary malic acid.•Distinct neuroimaging in MDH2: anterior-predominant cerebral atrophy and subependymal cysts with ventricular septations•MDH2 care team should include biochemical genetics, neurology, developmental pediatrics, cardiology & ophthalmology