Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy

Abstract

MDH2 encodes mitochondrial malate dehydrogenase (MDH), which is essential for the conversion of malate to oxaloacetate as part of the proper functioning of the Krebs cycle. We report bi-allelic pathogenic mutations in MDH2 in three unrelated subjects presenting with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate in the blood and cerebrospinal fluid. Functional studies in fibroblasts from affected subjects showed both an apparently complete loss of MDH2 levels and MDH2 enzymatic activity close to null. Metabolomics analyses demonstrated a significant concomitant accumulation of the MDH substrate, malate, and fumarate, its immediate precursor in the Krebs cycle, in affected subjects' fibroblasts. Lentiviral complementation with wild-type MDH2 cDNA restored MDH2 levels and mitochondrial MDH activity. Additionally, introduction of the three missense mutations from the affected subjects into Saccharomyces cerevisiae provided functional evidence to support their pathogenicity. Disruption of the Krebs cycle is a hallmark of cancer, and MDH2 has been recently identified as a novel pheochromocytoma and paraganglioma susceptibility gene. We show that loss-of-function mutations in MDH2 are also associated with severe neurological clinical presentations in children.

Social, neurodevelopmental, endocrine, and head size differences associated with atypical deletions in Williams–Beuren syndrome

“…Medical histories for the newly described patients were evaluated for findings established in the medical literature (Table ). Epilepsy has been linked to numerous genes distal to the WBSCR, including HIP1 (Fusco et al, ; Ramocki et al, ), MDH2 (Ait‐El‐Mkadem et al, ), YWHAG (Fusco et al, ; Komoike et al, ; Ramocki et al, ), and MAGI2 (Marshall et al, ; Röthlisberger et al, ), as well as to one gene from the centromeric side, KCTD7 (Kousi et al, ; Staropoli et al, ; Van Bogaert et al, ). After examining our cohort, only Patient A had a history of infantile spasms and seizures.…”

Mitochondrial dysfunction in human skeletal muscle biopsies of lipid storage disorder

“…Loss‐of‐function mutations in MDH2 gene are associated with severe neurological clinical presentations including early‐onset severe encephalopathy probably owing to mitochondrial accumulation of Malate and Fumarate (Ait‐El‐Mkadem et al . ).…”

Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients

“…In this regard, families affected with encephalopathy due to recessive MDH2 deficiency have been described. 38 One could expect to find PPGL patients in these families, but as it happens in pedigrees affected with the Leigh syndrome (OMIM 256000) associated with autosomal recessive PV in SDHA, 39 their members do not develop either these tumors.…”