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

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• Mitochondrial malate dehydrogenase (MDH), encoded by MDH2, is crucial for the Krebs cycle.
• Dysfunction in the Krebs cycle is implicated in various diseases, including cancer.

Purpose of the Study:

• To investigate the role of MDH2 in early-onset neurological disorders.
• To identify the genetic basis of severe hypotonia, psychomotor delay, and epilepsy in affected children.

Main Methods:

• Genetic analysis of three unrelated subjects with severe neurological symptoms.
• Functional studies using patient-derived fibroblasts to assess MDH2 levels and activity.
• Metabolomics to analyze Krebs cycle intermediates.
• Yeast complementation assays to validate mutation pathogenicity.

Main Results:

• Bi-allelic pathogenic mutations in MDH2 were identified in all subjects.
• Patient fibroblasts showed near-complete loss of MDH2 levels and activity.
• Accumulation of malate and fumarate was observed in patient fibroblasts.
• Lentiviral complementation restored MDH2 function.

Conclusions:

• Loss-of-function mutations in MDH2 are associated with severe neurological presentations in children.
• MDH2 deficiency disrupts the Krebs cycle, leading to significant clinical manifestations.
• MDH2 is essential for normal neurological development.