Type of mutation:
The only pathogenic variant reported so far is an autosomal recessive variant resulting in a missense mutation c.413C>T (p.Ala138Val). This substitution replaces a conserved alanine in the NAD+ binding domain impairing the activity and stability of the enzyme.
Suspected pathophysiologic mechanism:
MDH1 is an important enzyme in the malate-aspartate shuttle (MAS). It performs the reversible oxidation of L-malate to oxaloacetate. The MAS plays an integral role in TCA and amino acid metabolism. The MAS is important in mitochondrial NADH supply for oxidative phosphorylation. However, the pathophysiologic mechanism of this disorder remains unclear and under investigation.
MDH1