Bi‐allelic variants in MDH2: Expanding the clinical phenotype

Abstract

Bi-allelic alterations in the MDH2 gene have recently been reported in three unrelated toddlers with early-onset severe encephalopathy. Here, we describe a new case of a child carrying novel variants in MDH2. This child presented with early-onset encephalocardiopathy requiring heart transplant and showed cerebellar ataxia and drug-responsive epilepsy; his family history was significant for multiple cancers, a feature often associated with monoallelic variants in MDH2. Functional studies in cultured skin fibroblasts from the proband showed reduced protein levels and impaired enzyme activity, further corroborating the genetic results. The relatively mild neurological presentation and severe cardiac manifestations requiring heart transplant distinguish this case from previous reports. This patient thus expands the spectrum of clinical features associated with MDH2 variants.

Induced pluripotent stem cell-derived hepatocytes reveal TCA cycle disruption and the potential basis for triheptanoin treatment for malate dehydrogenase 2 deficiency

“…Thus far 12 individuals have been described with bi-allelic pathogenic variants in the MDH2 gene [ [4] , [5] , [6] , [7] ]. MDH2 dysfunction causes an energy deficit affecting many organs, leading to symptoms including early-onset encephalopathy, frequent seizures, psychomotor delay, and muscular hypotonia [ 4 ], although symptom onset and affected organs may vary by individual [ 6 , 7 ]. To date, there is no curative treatment for this devastating disease.…”