Submission Details

MCEE, which encodes methylmalonyl-CoA epimerase, was first reported in relation to autosomal recessive methylmalonyl-CoA epimerase deficiency in 2006 (Chandler et al, PMID: 16843692 AND Dobson et al, PMID: 16697227). The primary phenotype observed in probands is methylmalonic aciduria, with occasional metabolic acidosis or other phenotypes following febrile infections. Only four unique variants (e.g. missense, deep intronic, nonsense) have been reported in humans, with the founder null variant Arg47Ter in the predominance of cases. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in less than twenty probands mostly of European ancestry (PMIDs: 16697227, 17823972, 27699154, 29104221, 30682498, 31146325). These probands display various phenotypes, however the range from asymptomatic to neurodevelopmental phenotypes makes causation of any phenotype other than the methylmalonic aciduria uncertain. The mechanism for disease is biallelic loss of function, with defective protein activity causing a blockage in the propionyl-CoA to succinyl-CoA pathway in human cells and a resulting buildup of methylmalonic acid. This is also observed in other genes that encode in the similar pathway, such as MMUT, MMAA, MMAB, and MMADHC. This gene-disease association is also supported by biochemical function and functional alteration data. MCEE's place in the pathway and the predicted result of a blockage provides significant evidence towards the pathogenicity. In two different cell lines, HeLa cells and C. elegans nematodes, disruption of the MCEE gene led to a direct decrease in 1-[14C]-propionate incorporation and a resulting buildup of methylmalonic acid. In summary, MCEE is definitively associated with autosomal recessive methylmalonyl-CoA epimerase deficiency.This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.