A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria

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Abstract
Methylmalonic aciduria (MMA‐uria) is an autosomal recessive inborn error of amino acid metabolism, involving valine, threonine, isoleucine, and methionine. This organic aciduria may present in the neonatal period with life‐threatening metabolic acidosis, hyperammonemia, feeding difficulties, pancytopenia, and coma. Most affected patients have mutations in the methylmalonyl‐coenzyme A (methylmalonyl‐CoA) mutase gene. Mildly affected patients may present in childhood with failure to thrive and recurrent attacks of metabolic acidosis. Both a higher residual activity of methylmalonyl‐CoA mutase as well as the vitamin B12–responsive defects (cblA and cblB) may form the basis of the mild disorder. A few patients with moderate MMA‐uria are known in whom no defect could be identified. Here we present a 16‐year‐old female patient with persisting moderate MMA‐uria (∼50 mmol/mol creatinine). She was born to consanguineous Caucasian parents. Her fibroblast mutase activity was normal and no effect of vitamin B12 supplementation could be established. Reduced incorporation of 14C‐propionate into macromolecules suggested a defect in the propionate‐to‐succinate pathway. We found a homozygous nonsense mutation (c.139C>T) in the methylmalonyl‐CoA epimerase gene (MCEE), resulting in an early terminating signal (p.R47X). Both parents were heterozygous for this mutation; they were found to excrete normal amounts of methylmalonic acid (MMA). This is the first report of methylmalonyl‐CoA epimerase deficiency, thereby unequivocally demonstrating the biochemical role of this enzyme in human metabolism. Hum Mutat 27(7), 640–643, 2006.