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

✍ Scribed by H. Bikker; H.D. Bakker; N.G.G.M. Abeling; B.T. Poll-The; W.J. Kleijer; D.S. Rosenblatt; H.R. Waterham; R.J.A. Wanders; M. Duran

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 195 KB
• Volume: 27
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.20373

✦ Synopsis

Communicated by Johannes Zschocke

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 B 12 -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 B 12 supplementation could be established.

Reduced incorporation of 14 C-propionate into macromolecules suggested a defect in the propionateto-succinate pathway. We found a homozygous nonsense mutation (c.139C4T) 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. r