title: A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria.
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 (approximately 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.
authors.affiliation: Laboratory of Genetic Metabolic Diseases and Department of Clinical Genetics/Pediatrics/Pediatric Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Bikker
authors.forename: H D
authors.initials: HD
authors.lastname: Bakker
authors.forename: N G G M
authors.initials: NG
authors.lastname: Abeling
authors.forename: B T
authors.initials: BT
authors.lastname: Poll-The
authors.forename: W J
authors.initials: WJ
authors.lastname: Kleijer
authors.forename: D S
authors.initials: DS
authors.lastname: Rosenblatt
authors.forename: H R
authors.initials: HR
authors.lastname: Waterham
authors.forename: R J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: M
authors.initials: M
authors.lastname: Duran
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics*; D002675:Child, Preschool; D018389:Codon, Nonsense; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D006720:Homozygote; D006801:Humans; D008764:Methylmalonic Acid / Q000652:urine*; D019998:Racemases and Epimerases / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D008764:Methylmalonic Acid; D019998:Racemases and Epimerases; C021581:methylmalonyl-coenzyme A racemase