A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria.
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.
Bikker
H
H
Laboratory of Genetic Metabolic Diseases and Department of Clinical Genetics/Pediatrics/Pediatric Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Bakker
H D
HD
Abeling
N G G M
NG
Poll-The
B T
BT
Kleijer
W J
WJ
Rosenblatt
D S
DS
Waterham
H R
HR
Wanders
R J A
RJ
Duran
M
M
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*
D018389:Codon, Nonsense; D008764:Methylmalonic Acid; D019998:Racemases and Epimerases; C021581:methylmalonyl-coenzyme A racemase