Bikker H, Bakker H D, Abeling N G G M, Poll-The B T, Kleijer W J, Rosenblatt D S, Waterham H R, Wanders R J A, Duran M
Laboratory of Genetic Metabolic Diseases and Department of Clinical Genetics/Pediatrics/Pediatric Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Hum Mutat. 2006 Jul;27(7):640-3. doi: 10.1002/humu.20373.
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.
甲基丙二酸尿症（MMA-uria）是一种常染色体隐性遗传的氨基酸代谢先天性缺陷病，涉及缬氨酸、苏氨酸、异亮氨酸和蛋氨酸。这种有机酸尿症在新生儿期可能表现为危及生命的代谢性酸中毒、高氨血症、喂养困难、全血细胞减少和昏迷。大多数受影响患者的甲基丙二酰辅酶A（methylmalonyl-CoA）变位酶基因存在突变。轻度受影响患者在儿童期可能表现为发育不良和代谢性酸中毒反复发作。甲基丙二酰辅酶A变位酶较高的残余活性以及维生素B12反应性缺陷（cblA和cblB）可能是这种轻度疾病的基础。已知有少数中度MMA-uria患者，未发现缺陷。本文报告一名16岁女性患者，患有持续性中度MMA-uria（约50 mmol/mol肌酐）。她的父母是近亲结婚的白种人。她的成纤维细胞变位酶活性正常，补充维生素B12无效果。14C-丙酸盐掺入大分子减少提示丙酸盐到琥珀酸盐途径存在缺陷。我们在甲基丙二酰辅酶A差向异构酶基因（MCEE）中发现了一个纯合无义突变（c.139C>T），导致早期终止信号（p.R47X）。父母双方均为该突变的杂合子；他们的甲基丙二酸（MMA）排泄量正常。这是甲基丙二酰辅酶A差向异构酶缺乏症的首例报告，从而明确证明了该酶在人类代谢中的生化作用。
