Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency.

摘要: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most frequently diagnosed mitochondrial β-oxidation defect, and it potentially fatal. Eighty percent of patients are homozygous for a common mutation, 985A→G, further 18% have this mutation in only one disease allele. In addition, large number rare disease-causing mutations been identified characterized. There no clear genotype-phenotype correlation. High 985A→G carrier frequencies populations European descent usual avoidance recurrent episodes by with MCAD who comply simple dietary treatment suggest that candidate prospective screening newborns. Therefore, several such programs employing analysis acylcarnitines blood spots tandem mass spectrometry (MS/MS) currently used worldwide. No validation method has yet reported. We investigated newborns from US had MS/MS-based 930,078 spots. An MCAD-deficiency frequency 1/15,001 was observed. Our shows excellent detection but mutant allele positive acylcarnitine profile much lower than observed clinically affected patients. identification new 199T→C, which never manifested present proportion acylcarnitine-positive samples, may explain skewed ratio. Overexpression experiments showed mild folding exhibits decreased levels enzyme activity under stringent conditions. A 1/500 general population makes 199T→C three prevalent enzymes fatty-acid oxidation.