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首页> 美国卫生研究院文献>American Journal of Human Genetics >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
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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

机译：中链酰基辅酶A脱氢酶（MCAD）突变通过基于MS / MS的新生儿前瞻性筛查与临床症状患者中观察到的新生儿不同而鉴定：新的普遍突变导致轻度MCAD缺乏症的鉴定和表征

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Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most frequently diagnosed mitochondrial β-oxidation defect, and it is potentially fatal. Eighty percent of patients are homozygous for a common mutation, 985A→G, and a further 18% have this mutation in only one disease allele. In addition, a large number of rare disease-causing mutations have been identified and characterized. There is no clear genotype-phenotype correlation. High 985A→G carrier frequencies in populations of European descent and the usual avoidance of recurrent disease episodes by patients diagnosed with MCAD deficiency who comply with a simple dietary treatment suggest that MCAD deficiency is a candidate in prospective screening of newborns. Therefore, several such screening programs employing analysis of acylcarnitines in blood spots by tandem mass spectrometry (MS/MS) are currently used worldwide. No validation of this method by mutation analysis has yet been reported. We investigated for MCAD mutations in newborns from US populations who had been identified by prospective MS/MS-based screening of 930,078 blood spots. An MCAD-deficiency frequency of 1/15,001 was observed. Our mutation analysis shows that the MS/MS-based method is excellent for detection of MCAD deficiency but that the frequency of the 985A→G mutant allele in newborns with a positive acylcarnitine profile is much lower than that observed in clinically affected patients. Our identification of a new mutation, 199T→C, which has never been observed in patients with clinically manifested disease but was present in a large proportion of the acylcarnitine-positive samples, may explain this skewed ratio. Overexpression experiments showed that this is a mild folding mutation that exhibits decreased levels of enzyme activity only under stringent conditions. A carrier frequency of 1/500 in the general population makes the 199T→C mutation one of the three most prevalent mutations in the enzymes of fatty-acid oxidation.
机译：中链酰基辅酶A脱氢酶（MCAD）缺陷是最常被诊断的线粒体β-氧化缺陷，可能致命。 80％的患者是985A→G常见突变的纯合子，另外18％的患者仅在一个疾病等位基因中具有此突变。另外，已经鉴定和表征了大量罕见的致病突变。没有明确的基因型-表型相关性。在欧洲血统的人群中，较高的985A→G载流子频率以及通过简单饮食疗法诊断为MCAD缺乏症的患者通常避免复发性疾病发作表明，MCAD缺乏症是前瞻性筛查新生儿的候选者。因此，目前在世界范围内使用几种这样的筛选程序，其采用通过串联质谱法（MS / MS）分析血斑中的酰基肉碱。尚未通过突变分析对该方法进行验证。我们调查了美国人群新生儿中的MCAD突变，这些突变已通过基于MS / MS的930,078个血斑的前瞻性筛查得以确定。观察到MCAD缺陷频率为1 / 15,001。我们的突变分析表明，基于MS / MS的方法非常适合检测MCAD缺乏症，但是在酰基肉碱呈阳性的新生儿中985A→G突变等位基因的频率远低于在临床上受影响的患者中观察到的频率。我们鉴定出的新的突变199T→C，在临床表现出疾病的患者中从未观察到，但是在大部分的酰基肉碱阳性样品中都存在，这可能解释了这种偏斜率。过表达实验表明这是一个轻度的折叠突变，仅在严格条件下才表现出降低的酶活性水平。普通人群中1/500的载波频率使199T→C突变成为脂肪酸氧化酶中三个最普遍的突变之一。

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