Screening of MCAD deficiency in Japan: 16 years' experience of enzymatic and genetic evaluation
Screening of MCAD deficiency in Japan: 16 years' experience of enzymatic and genetic evaluation
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DOI：
10.1016/j.ymgme.2016.10.007
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发表时间：
2016-12-01
影响因子：
3.8
通讯作者：
Kobayashi, Masao
中科院分区：
文献类型：
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作者：
Tajima, Go;Hara, Keiichi;Kobayashi, Masao
背景资料：中链酰基辅酶A脱氢酶（MCAD）缺乏症是一种典型的脂肪酸氧化障碍，是高加索人群中最常见的先天性代谢缺陷之一。然而，在日本，它是迟至2000年时，第一个病人被发现，酶和遗传评估MCAD deficiency started.Methods：我们测量辛酰辅酶A脱氢酶活性的淋巴细胞的症状儿童和新生儿筛查（NBS）阳性的科目谁表现出升高水平的C8-酰基肉毒碱在血液中。结果：18例有症状的儿童中有9例确诊为ACADM。受影响的患者显示剩余活动从正常平均值的0%到3%，除了一名患者的10%的活动。关于50例NBS阳性受试者，18例酶活性约为10%或更低，14例活性范围为13%至30%，被判定为受影响患者，在大多数测试病例中检测到双等位基因变体。估计酶活性较高的新生儿为杂合子携带者或健康受试者，但其中5例检测到双等位基因变异。遗传分析共检测到22种变异等位基因。最常见的是c.449_452deICTGA（p.T150Rfs），随后是c.5OG>A（p.R17H），c.1085G>A（p.G362E），c.157C>T（p.R53C）和c.843A>T（p.R281S）;这五种变体占所有检测的等位基因的约60%。我们的研究揭示了日本人中MCAD缺乏症的独特遗传背景，基于最大系列的非高加索病例。在我们的一系列NBS阳性病例中也观察到了连续的严重程度谱，这表明每个国家和民族都必须积累自己的基因变异信息，以及对它们的酶促评价，以便建立一个有效的NBS系统来治疗MCAD缺乏症。(C)2016 Elsevier Inc. All rights reserved.
Background: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a representative disorder of fatty acid oxidation and is one of the most prevalent inborn errors of metabolism among Caucasian populations. In Japan, however, it was as late as 2000 when the first patient was found, and enzymatic and genetic evaluation of MCAD deficiency began.Methods: We measured octanoyl-CoA dehydrogenase activity in lymphocytes of symptomatic children and newborn screening (NBS)-positive subjects who showed elevated levels of C8-acylcarnitine in blood. The results were further confirmed by direct sequencing of the ACADM gene.Results: The disease was diagnosed in 9 out of 18 symptomatic children. The affected patients showed residual activities from 0% to 3% of the normal average value, except for one patient with 10% activity. Concerning 50 NBS-positive subjects, 18 with enzymatic activities around 10% or lower and 14 with activities ranging from 13% to 30% were judged to be affected patients, and biallelic variants were detected in most of the cases tested. Newborns with higher enzymatic activities were estimated to be heterozygous carriers or healthy subjects, though biallelic variants were detected in 5 of them. Genetic analysis detected 22 kinds of variant alleles. The most prevalent was c.449_452deICTGA (p.T150Rfs), which was followed by c.5OG>A (p.R17H), c.1085G>A (p.G362E), c.157C>T (p.R53C), and c.843A>T (p.R281S); these five variants accounted for approximately 60% of all the alleles examined.Conclusion: Our study has revealed the unique genetic backgrounds of MCAD deficiency among Japanese, based on the largest series of non-Caucasian cases. A continuous spectrum of severity was also observed in our series of NBS-positive cases, suggesting that it is essential for every nation and ethnic group to accumulate its own information on gene variants, together with their enzymatic evaluation, in order to establish an efficient NBS system for MCAD deficiency. (C) 2016 Elsevier Inc. All rights reserved.