CAD mutations and uridine-responsive epileptic encephalopathy
CAD mutations and uridine-responsive epileptic encephalopathy
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DOI：
10.1093/brain/aww300
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发表时间：
2017-02-01
期刊：
影响因子：
14.5
通讯作者：
Haack, Tobias B.
中科院分区：
文献类型：
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作者：
Koch, Johannes;Mayr, Johannes A.;Haack, Tobias B.
Koch等人报道了在4名患有发育障碍、癫痫性脑病、贫血和异异形红细胞增多症的儿童中CAD中的双等位基因突变，其编码嘧啶生物合成的酶。两名儿童在进行性神经变性后死亡;幸存的儿童对尿苷表现出显著的临床反应。研究结果证实CAD缺陷是一种可治疗的神经代谢紊乱，儿童期不明原因的全面发育迟缓和癫痫是主要的社会经济负担。在确定分子基础方面取得的进展往往不能转化为有效的治疗。值得注意的例外包括某些先天性代谢缺陷，可以通过饮食干预来解决。CAD编码参与从头嘧啶生物合成的多功能酶。或者，嘧啶可以从尿苷再循环。在三个家庭的外显子组测序确定双等位基因CAD突变的4名儿童与全球发展迟缓，癫痫性脑病，贫血与异异形红细胞。两人在神经退行性疾病病程后4年和5年死亡。两个幸存的儿童补充口服尿苷导致癫痫发作立即停止。一名4岁的女性，以前处于最低意识状态，在治疗9周后开始交流和行走。一名3岁的女性同样表现出发育进展。血涂片正常化，贫血消退。我们确定CAD是一个与这种神经代谢紊乱有关的基因，其特征是同时发生全面发育迟缓、红细胞生成障碍性贫血和癫痫发作。虽然自然病程在儿童早期可能是致命的，但我们的研究结果支持尿苷补充剂的疗效，使CAD缺乏症成为一种可治疗的神经代谢疾病，因此是未来（遗传）新生儿筛查的潜在条件。
Koch et al. report biallelic mutations in CAD, encoding an enzyme of pyrimidine biosynthesis, in four children with developmental disability, epileptic encephalopathy, anaemia and anisopoikilocytosis. Two died following progressive neurodegeneration; the surviving children showed a striking clinical response to uridine. The findings establish CAD deficiency as a treatable neurometabolic disorder.Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress in defining the molecular bases does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD encodes a multifunctional enzyme involved in de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine. Exome sequencing in three families identified biallelic CAD mutations in four children with global developmental delay, epileptic encephalopathy, and anaemia with anisopoikilocytosis. Two died aged 4 and 5 years after a neurodegenerative disease course. Supplementation of the two surviving children with oral uridine led to immediate cessation of seizures in both. A 4-year-old female, previously in a minimally conscious state, began to communicate and walk with assistance after 9 weeks of treatment. A 3-year-old female likewise showed developmental progress. Blood smears normalized and anaemia resolved. We establish CAD as a gene confidently implicated in this neurometabolic disorder, characterized by co-occurrence of global developmental delay, dyserythropoietic anaemia and seizures. While the natural disease course can be lethal in early childhood, our findings support the efficacy of uridine supplementation, rendering CAD deficiency a treatable neurometabolic disorder and therefore a potential condition for future (genetic) newborn screening.