ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency
ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency
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DOI：
10.1093/brain/awm135
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发表时间：
2007-08-01
期刊：
影响因子：
14.5
通讯作者：
Morris, Andrew A. M.
中科院分区：
文献类型：
--
作者：
Olsen, Rikke K. J.;Olpin, Simon E.;Morris, Andrew A. M.
多种酰基辅酶A脱氢酶缺乏症（MADD）是一种脂肪酸、氨基酸和胆碱代谢紊乱疾病，可由两种黄素蛋白，即电子传递黄素蛋白（ETF）或ETF - 泛醌氧化还原酶（ETF:QO）的缺陷引起。一些患者对药理剂量的核黄素治疗有反应。尚不清楚这些患者是黄素蛋白本身有缺陷，还是由核黄素形成辅因子FAD的过程有缺陷。我们报告了来自11个家系的15名患者。所有索引病例都表现出脑病或肌无力，或这些症状的组合；有几名患者此前曾有周期性呕吐症状。尿液有机酸和血浆酰基肉碱谱表明为MADD。经过核黄素治疗后，临床和生化指标全部或部分得到纠正。所有患者的ETF:QO基因都有突变。在一名患者中，我们发现ETF:QO突变与ETF:QO活性对核黄素敏感的损伤有关。该患者还存在黄素依赖的酰基辅酶A脱氢酶和呼吸链复合物的部分缺乏，其中大部分在核黄素治疗后恢复到对照水平。此前在我们的两名有ETF:QO突变的患者中，已报道过线粒体黄素蛋白或呼吸链复合物活性较低。我们推测，对核黄素有反应的MADD可能是由ETF:QO缺陷以及一般性线粒体功能障碍共同导致的。这是有史以来报道的对核黄素有反应的MADD患者数量最多的一次，也是首次对该疾病的分子遗传基础进行的论证。
Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETIF: ubiquinone oxidoreductase (ETF:QO). Some patients respond to pharmacological doses of riboflavin. It is unknown whether these patients have defects in the flavoproteins themselves or defects in the formation of the cofactor, FAD, from riboflavin.We report IS patients from I I pedigrees. All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms; several had previously suffered cyclical vomiting. Urine organic acid and plasma acyl-carnitine profiles indicated MADD. Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. All patients had mutations in the gene for ETF:QO. In one patient, we show that the ETF:QO mutations are associated with a riboflavin-sensitive impairment of ETF:QO activity. This patient also had partial deficiencies of flavin-dependent acyl-CoA dehydrogenases and respiratory chain complexes, most of which were restored to control levels after riboflavin treatment. Low activities of mitochondrial flavoproteins or respiratory chain complexes have been reported previously in two of our patients with ETF:QO mutations. We postulate that riboflavin-responsive MADD may result from defects of ETF:QO combined with general mitochondrial dysfunction. This is the largest collection of riboflavin-responsive MADD patients ever reported, and the first demonstration of the molecular genetic basis for the disorder.