Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency
Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency
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DOI：
10.1086/302261
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发表时间：
1999-02-01
影响因子：
9.8
通讯作者：
Gregersen, N
中科院分区：
文献类型：
--
作者：
Andresen, BS;Olpin, S;Gregersen, N
极长链酰基辅酶A脱氢酶（VLCAD）催化线粒体脂肪酸P-氧化的初始限速步骤。VLCAD缺乏症在临床上是异质性的，具有三种主要表型：严重的儿童形式，具有早发性、高死亡率和心肌病的高发病率;较轻的儿童形式，具有晚发性，通常以低酮性低血糖为主要表现特征，低死亡率和罕见心肌病;和成人型，伴有孤立的骨骼肌受累、横纹肌溶解和肌红蛋白尿，通常由运动或禁食引起。为了检查这些不同的表型是否是由于VLCAD基因型的差异，我们研究了代表所有已知临床表型的55名无关患者的58种不同突变，并将突变类型与临床表型相关联。我们的研究结果表明，突变的性质和疾病的严重程度之间存在明确的关系。具有严重儿童表型的患者具有导致无残留酶活性的突变，而具有较轻儿童和成人表型的患者具有可能导致残留酶活性的突变。这种明确的基因型-表型关系与中链酰基辅酶A脱氢酶缺乏症形成鲜明对比，在中链酰基辅酶A脱氢酶缺乏症中，基因型和表型之间没有相关性。
Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial rate-limiting step in mitochondrial fatty acid P-oxidation. VLCAD deficiency is clinically heterogenous, with three major phenotypes: a severe childhood form, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypoglycemia as the main presenting feature, low mortality and rare cardiomyopathy; and an adult form, with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria, usually triggered by exercise or fasting. To examine whether these different phenotypes are due to differences in the VLCAD genotype, we investigated 58 different mutations in 55 unrelated patients representing all known clinical phenotypes and correlated the mutation type with the clinical phenotype. Our results show a clear relationship between the nature of the mutation and the severity of disease. Patients with the severe childhood phenotype have mutations that result in no residual enzyme activity, whereas patients with the milder childhood and adult phenotypes have mutations that may result in residual enzyme activity. This clear genotype-phenotype relationship is in sharp contrast to what has been observed in medium-chain acyl-CoA dehydrogenase deficiency, in which no correlation between genotype and phenotype can be established.