Clinical and molecular heterogeneity in very-long-chain acyl-coenzyme A dehydrogenase deficiency
Clinical and molecular heterogeneity in very-long-chain acyl-coenzyme A dehydrogenase deficiency
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DOI：
10.1016/s0887-8994(99)00132-0
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发表时间：
2000-02-01
影响因子：
3.8
通讯作者：
Taroni, F
中科院分区：
文献类型：
--
作者：
Pons, R;Cavadini, P;Taroni, F
超长链酰基辅酶A脱氢酶(VLCAD)缺乏症是一种日益公认的线粒体脂肪酸β氧化缺陷，表现为代谢性失代偿或单纯性复发性肌红蛋白尿。在这份报告中，我们讨论了5名患者(4名意大利人和1名西班牙人)的临床、生化和分子研究。生化研究包括成纤维细胞底物氧化率和酶活性的测定以及VLCAD蛋白的蛋白质印迹分析。从基因组DNA中测序VLCAD基因，进行分子分析。临床特征在已报道的谱系内，四名患者在婴儿期或儿童期出现严重的代谢紊乱和二羧酸尿症，两名患者表现为心肌病。第5例患者表现为孤立的复发性横纹肌溶解，没有心肌病或二羧酸尿症，所有患者的VLCAD活性显著下降与VLCAD蛋白水平显著降低相关，分子分析揭示了一个新的错义突变(Cys437Tyr)和四个先前报道的突变，包括两个错义替换(Phe418Leu和Arg419Trp)、一个氨基酸缺失(Lys258del)和一个剪接位点突变(IVS8-C(-2))，这在所有四名意大利患者中都存在。所有患者都表现出复合杂合性。报道了这种遗传性代谢紊乱的表型、变异性和高度的基因异质性。(C)2000，爱思唯尔科学公司。保留所有权利。
Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency is an increasingly recognized defect of mitochondrial fatty acid beta-oxidation manifesting with episodes of metabolic decompensation or isolated recurrent myoglobinuria. In this report the clinical, biochemical, and molecular studies in a series of five patients (four Italian and one Spanish) with this disorder are discussed. Biochemical studies included the determination of fibroblast substrate oxidation rates and enzyme activiy and Western blot analysis of VLCAD protein. Molecular analysis was performed by sequencing the VLCAD gene from the genomic DNA. Clinical features were within the spectrum preciously reported, Four patients presented in infancy or childhood with episodes of severe metabolic decompensation and dicarboxylic aciduria, Two exhibited cardiomyopathy. The fifth patient presented with isolated recurrent rhabdomyolysis, with no cardiomyopathy or dicarboxylic aciduria, In all patients a significant loss of VLCAD activity associated with a marked reduction of VLCAD protein levels occurred, Molecular analysis disclosed one novel missense mutation (Cys437Tyr) and four previously reported mutations, including two missense substitutions (Phe418Leu and Arg419Trp), a single amino acid deletion (Lys258del), and one splice site mutation (IVS8-C(-2)), which was present in all four Italian patients. All patients exhibited compound heterozygosity. The phenotypic, variability and the high genotypic heterogeneity of this hereditary metabolic disorder is reported. (C) 2000 by Elsevier Science Inc. All rights reserved.