Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death
Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death
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DOI：
10.1161/01.cir.99.10.1337
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发表时间：
1999-03-16
期刊：
影响因子：
37.8
通讯作者：
Strauss, AW
中科院分区：
文献类型：
--
作者：
Mathur, A;Sims, HF;Strauss, AW
背景：遗传缺陷在原发性心肌病（CM）的病因学中得到越来越多的认识。超长链酰基辅酶a脱氢酶（VLCAD）催化脂肪酸代谢p -氧化螺旋的第一步，这是心脏能量产生的关键途径。方法和结果：我们研究了37例CM、非酮症性低血糖和肝功能障碍、骨骼肌病或婴儿猝死合并肝脂肪变性的患者，这些患者的特征提示脂肪酸氧化障碍。单链构象变异用于筛选基因组DNA。DNA测序和突变分析显示，18例患者中有21种不同的VLCAD基因突变。这些突变中，80%与CM相关。大多数患者（67%）在就诊时就认识到婴儿期严重CM。肝功能障碍很常见（33%）。RNA印迹分析和VLCAD酶分析显示，帧移位或剪接位点突变患者的VLCAD mRNA严重减少，所有患者的酶活性均不存在或严重降低。结论：婴儿CM是VLCAD缺乏症最常见的临床表型。人类VLCAD基因的突变是异质的。虽然死亡率很高，但代谢紊乱和心肌病都是可逆的。
Background-Genetic defects are being increasingly recognized in the etiology of primary cardiomyopathy (CM). Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the first step in the P-oxidation spiral of fatty acid metabolism, the crucial pathway for cardiac energy production.Methods and Results-We studied 37 patients with CM, nonketotic hypoglycemia and hepatic dysfunction, skeletal myopathy, or sudden death in infancy with hepatic steatosis, features suggestive of fatty acid oxidation disorders. Single-stranded conformational variance was used to screen genomic DNA. DNA sequencing and mutational analysis revealed 21 different mutations on the VLCAD gene in 18 patients. Of the mutations, 80% were associated with CM. Severe CM in infancy was recognized in most patients (67%) at presentation. Hepatic dysfunction was common (33%). RNA blot analysis and VLCAD enzyme assays showed a severe reduction in VLCAD mRNA in patients with frame-shift or Splice-site mutations and absent or severe reduction in enzyme activity in all.Conclusions-Infantile CM is the most common clinical phenotype of VLCAD deficiency. Mutations in the human VLCAD gene are heterogeneous. Although mortality at presentation is high, both the metabolic disorder and cardiomyopathy are reversible.