Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening
Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening
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DOI：
10.1007/s10545-010-9090-x
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发表时间：
2010-10-01
影响因子：
4.2
通讯作者：
Spiekerkoetter, Ute
中科院分区：
文献类型：
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作者：
Spiekerkoetter, Ute
不同的长链脂肪酸氧化缺陷具有相似的、不同程度的异质性临床表型。主要受影响的器官包括心脏、肝脏和骨骼肌。如果有足够的能量供应，所有症状都是可逆的。在一些长链脂肪酸氧化缺陷中，会出现疾病特有的症状。只有在线粒体三功能蛋白(TFP)复合体的紊乱中，包括长链3-羟基酰基辅酶A(CoA)脱氢酶(LCHAD)缺乏症，神经病变和视网膜病变才会发展为进行性和不可逆转的，尽管现有的治疗措施。在大多数长链脂肪酸氧化缺陷中，由于分子的异质性，不存在明显的基因-表型相关性。然而，一些分离的突变被鉴定为仅与轻微的表型相关，例如超长链酰辅酶A脱氢酶(VLCAD)缺陷的V243A突变。LCHAD缺乏症是由于普遍存在的1528G和GT；C纯合子突变所致，并表现出不同的临床表型，提示其他环境和遗传因素的重要性。对于某些疾病，在成纤维细胞或淋巴细胞中检测到的残留酶活性与临床表型的严重程度有关。新生儿筛查的实施大大降低了长链脂肪酸氧化缺陷的发病率和死亡率。然而，最严重的TFP缺乏症仍然与新生儿死亡高度相关。新生儿筛查还确定了大量受轻微影响的患者，他们可能一辈子都不会出现临床症状。然而，较晚发病的运动性肌病症状仍然是长链脂肪酸氧化缺陷的典型临床特征。随着新生儿筛查，疾病患病率有所增加。
The different long-chain fatty acid oxidation defects present with similar heterogeneous clinical phenotypes of different severity. Organs mainly affected comprise the heart, liver, and skeletal muscles. All symptoms are reversible with sufficient energy supply. In some long-chain fatty acid oxidation defects, disease-specific symptoms occur. Only in disorders of the mitochondrial trifunctional protein (TFP) complex, including long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase (LCHAD) deficiency, neuropathy and retinopathy develop that are progressive and irreversible despite current treatment measures. In most long-chain fatty acid oxidation defects, no clear genotype-phenotype correlation exists due to molecular heterogeneity. However, some isolated mutations have been identified to be associated with only mild phenotypes, e.g., the V243A mutation in very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. LCHAD deficiency is due to the prevalent homozygous 1528G > C mutation and presents with heterogeneous clinical phenotypes, suggesting the importance of other environmental and genetic factors. For some disorders, it was shown that residual enzyme activity measured in fibroblasts or lymphocytes correlated with severity of clinical phenotype. Implementation of newborn screening has significantly reduced morbidity and mortality of long-chain fatty acid oxidation defects. However, the severest forms of TFP deficiency are still highly associated with neonatal death. Newborn screening also identifies a great number of mildly affected patients who may never develop clinical symptoms throughout life. However, later-onset exercise-induced myopathic symptoms remain characteristic clinical features of long-chain fatty acid oxidation defects. Disease prevalence has increased with newborn screening.