Ibdah J A, Bennett M J, Rinaldo P, Zhao Y, Gibson B, Sims H F, Strauss A W
Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
N Engl J Med. 1999 Jun 3;340(22):1723-31. doi: 10.1056/NEJM199906033402204.
Acute fatty liver of pregnancy and the HELLP syndrome (hemolysis, elevated liver-enzyme levels, and a low platelet count) are serious hepatic disorders that may occur during pregnancy in women whose fetuses are later found to have a deficiency of long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase. This enzyme resides in the mitochondrial trifunctional protein, which also contains the active site of long-chain 2,3-enoyl-CoA hydratase and long-chain 3-ketoacyl-CoA thiolase. We undertook this study to determine the relation between mutations in the trifunctional protein in infants with defects in fatty-acid oxidation and acute liver disease during pregnancy in their mothers.
In 24 children with 3-hydroxyacyl-CoA dehydrogenase deficiency, we used DNA amplification and nucleotide-sequence analyses to identify mutations in the alpha subunit of the trifunctional protein. We then correlated the results with the presence of liver disease during pregnancy in the mothers.
Nineteen children had a deficiency only of long-chain 3-hydroxyacyl-CoA dehydrogenase and presented with hypoketotic hypoglycemia and fatty liver. In eight children, we identified a homozygous mutation in which glutamic acid at residue 474 was changed to glutamine. Eleven other children were compound heterozygotes, with this mutation in one allele of the alpha-subunit gene and a different mutation in the other allele. While carrying fetuses with the Glu474Gln mutation, 79 percent of the heterozygous mothers had fatty liver of pregnancy or the HELLP syndrome. Five other children, who presented with neonatal dilated cardiomyopathy or progressive neuromyopathy, had complete deficiency of the trifunctional protein (loss of activity of all three enzymes). None had the Glu474Gln mutation, and none of their mothers had liver disease during pregnancy.
Women with acute liver disease during pregnancy may have a Glu474Gln mutation in long-chain hydroxyacyl-CoA dehydrogenase. Their infants are at risk for hypoketotic hypoglycemia and fatty liver.
妊娠急性脂肪肝和HELLP综合征（溶血、肝酶水平升高和血小板计数降低）是严重的肝脏疾病，可能发生在胎儿后来被发现缺乏长链3-羟酰基辅酶A（CoA）脱氢酶的孕妇中。这种酶存在于线粒体三功能蛋白中，该蛋白还包含长链2,3-烯酰-CoA水合酶和长链3-酮酰-CoA硫解酶的活性位点。我们进行这项研究以确定脂肪酸氧化缺陷婴儿的三功能蛋白突变与其母亲孕期急性肝病之间的关系。
在24名患有3-羟酰基辅酶A脱氢酶缺乏症的儿童中，我们使用DNA扩增和核苷酸序列分析来鉴定三功能蛋白α亚基中的突变。然后我们将结果与母亲孕期肝病的存在情况进行关联。
19名儿童仅缺乏长链3-羟酰基辅酶A脱氢酶，表现为低酮性低血糖和脂肪肝。在8名儿童中，我们鉴定出一种纯合突变，其中第474位残基的谷氨酸被改变为谷氨酰胺。另外11名儿童是复合杂合子，α亚基基因的一个等位基因中有此突变，另一个等位基因中有不同突变。在携带具有Glu474Gln突变胎儿的杂合子母亲中，79%患有妊娠急性脂肪肝或HELLP综合征。另外5名表现为新生儿扩张型心肌病或进行性神经病变的儿童，三功能蛋白完全缺乏（所有三种酶均丧失活性）。他们均无Glu474Gln突变，且他们的母亲在孕期均无肝病。
孕期患有急性肝病的女性可能在长链羟酰基辅酶A脱氢酶中存在Glu474Gln突变。她们的婴儿有发生低酮性低血糖和脂肪肝的风险。
