A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women

Background Acute fatty liver of pregnancy and the HELLP syndrome (hemolysis , elevated liver-enzyme levels, and a low platelet count) are serious hepat ic disorders that may occur during pregnancy in women whose fetuses are lat er found to have a deficiency of long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase. This enzyme resides in the mitochondrial trifunctional prote in, which also contains the active site of long-chain 2,3-enoyl-CoA hydrata se and long-chain 3-ketoacyl-CoA thiolase. We undertook this study to deter mine the relation between mutations in the trifunctional protein in infants with defects in fatty-acid oxidation and acute liver disease during pregna ncy in their mothers. Methods In 24 children with 3-hydroxyacyl-CoA dehydrogenase deficiency, we used DNA amplification and nucleotide-sequence analyses to identify mutatio ns in the alpha subunit of the trifunctional protein. We then correlated th e results with the presence of liver disease during pregnancy in the mother s. Results Nineteen children had a deficiency only of long-chain 3-hydroxyacyl -CoA dehydrogenase and presented with hypoketotic hypoglycemia and fatty li ver. In eight children, we identified a homozygous mutation in which glutam ic acid at residue 474 was changed to glutamine. Eleven other children were compound heterozygotes, with this mutation in one allele of the alpha-subu nit gene and a different mutation in the other allele. While carrying fetus es with the Glu474Gln mutation, 79 percent of the heterozygous mothers had fatty liver of pregnancy or the HELLP syndrome. Five other children, who pr esented with neonatal dilated cardiomyopathy or progressive neuromyopathy, had complete deficiency of the trifunctional protein (loss of activity of a ll three enzymes). None had the Glu474Gln mutation, and none of their mothe rs had liver disease during pregnancy. Conclusions Women with acute liver disease during pregnancy may have a Glu4 74Gln mutation in long-chain hydroxyacyl-CoA dehydrogenase. Their infants a re at risk for hypoketotic hypoglycemia and fatty liver. (N Engl J Med 1999 ;340:1723-31.) (C) 1999, Massachusetts Medical Society.