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Previous Volume 340:1723-1731 June 3, 1999 Number 22 Next

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ABSTRACT

Background 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.

Methods In 24 children with 3-hydroxyacyl-CoA dehydrogenase deficiency, we used DNA amplification and nucleotide-sequence analyses to identify mutations in the subunit of the trifunctional protein. We then correlated the results with the presence of liver disease during pregnancy in the mothers.

Results 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 -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.

Conclusions 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.

Source Information

From the Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, N.C. (J.A.I., Y.Z.); the Departments of Pathology and Pediatrics, University of Texas Southwestern Medical Center, Dallas (M.J.B.); the Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn. (P.R.); and the Departments of Pediatrics (B.G., H.F.S., A.W.S.) and Molecular Biology and Pharmacology (A.W.S.), Washington University School of Medicine, St. Louis.

Address reprint requests to Dr. Strauss at St. Louis Children's Hospital, 1 Children's Pl., St. Louis, MO 63110, or at strauss{at}kids.wustl.edu.

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