Ictericia

F ETA L FAT T Y- ACID OXIDAT ION DISOR D ER AS A C AUS E OF LIV ER D IS EASE IN PR EGNA NT WOMEN

A FETAL FATTY-ACID OXIDATION DISORDER AS A CAUSE OF LIVER DISEASE IN PREGNANT WOMEN
JAMAL A. IBDAH, M.D., PH.D., MICHAEL J. BENNETT, PH.D., PIERO RINALDO, M.D., PH.D., YIWEN ZHAO, B.S., BEVERLY GIBSON, B.S., HAROLD F. SIMS, B.A., AND ARNOLD W. STRAUSS, M.D.

ABSTRACT
Background Acute fattyliver 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 oflong-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 analysesto identify mutations in the a 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 glutamicacid at residue 474 was changed to glutamine. Eleven other children were compound heterozygotes, with this mutation in one allele of the a-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 dilatedcardiomyopathy 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 forhypoketotic hypoglycemia and fatty liver. (N Engl J Med 1999;340:1723-31.)
©1999, Massachusetts Medical Society.

CUTE fatty liver of pregnancy is a devastating disorder associated with substantial maternal and neonatal morbidity and mortality.1-4 The HELLP syndrome (hemolysis, elevated liver-enzyme levels, and a low platelet count) is a more common maternal illness of late pregnancy and isassociated with a better prognosis.2,5 The clinical and biochemical features of these two disorders overlap, suggesting that their underlying pathophysiologic mechanisms may be similar. Long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase catalyzes the third step in the b-oxidation of fatty acids in mitochondria (Fig. 1). The active site of this enzyme is located in the C-terminal domain of each of thefour a subunits of the trifunctional protein that is associated with the inner mitochondrial membrane.6,7 The N-terminal domain of each of the a subunits is the site of long-chain 2,3-enoyl-CoA hydratase activity. The active site of long-chain 3-ketoacyl-CoA thiolase is in the four b subunits of the protein; this enzyme catalyzes the last step in the b-oxidation of fatty acids. The formation of astable trifunctional-protein complex and the expression of all three enzymes require the presence of intact a and b subunits. The genes that encode the a and b subunits are closely linked on chromosome 2.8-10 Patients with either an isolated deficiency of longchain 3-hydroxyacyl-CoA dehydrogenase or complete deficiency of the trifunctional protein (a loss of activity of all three enzymes) have...