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.