Yiwen Zhao

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 hepatic disorders that may occur during pregnancy in...

Lack of mitochondrial trifunctional protein in mice causes neonatal hypoglycemia and sudden death

Mitochondrial trifunctional protein (MTP) is a hetero-octamer of four alpha and four beta subunits that catalyzes the final three steps of mitochondrial long chain fatty acid beta-oxidation. Human MTP deficiency causes Reye-like syndrome, cardiomyopathy, or sudden unexpected death. We used gene targeting to generate an MTP alpha subunit null allele and to produce mice that lack MTP alpha and beta subunits. The Mtpa(-/-) fetuses accumulate long chain fatty acid metabolites and have low birth weight compared with the Mtpa(+/-) and Mtpa(+/+) littermates. Mtpa(-/-) mice suffer neonatal hypoglycemia and sudden death 6-36 hours after birth. Analysis of the histopathological changes in the Mtpa(-/-) pups revealed rapid development of hepatic steatosis after birth and, later, significant necrosis and acute degeneration of the cardiac and diaphragmatic myocytes. This mouse model documents that intact mitochondrial long chain fatty acid oxidation is essential for fetal development and for survival after birth. Deficiency of MTP causes fetal growth retardation, neonatal hypoglycemia, and sudden death.

Inherited long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and a fetal-maternal interaction cause maternal liver disease and other pregnancy complications

Fetal-maternal interactions are critical determinants of maternal health during pregnancy and perinatal outcome. This review explores the causative relationship of a fetal disorder of mitochondrial fatty acid oxidation, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, and the serious maternal liver diseases of pregnancy-preeclampsia, the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet counts), and acute fatty liver of pregnancy. Features of the metabolic adaptation necessitated during the fetal-neonatal transition; common phenotypes of pediatric fatty acid oxidation disorders, including neonatal hypoketotic, hypoglycemia and hepatic crisis; and clinical abnormalities of HELLP and acute fatty liver of pregnancy are presented. Evidence that a common mutation in the alpha-subunit (LCHAD) of trifunctional protein, E474Q, is always one of the mutant alleles in fetal isolated LCHAD deficiency associated with these disorders of pregnancy that cause high maternal, fetal, and newborn morbidity and mortality is reviewed. Recommendations for molecular testing for LCHAD deficiency in families with life-threatening maternal liver disease are given.

Prospective screening for pediatric mitochondrial trifunctional protein defects in pregnancies complicated by liver disease

About 1 in 13,000 pregnancies is complicated by acute fatty liver of pregnancy (AFLP), a serious disorder that carries significant risk of maternal or perinatal death. Five in 1000 pregnancies are complicated by the HELLPsyndrome (hemolysis, elevated liver enzymes, low platelets), which is a complication of severe preeclampsia. Recent reports have associated a fetal deficiency of long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) with AFLP, HELLP syndrome, and both. This enzyme is part of a mitochondrial trifunctional protein (MTP) complex catalyzing the final steps in oxidation of long-chain fatty acids, and it resides in the MTP-a subunit. Defects in the MTP complex are recessively inherited. This cohort study included consecutive blood samples from 27 women having AFLP and 81 who developed HELLP syndrome as well as their partners and offspring. Screening of DNA for mutations in the α-subunit of MTP demonstrated mutations causing a fetal deficiency of LCHAD in five families with a maternal history of AFLP (19%). The maternal allele carried a prevalent glutamic acid 474-to-glutamine (E474Q) mutation. The paternal allele carried the same mutation in three of the families and a stop codon mutation in the other two. A single woman with HELLP syndrome was heterozygous for the E474Q mutation, and no mutation was discovered in the DNA of her newborn infant. The investigators believe that the association of AFLP with the fetal E474Q mutation is a significant one. Prospectively screening newborn infants for this mutation in pregnancies accompanied by AFLP would permit early diagnosis and treatment as well as genetic counseling and prenatal diagnosis in any subsequent pregnancies. Such screening seems unwarranted in pregnancies complicated by HELLP syndrome except possibly for recurrent cases or in families with a history of sudden, unexplained infant death.

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 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 alpha 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 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. 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.