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Brief Report |

Prospective Screening for Pediatric Mitochondrial Trifunctional Protein Defects in Pregnancies Complicated by Liver Disease FREE

Zi Yang, MD; Jennifer Yamada, MD; Yiwen Zhao, BS; Arnold W. Strauss, MD; Jamal A. Ibdah, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Internal Medicine, Division of Gastroenterology, Wake Forest University School of Medicine, Winston-Salem, NC (Drs Yang, Yamada, and Ibdah and Ms Zhao); and Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tenn (Dr Strauss). Dr Yamada is now at the Department of Anesthesiology, Loma Linda Medical Center, Loma Linda, Calif.


JAMA. 2002;288(17):2163-2166. doi:10.1001/jama.288.17.2163.
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Published online

Context Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome are serious complications of pregnancy. Studies in families with recessively inherited mitochondrial trifunctional protein defects documented an association between these maternal illnesses and fetal deficiency of long-chain 3-hydroxyacyl coenzyme A dehydrogenase; this enzyme resides in the α subunit of the trifunctional protein and catalyzes the third step in long-chain fatty acid β oxidation.

Objective To estimate the frequency of fetal long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency in pregnancies complicated by AFLP or HELLP syndrome.

Design, Setting, and Subjects Cohort study in which 108 consecutive blood samples from women who developed AFLP or HELLP syndrome, from their offspring, or from their partners were referred to our laboratory for molecular screening from January 1997 to December 2001. Twenty-seven women had AFLP and 81 had HELLP syndrome. We screened the DNA for mutations in the α subunit of the trifunctional protein.

Main Outcome Measure Presence of mutations that cause 3-hydroxyacyl coenzyme A dehydrogenase deficiency in the offspring.

Results We detected mutations causing pediatric long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency in 5 families (19%) with maternal history of AFLP (95% confidence interval, 9%-54%). The maternal allele carried a prevalent glutamic acid 474 to glutamine (E474Q) mutation. The paternal allele carried the E474Q mutation in 3 families and a stop codon mutation in the other 2 families. Only 1 woman with HELLP syndrome was heterozygous for the E474Q mutation; no mutations were detected in the newborn.

Conclusion The association between AFLP and the E474Q mutation in the fetus is significant. Screening newborns for this mutation in pregnancies complicated by AFLP could allow early diagnosis and treatment in newborns and genetic counseling and prenatal diagnosis in subsequent pregnancies in affected families.

Acute fatty liver of pregnancy (AFLP) is a devastating disorder of the third trimester that carries significant perinatal and maternal morbidity and mortality. Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome is also a maternal illness of the third trimester that is a complication of severe preeclampsia and has a better prognosis than AFLP. The prevalence of AFLP and HELLP syndrome is approximately 1 in 13 000 and 5 in 1000 pregnancies, respectively.1,2 Recent evidence has linked these maternal disorders, which have long been considered mysterious syndromes of unknown etiology, to an inherited fetal disorder of fatty acid oxidation.

Throughout the past decade, several case reports have noted fetal deficiency of long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) in the offspring of women who had developed AFLP, HELLP syndrome, or both during gestation.38 Long-chain 3-hydroxyacyl coenzyme A dehydrogenase is part of a mitochondrial trifunctional protein (MTP) complex that catalyzes the last 3 steps in long-chain fatty acid oxidation and is a hetero-octamer of 4-α and 4-β subunits.9,10 Long-chain 3-enoyl coenzyme A hydratase and LCHAD activity reside in the MTP α subunit. The β subunit has the long-chain 3-ketoacyl coenzyme A thiolase activity. The human complementary DNA and genes encoding both subunits have been isolated and characterized.6,1113

Human defects in the MTP complex are recessively inherited and cause either LCHAD deficiency with normal or partially reduced thiolase and hydratase activity or complete MTP deficiency with markedly reduced activity of all 3 enzymes.12,1417 Recently, we reported the α subunit molecular defects and phenotypes in 24 patients with documented LCHAD deficiency or complete MTP deficiency.17 Patients with the more common LCHAD deficiency present predominantly at a few months of age with hypoglycemia and liver dysfunction and carry a prevalent mutation that changes glutamate to glutamine at position 474 (E474Q) in the mature MTP α subunit, whereas patients with complete MTP deficiency present predominantly with cardiomyopathy or neuromyopathy and carry mutations other than the E474Q mutation.17 The estimated prevalence of LCHAD deficiency in the United States is 1 in 62 000 pregnancies.17

The initial case reports that linked the maternal liver syndromes to the fetal LCHAD deficiency used biochemical or enzymatic assays as the diagnostic criteria in the pediatric patients.35 Recently we correlated the pediatric genotype to pregnancy maternal history in 24 families with documented pediatric MTP defects.17 In 19 heterozygous mothers who carried fetuses with LCHAD deficiency, 15 (79%) developed AFLP or HELLP syndrome. All fetuses in these affected pregnancies were either homozygous for the E474Q mutation or compound heterozygous with one mutation as the E474Q and the other mutation producing a stop codon or altering a splice site. These studies suggest that fetal LCHAD deficiency is unique among fatty acid oxidation disorders in its common association with maternal liver disease. It is rather striking that only 1 case of maternal liver disease has been reported in association with fetal medium-chain acyl coenzyme A dehydrogenase deficiency, the most common fatty acid oxidation disorder.18 Two other single-case reports have linked maternal complications to other fatty acid oxidation disorders.19,20 There seems to be a mechanism peculiar to LCHAD deficiency that causes this fetal-maternal interaction and may involve generation by the placenta or fetus of 3-hydroxy fatty acid metabolites toxic to the maternal liver.17

Although the association between liver disease in pregnancy and fetal LCHAD deficiency is well documented, the proportion of women who carry LCHAD-deficient fetuses in all pregnancies complicated by maternal AFLP or HELLP syndrome is unknown, which is relevant to the critical issue of whether newborns in all pregnancies complicated by AFLP or HELLP syndrome should undergo screening for LCHAD deficiency. Identifying LCHAD-deficient offspring can be lifesaving because this inborn error of metabolism is potentially treatable through diet modification.

Subjects

From January 1997 to December 2001, 108 consecutive blood samples obtained from women who developed AFLP or HELLP syndrome, from their offspring, or from their partners were referred to our laboratory for molecular screening for MTP mutations. The sole criterion for conducting the molecular analysis was the maternal history of AFLP or HELLP syndrome. Records of the maternal obstetric histories were reviewed. Published criteria1,2,21 were used to classify patients as having HELLP syndrome or AFLP.

The obstetric history revealed a course compatible with AFLP in 27 women, and this diagnosis was proven by liver biopsy in 6 women. The remaining 81 women had clinical and biochemical abnormalities consistent with HELLP syndrome. Forty-eight cases were referred from North Carolina (7 AFLP and 41 HELLP syndrome); the remaining 60 cases (20 AFLP and 40 HELLP syndrome) were referred from 16 other states (California, Connecticut, Georgia, Illinois, Indiana, Kansas, Maine, Maryland, Missouri, New Jersey, New York, Ohio, Pennsylvania, Tennessee, Texas, and Virginia).

The institutional review board of Wake Forest University School of Medicine approved this study, and informed consent was obtained from the parents.

Mutation Analysis

We used single-strand conformation variance analysis to detect mutations in the MTP α subunit, as described previously.17,22 Nucleotide sequences of exons with abnormal single-strand conformation variance were determined with either the standard dideoxy chain termination method or an automated sequencer and the Taq Dye Deoxy Terminator Cycle Sequencing Kit (Perkin Elmer, Wellesley, Mass).

We also used restriction fragment length polymorphism analysis to detect the E474Q mutation in exon 15 of the MTP α subunit, as described previously.6 This method allows rapid diagnosis for homozygosity and heterozygosity for this mutation.

Clinical Findings

Table 1 summarizes the demographics and some clinical and laboratory characteristics of the women who developed AFLP or HELLP syndrome. All pregnancies resulted in live births, except 3 that were associated with stillbirths (2 complicated by maternal AFLP and 1 by HELLP syndrome). No DNA could be obtained from the 3 stillborn fetuses, but molecular analysis was conducted on both parents to evaluate for MTP mutations.

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of Patients With Maternal Liver Disease
Mutation Analysis

Pregnancies Complicated by AFLP. Mutations in the MTP α subunit that cause LCHAD deficiency were identified in 5 of the 27 families (19%; 95% confidence interval, 9%-54%) with a history of maternal AFLP. All these families were white and of European origin. The pediatric and maternal genotypes and phenotypes in these 5 families are shown in Table 2. In the first family, the mother developed AFLP at 37 weeks of gestation, with complete recovery following cesarean delivery. Blood was obtained for genetic testing 9 weeks after delivery because of the maternal history. As mutational analysis was under way, the infant became ill with a metabolic crisis associated with cardiogenic shock. Molecular analysis revealed compound heterozygosity of the infant for mutations in exons 4 and 15.17 The currently 5-year-old child is receiving dietary treatment (a low-fat, high-carbohydrate diet) and doing well. The mothers in families 2 and 3 developed AFLP at 32 and 35 weeks of gestation, respectively. Both recovered completely after prompt delivery. The LCHAD-deficient newborns were clinically asymptomatic at molecular diagnosis (2 and 3 months after birth, respectively). Single-strand conformation variance analysis and nucleotide sequencing revealed homozygosity of both infants for the E474Q mutation. Both infants have remained asymptomatic while receiving treatment with frequent feedings of a low-fat diet in which the fats were medium-chain triglycerides (current age of infants, 24 and 16 months [from families 2 and 3, respectively]). The mother in family 4 developed severe AFLP at 25 weeks of gestation but recovered completely 1 week after delivery. The newborn was homozygous for the E474Q mutation. He died because of severe prematurity. The maternal AFLP in family 5 was associated with intrauterine fetal demise at 36 weeks of gestation. The mother was heterozygous for the common exon 15 mutation; the father was heterozygous for an exon 12 donor-site splice mutation (T to C transversion at +2 position). Unfortunately, there was no tissue available from the presumably affected fetus to test for these mutations.

Table Graphic Jump LocationTable 2. Prospective Screening in Families With Maternal Acute Fatty Liver of Pregnancy*

Pregnancies Complicated by HELLP Syndrome. Heterozygosity for the E474Q mutation was detected in only 1 woman with HELLP syndrome. She had HELLP syndrome at 38 weeks, with full recovery after induced vaginal delivery. No MTP mutations were detected in the newborn, who is now aged 2 years.

Our results document that the association between AFLP and the recessively inherited fetal LCHAD deficiency is significant: 19% of AFLP cases were associated with fetal MTP mutations that cause LCHAD deficiency. In our study, none of the children born to mothers diagnosed as having HELLP syndrome carried MTP mutations.

Three previous reports assessing women with a history of AFLP or HELLP syndrome had contradictory results. In the first report, Treem and coworkers23 reported enzymatic activity levels consistent with LCHAD deficiency in the offspring of 7 of 12 women diagnosed as having AFLP or HELLP syndrome. In the second report,24 no E474Q mutation was detected in 14 women diagnosed as having AFLP. In the third report, 113 Dutch women with a history of HELLP syndrome were screened for the E474Q mutation, and only 1 was heterozygous for it.25 Molecular genetic studies were not universally done on the mothers and their offspring in these studies.

Our results justify screening newborns prospectively for the E474Q mutation at birth in all pregnancies complicated by AFLP. Initial screening for the E474Q mutation is crucial because all LCHAD-deficient fetuses were either homozygous for this mutation or compound heterozygous with the E474Q mutation on 1 allele. Homozygosity and heterozygosity for this mutation can be detected rapidly by restriction fragment length polymorphism or single-strand conformation variance.6,17 Treatment with a low-fat diet in which long-chain fatty acids are replaced by medium-chain fatty acids and avoidance of prolonged fasting should be implemented promptly if the E474Q mutation is detected. If the newborn is only heterozygous for the E474Q mutation, further analysis is necessary to search for another mutation on the other allele.

It is important for pediatricians, perinatologists, obstetricians, and gastroenterologists to be informed about the association between pediatric LCHAD deficiency and AFLP. Newborn screening for LCHAD deficiency and other fatty acid oxidation disorders is a public health issue that is being debated in the United States and has already been implemented in 9 states.26 To our knowledge, our results demonstrate for the first time that prospective screening of newborns for the E474Q mutation in pregnancies complicated by AFLP is useful and can be lifesaving because it allows early diagnosis and dietary treatment in affected infants before clinical manifestations. In addition, identification of heterozygous women with risk of recurrence of maternal complications enables genetic counseling and molecular prenatal diagnosis in subsequent pregnancies by using chorionic villous sampling.27

In contrast, our results do not justify screening newborns in pregnancies complicated by HELLP syndrome. However, screening might be considered in cases of recurrent HELLP syndrome and families with a history of sudden unexplained infant death.

Knox TA, Olans LB. Liver disease in pregnancy.  N Engl J Med.1996;335:569-576.
Riely CA. Liver disease in the pregnant patient.  Am J Gastroenterol.1999;94:1728-1732.
Schoeman MN, Batey RG, Wilcken B. Recurrent acute fatty liver of pregnancy associated with a fatty-acid oxidation defect in the offspring.  Gastroenterology.1991;100:544-548.
Wilcken B, Leung KC, Hammond J, Kamath R, Leonard JV. Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency.  Lancet.1993;341:407-408.
Treem WR, Rinaldo P, Hale DE.  et al.  Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.  Hepatology.1994;19:339-345.
Sims HF, Brackett JC, Powell CK.  et al.  The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy.  Proc Natl Acad Sci U S A.1995;92:841-845.
Isaacs Jr JD, Sims HF, Powell CK.  et al.  Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency: molecular characterization of a novel maternal mutant allele.  Pediatr Res.1996;40:393-398.
Tyni T, Ekholm E, Pihko H. Pregnancy complications are frequent in long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.  Am J Obstet Gynecol.1998;178:603-608.
Uchida Y, Izai K, Orii T, Hashimoto T. Novel fatty acid beta-oxidation enzymes in rat liver mitochondria, II: purification and properties of enoyl-coenzyme A (CoA) hydratase/3-hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase trifunctional protein.  J Biol Chem.1992;267:1034-1041.
Jackson S, Kler RS, Bartlett K.  et al.  Combined enzyme defect of mitochondrial fatty acid oxidation.  J Clin Invest.1992;90:1219-1225.
Kamijo T, Aoyama T, Komiyama A, Hashimoto T. Structural analysis of cDNAs for subunits of human mitochondrial fatty acid beta-oxidation trifunctional protein.  Biochem Biophys Res Comm.1994;199:818-825.
Ushikubo S, Aoyama T, Kamijo T.  et al.  Molecular characterization of mitochondrial trifunctional protein deficiency: formation of the enzyme complex is important for stabilization of both alpha- and beta-subunits.  Am J Hum Genet.1996;58:979-988.
Ijlst L, Ruiter JP, Hoovers JM, Jakobs ME, Wanders RJ. Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene.  J Clin Invest.1996;98:1028-1033.
Kamijo T, Wanders RJ, Saudubray JM, Aoyama T, Komiyama A, Hashimoto T. Mitochondrial trifunctional protein deficiency: catalytic heterogeneity of the mutant enzyme in two patients.  J Clin Invest.1994;93:1740-1747.
Brackett JC, Sims HF, Rinaldo P.  et al.  Two alpha subunit donor splice site mutations cause human trifunctional protein deficiency.  J Clin Invest.1995;95:2076-2082.
Ibdah JA, Tein I, Dionisi-Vici C.  et al.  Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation.  J Clin Invest.1998;102:1193-1199.
Ibdah JA, Bennett MJ, Rinaldo P.  et al.  A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women.  N Engl J Med.1999;340:1723-1731.
Nelson J, Lewis B, Walters B. The HELLP syndrome associated with fetal medium-chain acyl-CoA dehydrogenase deficiency.  J Inherit Metab Dis.2000;23:518-519.
Innes AM, Seargeant LE, Balachandra K.  et al.  Hepatic carnitine palmitoyltransferase I deficiency presenting as maternal illness in pregnancy.  Pediatr Res.2000;47:43-45.
Matern D, Hart P, Murtha AP.  et al.  Acute fatty liver of pregnancy associated with short-chain acyl-coenzyme A dehydrogenase deficiency.  J Pediatr.2001;138:585-588.
Sibai BM. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing?  Am J Obstet Gynecol.1990;162:311-316.
Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms.  Proc Natl Acad Sci U S A.1989;86:2766-2770.
Treem WR, Shoup ME, Hale DE.  et al.  Acute fatty liver of pregnancy, hemolysis, elevated liver enzymes, and low platelets syndrome, and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.  Am J Gastroenterol.1996;91:2293-2300.
Mansouri A, Fromenty B, Durand F, Degott C, Bernuau J, Pessayre D. Assessment of the prevalence of genetic metabolic defects in acute fatty liver of pregnancy.  J Hepatol.1996;25:781-784.
den Boer ME, Ijlst L, Wijburg FA.  et al.  Heterozygosity for the common LCHAD mutation (1528G>C) is not a major cause of HELLP syndrome and the prevalence of the mutation in the Dutch population is low.  Pediatr Res.2000;48:151-154.
Marshall E. Fast technology drives new world of newborn screening.  Science.2001;294:2272-2274.
Ibdah JA, Zhao Y, Viola J, Gibson B, Bennett MJ, Strauss AW. Molecular prenatal diagnosis in families with mitochondrial trifunctional protein mutations.  J Pediatr.2001;138:396-399.

Figures

Tables

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of Patients With Maternal Liver Disease
Table Graphic Jump LocationTable 2. Prospective Screening in Families With Maternal Acute Fatty Liver of Pregnancy*

References

Knox TA, Olans LB. Liver disease in pregnancy.  N Engl J Med.1996;335:569-576.
Riely CA. Liver disease in the pregnant patient.  Am J Gastroenterol.1999;94:1728-1732.
Schoeman MN, Batey RG, Wilcken B. Recurrent acute fatty liver of pregnancy associated with a fatty-acid oxidation defect in the offspring.  Gastroenterology.1991;100:544-548.
Wilcken B, Leung KC, Hammond J, Kamath R, Leonard JV. Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency.  Lancet.1993;341:407-408.
Treem WR, Rinaldo P, Hale DE.  et al.  Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.  Hepatology.1994;19:339-345.
Sims HF, Brackett JC, Powell CK.  et al.  The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy.  Proc Natl Acad Sci U S A.1995;92:841-845.
Isaacs Jr JD, Sims HF, Powell CK.  et al.  Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency: molecular characterization of a novel maternal mutant allele.  Pediatr Res.1996;40:393-398.
Tyni T, Ekholm E, Pihko H. Pregnancy complications are frequent in long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.  Am J Obstet Gynecol.1998;178:603-608.
Uchida Y, Izai K, Orii T, Hashimoto T. Novel fatty acid beta-oxidation enzymes in rat liver mitochondria, II: purification and properties of enoyl-coenzyme A (CoA) hydratase/3-hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase trifunctional protein.  J Biol Chem.1992;267:1034-1041.
Jackson S, Kler RS, Bartlett K.  et al.  Combined enzyme defect of mitochondrial fatty acid oxidation.  J Clin Invest.1992;90:1219-1225.
Kamijo T, Aoyama T, Komiyama A, Hashimoto T. Structural analysis of cDNAs for subunits of human mitochondrial fatty acid beta-oxidation trifunctional protein.  Biochem Biophys Res Comm.1994;199:818-825.
Ushikubo S, Aoyama T, Kamijo T.  et al.  Molecular characterization of mitochondrial trifunctional protein deficiency: formation of the enzyme complex is important for stabilization of both alpha- and beta-subunits.  Am J Hum Genet.1996;58:979-988.
Ijlst L, Ruiter JP, Hoovers JM, Jakobs ME, Wanders RJ. Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene.  J Clin Invest.1996;98:1028-1033.
Kamijo T, Wanders RJ, Saudubray JM, Aoyama T, Komiyama A, Hashimoto T. Mitochondrial trifunctional protein deficiency: catalytic heterogeneity of the mutant enzyme in two patients.  J Clin Invest.1994;93:1740-1747.
Brackett JC, Sims HF, Rinaldo P.  et al.  Two alpha subunit donor splice site mutations cause human trifunctional protein deficiency.  J Clin Invest.1995;95:2076-2082.
Ibdah JA, Tein I, Dionisi-Vici C.  et al.  Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation.  J Clin Invest.1998;102:1193-1199.
Ibdah JA, Bennett MJ, Rinaldo P.  et al.  A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women.  N Engl J Med.1999;340:1723-1731.
Nelson J, Lewis B, Walters B. The HELLP syndrome associated with fetal medium-chain acyl-CoA dehydrogenase deficiency.  J Inherit Metab Dis.2000;23:518-519.
Innes AM, Seargeant LE, Balachandra K.  et al.  Hepatic carnitine palmitoyltransferase I deficiency presenting as maternal illness in pregnancy.  Pediatr Res.2000;47:43-45.
Matern D, Hart P, Murtha AP.  et al.  Acute fatty liver of pregnancy associated with short-chain acyl-coenzyme A dehydrogenase deficiency.  J Pediatr.2001;138:585-588.
Sibai BM. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing?  Am J Obstet Gynecol.1990;162:311-316.
Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms.  Proc Natl Acad Sci U S A.1989;86:2766-2770.
Treem WR, Shoup ME, Hale DE.  et al.  Acute fatty liver of pregnancy, hemolysis, elevated liver enzymes, and low platelets syndrome, and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.  Am J Gastroenterol.1996;91:2293-2300.
Mansouri A, Fromenty B, Durand F, Degott C, Bernuau J, Pessayre D. Assessment of the prevalence of genetic metabolic defects in acute fatty liver of pregnancy.  J Hepatol.1996;25:781-784.
den Boer ME, Ijlst L, Wijburg FA.  et al.  Heterozygosity for the common LCHAD mutation (1528G>C) is not a major cause of HELLP syndrome and the prevalence of the mutation in the Dutch population is low.  Pediatr Res.2000;48:151-154.
Marshall E. Fast technology drives new world of newborn screening.  Science.2001;294:2272-2274.
Ibdah JA, Zhao Y, Viola J, Gibson B, Bennett MJ, Strauss AW. Molecular prenatal diagnosis in families with mitochondrial trifunctional protein mutations.  J Pediatr.2001;138:396-399.
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