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Maternal heterozygosity for a mitochondrial trifunctional protein mutation as a cause for liver disease in pregnancy.
Med Hypotheses. 2005; 64(1):96-100.MH

Abstract

Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome are serious complications of pregnancy associated with significant maternal and perinatal morbidity and mortality. In previous reports, we have documented an association between AFLP and fetal deficiency of long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) [N. Engl. J. Med. 340 (1999) 1723-1731; JAMA 288 (2002) 2163-2166]. LCHAD activity resides in the alpha-subunit of the mitochondrial trifunctional protein (MTP), a complex protein that catalyzes beta-oxidation of long chain fatty acids. In all reported cases, the fetus carried a common alpha-subunit MTP mutation (G1528C, E474Q) on one or both alleles. However, the association between fetal LCHAD deficiency and the maternal HELLP syndrome has been limited. Here, we report a case history of a 27-year-old black female who underwent Cesarean section for placenta previa and fetal distress at 36 weeks gestation. The newborn was a healthy male child. Post-delivery, the mother developed severe HELLP syndrome with complications resulting in death of the patient. We used single strand conformation variance and nucleotide sequence analyses to screen DNA isolated from the mother and the newborn for mutations in the MTP alpha-subunit. The mother was heterozygous for a novel mutation (C1072A, Q322K) in exon 11 of the LCHAD domain of the MTP, while the fetal genotype was completely normal. We hypothesize that, in some cases, maternal heterozygosity for an MTP mutation maybe sufficient to cause the development of maternal liver disease without carrying an affected fetus. Combination of the metabolic stress of pregnancy and other environmental stresses may overwhelm the heterozygous mother's capacity for effective metabolism of long chain fatty acids, leading to an accumulation of potentially toxic fatty acid metabolites in the maternal circulation with subsequent damage to the maternal liver.

Authors+Show Affiliations

Division of Gastroenterology, Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15533621

Citation

Blish, Kimberly R., and Jamal A. Ibdah. "Maternal Heterozygosity for a Mitochondrial Trifunctional Protein Mutation as a Cause for Liver Disease in Pregnancy." Medical Hypotheses, vol. 64, no. 1, 2005, pp. 96-100.
Blish KR, Ibdah JA. Maternal heterozygosity for a mitochondrial trifunctional protein mutation as a cause for liver disease in pregnancy. Med Hypotheses. 2005;64(1):96-100.
Blish, K. R., & Ibdah, J. A. (2005). Maternal heterozygosity for a mitochondrial trifunctional protein mutation as a cause for liver disease in pregnancy. Medical Hypotheses, 64(1), 96-100.
Blish KR, Ibdah JA. Maternal Heterozygosity for a Mitochondrial Trifunctional Protein Mutation as a Cause for Liver Disease in Pregnancy. Med Hypotheses. 2005;64(1):96-100. PubMed PMID: 15533621.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Maternal heterozygosity for a mitochondrial trifunctional protein mutation as a cause for liver disease in pregnancy. AU - Blish,Kimberly R, AU - Ibdah,Jamal A, PY - 2004/06/02/received PY - 2004/06/04/accepted PY - 2004/11/10/pubmed PY - 2005/4/22/medline PY - 2004/11/10/entrez SP - 96 EP - 100 JF - Medical hypotheses JO - Med Hypotheses VL - 64 IS - 1 N2 - Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome are serious complications of pregnancy associated with significant maternal and perinatal morbidity and mortality. In previous reports, we have documented an association between AFLP and fetal deficiency of long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) [N. Engl. J. Med. 340 (1999) 1723-1731; JAMA 288 (2002) 2163-2166]. LCHAD activity resides in the alpha-subunit of the mitochondrial trifunctional protein (MTP), a complex protein that catalyzes beta-oxidation of long chain fatty acids. In all reported cases, the fetus carried a common alpha-subunit MTP mutation (G1528C, E474Q) on one or both alleles. However, the association between fetal LCHAD deficiency and the maternal HELLP syndrome has been limited. Here, we report a case history of a 27-year-old black female who underwent Cesarean section for placenta previa and fetal distress at 36 weeks gestation. The newborn was a healthy male child. Post-delivery, the mother developed severe HELLP syndrome with complications resulting in death of the patient. We used single strand conformation variance and nucleotide sequence analyses to screen DNA isolated from the mother and the newborn for mutations in the MTP alpha-subunit. The mother was heterozygous for a novel mutation (C1072A, Q322K) in exon 11 of the LCHAD domain of the MTP, while the fetal genotype was completely normal. We hypothesize that, in some cases, maternal heterozygosity for an MTP mutation maybe sufficient to cause the development of maternal liver disease without carrying an affected fetus. Combination of the metabolic stress of pregnancy and other environmental stresses may overwhelm the heterozygous mother's capacity for effective metabolism of long chain fatty acids, leading to an accumulation of potentially toxic fatty acid metabolites in the maternal circulation with subsequent damage to the maternal liver. SN - 0306-9877 UR - https://www.unboundmedicine.com/medline/citation/15533621/Maternal_heterozygosity_for_a_mitochondrial_trifunctional_protein_mutation_as_a_cause_for_liver_disease_in_pregnancy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-9877(04)00374-3 DB - PRIME DP - Unbound Medicine ER -