Abstract
Mitochondrial trifunctional protein (TFP) catalyzes the final 3 steps of long chain fatty acid oxidation. Patients with TFP mutations have either isolated deficiency of long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) or complete TFP deficiency of all 3 enzymes. Recently, we characterized the genotypes and phenotypes in pediatric TFP defects and documented an association between fetal LCHAD deficiency and maternal liver disease (Ibdah et al, N. Engl. J. Med. 340:1723-31, 1999). To further characterize the association between TFP mutations, pregnancy outcome, and sudden infant death, we analyzed the pregnancy history and offspring genotypes and phenotypes in all affected and non-affected pregnancies in 31 families with mutations in TFP. 26 of these families had offspring with isolated LCHAD-deficiency and 5 with complete TFP deficiency. In 75 pregnancies, 72% of women who carried affected fetuses with isolated LCHAD deficiency developed acute fatty liver of pregnancy, HELLP syndrome or preeclampsia. 64% and 42% of pregnancies carrying fetuses with isolated LCHAD deficiency or complete TFP deficiency were also associated with premature delivery and birth weight that was small for gestational age, respectively. All pregnancies with heterozygous or wild-type fetal genotypes were uncomplicated. 39% (12/31) of the affected children died. Ten with isolated LCHAD deficiency and 2 with complete TFP deficiency. Four of these children had sudden, unexplained death at few months of age and certified initially as SIDS. Autopsy revealed micro- and macro- vesicular hepatic steatosis. Screening for TFP mutations revealed homozygosity for the prevalent (G1528C, E474Q) mutation in all four children. In five families, there was a history of sudden, unexplained death in a sibling of unknown genotype. These results document that: 1) fetal genotype affects both maternal and fetal outcomes in families with TFP mutations; 2) affected children, if unrecognized and untreated, may suffer sudden death. [Supported by a grant from NIH (DK-02574) and a grant from March of Dimes (#6-FY99-376)]
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Ibdah, J., Zhao, Y., Viola, J. et al. Maternal complications and sudden infant death in families with mutations in mitochondrial trifunctional protein. Genet Med 2, 62 (2000). https://doi.org/10.1097/00125817-200001000-00049
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DOI: https://doi.org/10.1097/00125817-200001000-00049