Acute fatty liver of pregnancy (AFLP) and the syndrome of hemolysis, elevated liver enzymes, and low platelets (the HELLP syndrome) are serious disorders of the third trimester with high maternal and perinatal morbidity and mortality. Over the past decade, several clinical observations have demonstrated an association between these maternal syndromes and a recessively inherited fatty acid oxidation disorder, long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. Many women who carried LCHAD-deficient fetuses developed maternal liver disease. Over the past few years, we and others have made significant progress in understanding the molecular basis for this fetal-maternal interaction. Here, we review the studies in literature that led to the establishment of this causative association with particular emphasis on the molecular analysis that delineated the molecular basis of this association. The likely mechanisms for the genotype-phenotype correlations in pediatric LCHAD deficiency and the fetal-maternal interaction are discussed. Finally, the potential implications of our current knowledge for families with pediatric LCHAD deficiency and for women who develop AFLP and HELLP syndrome are discussed.

3-Hydroxyacyl CoA Dehydrogenases↗

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Synergistic heterozygosity: disease resulting from multiple partial defects in one or more metabolic pathways.

Inborn errors of metabolism show considerable variation in the severity of symptoms. This is often ascribed to the differential effects of specific mutations on gene/enzyme function; however, such genotype/phenotype correlations are usually imprecise. In addition, in some patients with clinical and biochemical findings consistent with a defect in a particular metabolic pathway, it is ultimately impossible to arrive at a precise enzymatic diagnosis. In this situation, we have increasingly been identifying concurrent partial defects in more than one pathway, or at multiple steps in one pathway. In this study, we present the clinical, biochemical, and molecular findings from several patients showing multiple partial defects in energy metabolism. These patients show clinical symptoms consistent with a defect in the affected pathways even though they do not have a complete deficiency in any one enzyme. We hypothesize that such patients are exhibiting clinically significant reductions in energy metabolism related to the compound effects of these partial defects, a phenomenon we term "synergistic heterozygosity." Based on the frequencies of known disorders of energy metabolism, we propose that this may represent a previously unrecognized, relatively common mechanism of disease of potentially great clinical relevance.

AMP Deaminase↗

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Fatal hepatic short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency: clinical, biochemical, and pathological studies on three subjects with this recently identified disorder of mitochondrial beta-oxidation.

This report describes the clinical, biochemical, and pathological findings in three infants with hepatic short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD) deficiency, a recently recognized disorder of the mitochondrial oxidation of straight-chain fatty acids. Candidate subjects were identified from an ongoing study of infant deaths. SCHAD analysis was performed on previously frozen liver and skeletal muscle on subjects with a characteristic urine organic acid profile. Autopsy findings were correlated with the biochemical abnormalities. Enzyme analysis in liver revealed marked deficiency in SCHAD with residual activities of 3-11%. All subjects had normal activity in skeletal muscle. However, Western blot analysis of SCHAD revealed an identical truncated protein in both liver and muscle from one patient, suggesting that SCHAD is similar in liver and muscle and that the normal activity in muscle may be due to other enzymes with C4 activity. Autopsy findings revealed marked steatosis and a muscle pattern consistent with spinal muscular atrophy in one patient. Lipid storage was less pronounced in one patient and not detected in the third patient who had a well-documented history of recurrent hypoglycemia. This is the initial pathological characterization of this enzyme defect, and our observations suggest that SCHAD deficiency is a very severe disorder contributing to early infant death.

3-Hydroxyacyl CoA Dehydrogenases↗

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Screening siblings for inborn errors of fatty acid metabolism in families with a history of sudden infant death.

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Fatty Acids↗

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WIDETIME: an HIV Odyssey and hopes and fears: Rusti's story.

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Adaptation, Psychological↗

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Ipsilateral and contralateral acoustic reflexes in neonates.

Ipsilateral and contralateral acoustic reflexes were studied in neonates using 220 and 660 Hz probe tones and 500, 1000, 2000, and 4000 Hz activators. Activator sound pressure level was measured in all ears. Ipsilateral and contralateral reflexes were detected three times more frequently with a 660 Hz probe tone than with a 220 Hz probe tone. The maximum detection rate (76%) occurred with 1000 and 2000 Hz ipsilateral activators and the 660 probe tone. There was no significant difference between neonatal and adult ipsilateral thresholds at 500, 1000, and 4000 Hz. Neonatal intrameatal sound pressure levels for ipsilateral activators were found to be significantly higher than would be indicated from the otoadmittance meter manufacturer's specifications.

Acoustic Impedance Tests↗

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Plasma homocysteine levels and folate status in children with sickle cell anemia.

PURPOSE: A sensitive inverse relationship between plasma homocysteine concentration and folate status has been demonstrated. Although children with sickle cell anemia (SCA) are at potential risk for folate deficiency, plasma homocysteine levels have not been reported in such patients. Therefore, a study was designed to assess plasma homocysteine levels as a marker of folate status. DESIGN: Plasma homocysteine concentrations were measured in 120 children with SCA (102 in steady state and 18 during an acute complication) who had never received supplemental folic acid. Folate status was directly assessed in 34 of these patients. RESULTS: Plasma homocysteine levels in the patients with SCA and control subjects were similar. The mean value +/- 1 SD was 5.8+/-2.5 micromol/L (range, 1.6 to 14.1 micromol/L) in the patients with SCA and 6.1+/-2.7 micromol/L (range, 1.7 to 15.3 micromol/L) in 73 pediatric control subjects. In a subpopulation of the study group (34 children), simultaneous serum folate, red cell folate, and total homocysteine concentrations were also measured. Their serum folate and red cell folate concentrations were normal: 12.4+/-10.0 nmol/L (range, 1 to 42 nmol/L) and 604+/-374.7 nmol/L (range, 205 to 1741 nmol/L), respectively. There was no correlation of plasma homocysteine concentration with various clinical or laboratory measures or with red cell folate concentration. CONCLUSION: Folate stores in children with SCA not receiving folic acid supplements are adequate despite an underlying hemolytic anemia.

Adolescent↗