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Long-chain acyl-coenzyme A dehydrogenase deficiency: biochemical studies in fibroblasts from three patients
1Department of Pediatrics, University of Iowa, Iowa City 52242.
Insights
Long-chain acyl-coenzyme A dehydrogenase (LCADH) deficiency impacts fatty acid oxidation. Despite reduced LCADH activity in fibroblasts, the severity of clinical symptoms varied among patients, suggesting other factors influence disease presentation.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Long-chain acyl-coenzyme A dehydrogenase (LCADH) is crucial for mitochondrial fatty acid oxidation.
- LCADH deficiency is a rare inherited metabolic disorder affecting energy production.
- Fibroblast studies are valuable for investigating inborn errors of metabolism.
Purpose of the Study:
- To investigate the biochemical basis of LCADH deficiency in fibroblasts from three patients.
- To correlate enzyme activity with clinical phenotypes in patients with LCADH deficiency.
- To explore potential regulatory mechanisms or contributing factors to disease heterogeneity.
Main Methods:
- Cultured fibroblasts from patients and controls were used.
- Fatty acid oxidation was measured using radiolabeled palmitate.
- Mitochondrial LCADH activity was assayed under various conditions, including cofactor addition and antibody inhibition.
- Activities of short-chain and medium-chain acyl-coenzyme A dehydrogenases were assessed.
Main Results:
- Patients exhibited reduced [3H]palmitate oxidation (28-50% of control) compared to controls.
- Mitochondrial LCADH activity was significantly decreased in all patients (17-21% of control).
- Flavin adenine dinucleotide (FAD) supplementation partially restored LCADH activity.
- Enzyme activity assays did not fully explain the observed heterogeneity in fatty acid oxidation rates.
Conclusions:
- LCADH deficiency directly impairs fatty acid oxidation in patient fibroblasts.
- The degree of residual enzyme activity does not fully correlate with clinical phenotype severity.
- Further research is needed to understand the factors contributing to the variable clinical presentation of LCADH deficiency.
Abstract:
We studied fibroblasts from three patients with long-chain acyl-coenzyme A dehydrogenase (LCADH) deficiency; siblings H.C. and J.C. had milder clinical phenotypes than unrelated patient R-1. In H.C., J.C., and R-1 oxidation of [9,10(n)-3H]palmitate was 50, 48, and 28% of control, respectively, with R-1 having significantly less activity than H.C. and J.C. (p less than 0.05). Assays of mitochondrial short-chain and medium-chain acyl-coenzyme A dehydrogenases were normal in H.C. and J.C. However, mitochondrial LCADH activities in all three ranged from 17 to 21% of control. Flavin adenine dinucleotide addition increased LCADH activities in all three to 27-36% of control. In the presence of monospecific medium-chain acyl-coenzyme A dehydrogenase antiseria, LCADH activity decreased 17% in controls, and fell to less than or equal to 11% of control in J.C. and R-1. The heterogeneity observed in the [3H]palmitate oxidation studies was not explained by differences in LCADH activities under any assay condition.