| Přispěvatelé: |
Wijburg, F.A., Nieuwenhuis, E.E.E.S., Visser, G., Houtkooper, R.H., Faculteit der Geneeskunde |
| Popis: |
Long-chain fatty acid oxidation disorders (lcFAODs) are autosomal recessive inherited disorders in which one of the mitochondrial enzymes involved in oxidation of long-chain fatty acids is functioning insufficiently, resulting in compromised energy homeostasis and accumulation of toxic intermediates. The major clinical complications are hypoglycemia, cardiomyopathy, cardiac rhythm disturbances and myopathy. Even though lcFAODs cannot be cured and there is still no therapy available that effectively improves lcFAO capacity, (dietary) interventions can significantly improve the outcome in the majority of lcFAOD patients, hence their introduction in newborn screening (NBS) programs. We observed that NBS for very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) detects biochemically milder phenotypes and fails to prevent complications and death in patients with no residual lcFAO capacity. It did however prevent hypoglycemia in individuals with some residual lcFAO capacity. We also observed that cardiac abnormalities in VLCADD patients is uncommon and only seen in patients with very low residual enzyme activity. The second part of the thesis focuses on dietary interventions in a cohort of VLCADD patients. Physicians should be aware of the risk for essential fatty acid deficiency in these patients. Moreover, poor clinical outcome can be predicted by LC-FAO flux measured in cultured skin fibroblasts and could not be prevented by dietary intervention. Therefore, we proposed a standardized treatment strategy based on LC-FAO flux. Finally, we observed that a drink containing a ketone ester prior to exercise can improve muscular ATP homeostasis, in exercising VLCADD patients. These results provide a rational basis for future clinical studies of ketone ester supplementation in patients with FAO defects. |
