MCAD deficiency: To be, or not to be at risk

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most prevalent inborn error of mitochondrial fatty acid oxidation (mFAO). Patients are at risk of sudden death due to hypoketotic hypoglycemia, particularly during illness. MCAD deficiency has been included in the national newborn screening (NBS) program, resulting in decreased mortality and morbidity. The phenotype varies widely, from an acute phenotype with neonatal death, to a chronic phenotype with lowered exercise tolerance, or remaining asymptomatic. No genotype-phenotype correlations exist. Moreover, NBS has identified newborns with new mutations in the gene encoding MCAD, of which the clinical relevance remains to be determined. The pathophysiology of the disease also remains elusive.
We performed risk stratification after positive NBS. Residual MCAD enzyme activity was found to be central to this stratification. The mechanism behind the acute phenotype was studied in a mouse model and with mathematical models for mFAO. MCAD deficiency was found to increase sensitivity of mFAO to a sudden collapse and inhibition of the mFAO. Next, we studied the chronic phenotype in patients. We observed oxidative damage in blood. Applying advanced magnetic resonance spectroscopy (MRS) methodology, we observed a perturbed energy balance in quadriceps muscle of patients during prolonged exercise. Based on a literature study we proposed a new disease mechanism. The clinical phenotype appears to reflect how successful cells are in counteracting perturbations of the metabolic homeostasis by activating nutrient-sensing networks adapting gene expression. Together the studies described in this thesis form the basis for ‘personalized medicine’ in patients with MCAD deficiency.