Mitochondrial Fatty Acid Oxidation Disorders

Abstract

Mitochondrial fatty acid oxidation disorders have been included in newborn screening programs worldwide since the implementation of tandem mass spectrometry-based screening. Disease-specific acylcarnitine profiles pinpoint at the respective enzyme defect; however, the diagnosis has invariably to be confirmed by enzyme assay and/or molecular analysis. Metabolic profiles can be normal in the anabolic state and, consequently, newborn screening may miss the diagnosis when performed outside the catabolic state on days 2 and 3 of life. Mitochondrial fatty acid oxidation disorders comprise four groups: (1) disorders of the entry of long-chain fatty acids into mitochondria, (2) intramitochondrial β-oxidation defects of long-chain fatty acids affecting membrane-bound enzymes, (3) β-oxidation defects of short- and medium-chain fatty acids affecting enzymes of the mitochondrial matrix, and (4) disorders of impaired electron transfer to the respiratory chain from mitochondrial β-oxidation. The main pathogenic mechanisms of fatty acid oxidation defects include toxic effects by accumulating acylcarnitine and acyl-CoA species and energy deficiency due to impaired fatty acid oxidation and ketone body formation. The respective disorders present with heterogeneous phenotypes. Before newborn screening (NBS) was introduced, the most common clinical presentations were hypoketotic hypoglycemia and sudden death, usually precipitated by an infection or fasting in the neonatal period or early childhood. In addition, severe cardiomyopathy and arrhythmias were leading clinical signs in the first months of life. Older children or adults may present with exercise- or illness-induced rhabdomyolysis. Patients can remain asymptomatic throughout life if they have mild defects and are not exposed to metabolic stress. Correlation of genotype and/or residual enzyme activity with disease phenotype has been reported for some defects, whereas in others additional disease modifiers are suspected. With newborn screening, disease incidence has significantly increased and the proportion of milder phenotypes has grown. Newborn screening greatly reduces the morbidity and mortality, though it does not eliminate early neonatal death in severe phenotypes. With respect to the heterogeneous clinical presentation, treatment needs to be tailored to the severity of the respective phenotype and the specific disorder.