Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening

The different long-chain fatty acid oxidation defects present with similar heterogeneous clinical phenotypes of different severity. Organs mainly affected comprise the heart, liver, and skeletal muscles. All symptoms are reversible with sufficient energy supply. In some long-chain fatty acid oxidation defects, disease-specific symptoms occur. Only in disorders of the mitochondrial trifunctional protein (TFP) complex, including long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase (LCHAD) deficiency, neuropathy and retinopathy develop that are progressive and irreversible despite current treatment measures. In most long-chain fatty acid oxidation defects, no clear genotype-phenotype correlation exists due to molecular heterogeneity. However, some isolated mutations have been identified to be associated with only mild phenotypes, e.g., the V243A mutation in very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. LCHAD deficiency is due to the prevalent homozygous 1528G > C mutation and presents with heterogeneous clinical phenotypes, suggesting the importance of other environmental and genetic factors. For some disorders, it was shown that residual enzyme activity measured in fibroblasts or lymphocytes correlated with severity of clinical phenotype. Implementation of newborn screening has significantly reduced morbidity and mortality of long-chain fatty acid oxidation defects. However, the severest forms of TFP deficiency are still highly associated with neonatal death. Newborn screening also identifies a great number of mildly affected patients who may never develop clinical symptoms throughout life. However, later-onset exercise-induced myopathic symptoms remain characteristic clinical features of long-chain fatty acid oxidation defects. Disease prevalence has increased with newborn screening.