Mitochondrial Fatty Acid Oxidation Disorders

Mitochondrial fatty acid oxidation disorders (FAODs) impair the ability of the body to utilize fats for energy production during times of physiologic stress such as fasting or illness, and thus can be asymptomatic and difficult to diagnose when a patient is well. Reducing equivalents from fatty acid oxidation (FAO) enzyme reactions directly enter the electron transfer chain (ETC) to support generation of adenosine triphosphate (ATP) through oxidative phosphorylation (oxphos), or by entry of its end product acetyl-coenzyme A (acetyl-CoA) into the tricarboxylic acid cycle (TCA or Krebs cycle). Acetyl-CoA from FAO can also be used to synthesize ketones, a fuel source that is used by some peripheral tissues and especially the brain during catabolic situations. Due to the ability to prevent life-threatening symptoms through early diagnosis, FAODs have been included in newborn screening (NBS) panels worldwide through tandem mass spectrometry-based screening. Acylcarnitine profiles are specific for the respective enzyme defects; however, the diagnosis should be confirmed by enzyme assay and/or molecular analysis as they may also offer insight into clinical severity. 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 are comprised of four groups: (1) disorders of the entry of long-chain fatty acids into mitochondria (often referred to as carnitine cycle defects), (2) intramitochondrial ß-oxidation defects of long-chain fatty acids, (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. All told, more than 20 different genetic enzyme defects of FAO have now been identified, some with disease-specific characteristics that distinguish them from others in the group. The main pathophysiologic mechanism of all FAODs is an energy deficiency due to impaired fatty acid oxidation and ketone body formation. Toxic effects of accumulating acylcarnitine and acyl-CoA species may also play a role. FAODs present with heterogeneous phenotypes. Before addition of FAODs to newborn screening (NBS) panels in many countries, the commonest clinical presentations were hypoketotic hypoglycemia and sudden death, usually precipitated by an infection or fasting in the neonatal period or early childhood. With newborn screening, apparent disease incidence has significantly increased, while 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 in some of the defects. Three major phenotypes are now recognized. Non-ketotic hypoglycemia predominates in the first few years of life, but is uncommon after age 4–6 years. Cardiomyopathy and arrhythmias are seen at any time, may be of acute onset, and can also be reversible. Exercise- or illness-induced rhabdomyolysis is a common presentation in adolescents or young adults, but muscle pain and elevated creatine kinase (CK) can occur in infancy. With some disorders, patients can remain asymptomatic throughout life if they have mild defects and are not exposed to the metabolic stress. Affected asymptomatic mothers have been identified due to pathological newborn screening in their child. Correlation of genotype and/or residual enzyme activity with disease phenotype has been reported for some defects but is imperfect, suggesting an additional role for disease modifiers and environment. Treatment must be tailored to the severity of the phenotype and the specific disorder, with a focus on avoidance of fasting, mitigation of stress, and fluid and caloric support through episodes of rhabdomyolysis. New therapies are in development and may change significantly the long-term prognosis for patients.