Clinical manifestations and management of fatty acid oxidation disorders

Abstract

Fatty acid oxidation disorders (FAOD) are a group of rare, autosomal recessive, metabolic disorders caused by variants of the genes for the enzymes and proteins involved in the transport and metabolism of fatty acids in the mitochondria. Those affected by FAOD are unable to convert fatty acids into tricarboxylic acid cycle intermediates such as acetyl-coenzyme A, resulting in decreased adenosine triphosphate and glucose for use as energy in a variety of high-energy-requiring organ systems. Signs and symptoms may manifest in infants but often also appear in adolescents or adults during times of increased metabolic demand, such as fasting, physiologic stress, and prolonged exercise. Patients with FAOD present with a highly heterogeneous clinical spectrum. The most common clinical presentations include hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Despite efforts to detect FAOD through newborn screening and manage patients early, symptom onset can be sudden and serious, even resulting in death. Therefore, it is critical to identify quickly and accurately the key signs and symptoms of patients with FAOD to manage metabolic decompensations and prevent serious comorbidities.

Keywords: Cardiomyopathy; FAOD; Fatty acid oxidation disorder; Hypoglycemia; Metabolism; Rhabdomyolysis.

Fig. 1

Role of key enzymes in the oxidation of fatty acids in the mitochondria. Adapted with permission from Vockley J, et al. Mol Genet Metab. 2015;116:53–60. αKG, α-ketoglutarate; AC-CoA, acyl-coenzyme A; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CACT, carnitine acylcarnitine translocase; CIT, citrate synthase; CPT, carnitine palmitoyl transferase; FADH, flavin adenine dinucleotide; FUM, fumarase; ICIT, isocitrate dehydrogenase; LCHAD, long-chain L-3 hydroxyacyl-CoA dehydrogenase; MAL, malate dehydrogenase; MMA-CoA, methylmalonyl-CoA mutase; NADH, nicotinamide adenine dinucleotide; OAA, oxaloacetic acid; PROP-CoA, propionyl-CoA carboxylase; SUCC, succinate dehydrogenase; SUCC-CoA, succinyl-CoA synthetase; TCA, tricarboxylic acid; TFP, trifunctional protein; VLCAD, very-long-chain acyl-CoA dehydrogenase

Fig. 2

FAOD: clinical manifestations of disease can be serious, unpredictable, and precipitous in nature. Genotype-specific manifestations are denoted in parentheses, with others broadly applicable. FAOD, fatty acid oxidation disorder; LC-FAOD, long-chain fatty acid oxidation disorders; LCHADD, long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency; TFPD, tri-functional protein deficiency; QoL, quality of life.