Fatty Acid Oxidation Disorders / Beta-oxidation Defects / Fatty Acid Transport and Mitochondrial Oxidation Disorders

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Beta-oxidation cycle disorders are among the fatty acid and glycerol metabolism disorders. Acetyl CoA is generated from fatty acids through repeated beta-oxidation cycles. Sets of 4 enzymes (an acyl dehydrogenase, a hydratase, a hydroxyacyl dehydrogenase, and a lyase) specific for different chain lengths (very long chain, long chain, medium chain, and short chain) are required to break down a long-chain fatty acid completely. Inheritance for all fatty acid oxidation defects is autosomal recessive. Fatty acid transport and mitochondrial oxidation disorders include many disorders. See also:

Systemic Primary Carnitine Deficiency – presents with high urinary carnitine excretion despite very low plasma carnitine, as well as an absence of significant dicarboxylic aciduria. Clinically, patients present with hypoketotic hypoglycemia, fasting intolerance with hypotonia, depressed CNS, apnea, seizures, dilated cardiomyopathy, and developmental delay. The treatment includes carnitine supplementation.

Long Chain Fatty Acid Transport Deficiency – presents with low to normal free carnitine. Clinically patients may experience episodic acute liver failure, hyperammonemia, and encephalopathy. Treatment includes liver transplantation.

Carnitine Palmitoyl Transferase I (CPT-I) Deficiency – Patients present with normal to elevated total and free plasma carnitine with no dicarboxylic aciduria. Fasting intolerance, hypoketotic hypoglycemia, hepatomegaly, seizures, coma, and elevated creatine kinase may be noted. Treatment includes avoidance of fasting, frequent feeding, high-dose glucose during acute episodes and replacement of long-chain dietary fat with medium-chain fats.
Carnitine/Acylcarnitine Translocase Deficiency – Biochemically, patients presents with low total plasma carnitine, with most of the carnitine conjugated to long-chain fatty acids, and elevated C16 carnitine ester. In the neonatal form, patients may experience fasting intolerance with hypoglycemic coma, vomiting, weakness, cardiomyopathy, arrhythmia, mild hyperammonemia. In the mild form, recurrent hypoglycemia with no cardiac involvement may been seen. Treatment includes avoidance of fasting, frequent feeding, if plasma level is low, carnitine if plasma levels are low, and high-dose glucose during acute episodes.

Carnitine Palmitoyl Transferase II (CPT-II) Deficiency – Biochemically, elevated C16 carnitine ester is noted, yet in the classical muscle form, carnitine is usually normal. In the severe form, low total plasma carnitine is noted, with most conjugated to long-chain fatty acids. Clinical features in the classical muscle form include a presentation in adulthood with episodic myoglobinuria and weakness after prolonged exercise, fasting, intercurrent illness, or stress. In the severe form, presentation occurs in the neonatal period or infancy with hypoketotic hypoglycemia, cardiomyopathy, arrhythmia, hepatomegaly, coma, or seizures. Avoidance of fasting, frequent feeding, carnitine if plasma level is low, and during acute episodes, high-dose glucose are the current treatments.

Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency – This deficiency is similar to LCHADD but is commonly associated with significant cardiomyopathy. The biochemical profile includes an elevated saturated and unsaturated C14–C18 acylcarnitine esters, and elevated urinary C6–C14 dicarboxylic acids. Presentation varies by type of VLCAD. In the VLCAD-C type, arrhythmia, hypertrophic cardiomyopathy, and sudden death are noted, yet in the VLCAD-H type, recurrent hypoketotic hypoglycemia, encephalopathy, mild acidosis, mild hepatomegaly, hyperammonemia, and elevated liver enzymes are more common. Treatment for either type includes: avoidance of fasting, high-carbohydrate diet, carnitine, medium-chain triglycerides, and during acute episodes, high-dose glucose is needed.

Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency – This deficiency is the second most common fatty acid oxidation defect. Elevated saturated and unsaturated C16–C18 acylcarnitine esters, and elevated urinary C6–C14 3-hydroxydicarboxylic acids are typical biochemical findings. Sharing many features of MCADD, LCHADD patients may also have cardiomyopathy, rhabdomyolysis, fasting-induced hypoketotic hypoglycemia, cholestatic liver disease, massive creatine kinase elevations, myoglobinuria with muscle exertion, peripheral neuropathy, retinopathy, and abnormal liver function. Mothers with an LCHADD fetus often have HELLP syndrome (hemolysis, elevated liver function tests, and low platelet count) during pregnancy. Diagnosis of LCHADD is based on the presence of excess long-chain hydroxy acids on organic acid analysis and on the presence of their carnitine conjugates in an acylcarnitine profile or glycine conjugates in an acylglycine profile. LCHADD can be confirmed by enzyme study in skin fibroblasts. Treatment during acute exacerbations includes hydration, high-dose glucose, bed rest, urine alkalinization, and carnitine supplementation. Long-term treatment includes a high-carbohydrate diet, medium-chain triglyceride supplementation, and avoidance of fasting and strenuous exercise.

Mitochondrial Trifunctional Protein (TFP) Deficiency – is similar to LCHAD deficiency with clinical features including liver failure, cardiomyopathy, fasting hypoglycemia, myopathy, and sudden death. Treatment is also similar to LCHAD deficiency.

Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency – This deficiency is the most common defect in the β-oxidation cycle and has been incorporated into expanded neonatal screening in many states. Biochemically, elevated saturated and unsaturated C8–C10 acylcarnitine esters, elevated urinary C6–C10 dicarboxylic acids, suberylglycine, and hexanoylglycine, and low free carnitine may be noted. Clinical manifestations typically begin after 2 to 3 months of age and usually follow fasting (as little as 12 hours) and include episodic hypoketotic hypoglycemia after fasting, vomiting, hepatomegaly, lethargy, coma, acidosis, SIDS, and Reye-like syndrome. During attacks, patients have hypoglycemia, hyperammonemia, and unexpectedly low urinary and serum ketones. Metabolic acidosis is often present but may be a late manifestation. Diagnosis of MCADD is by detecting medium-chain fatty acid conjugates of carnitine in plasma or glycine in urine or by detecting enzyme deficiency in cultured fibroblasts; however, DNA testing can confirm most cases. Treatment of acute attacks is with 10% dextrose IV at 1.5 times the fluid maintenance rate; some clinicians also advocate carnitine supplementation during acute episodes. Prevention is a low-fat, high-carbohydrate diet and avoidance of prolonged fasting. Cornstarch therapy is often used to provide a margin of safety during overnight fasting.
Short-Chain Acyl-CoA Dehydrogenase (SCAD) Deficiency – In the neonatal form, intermittent ethylmalonic aciduria is noted with neonatal acidosis, vomiting, and growth and developmental delay. In the chronic form, low muscle carnitine is present with progressive myopathy. Treatment for SCAD deficiency includes an avoidance of fasting.

Glutaric Aciduria Type II – is caused by a defect in the transfer of electrons from the coenzyme of fatty acyl dehydrogenases to the electronic transport chain affects reactions involving fatty acids of all chain lengths (multiple acyl-coA dehydrogenase deficiency). Oxidation of several amino acids is also affected. Biochemical presentation includes elevated urinary ethylmalonic, glutaric, 2-hydroxyglutaric, 3-hydroxyisovaleric, and C6–C10 dicarboxylic acids and isovalerylglycine, elevated glutarylcarnitine, isovalerylcarnitine, and straight-chain acylcarnitine esters of C4, C8, C10, C10:1, and C12 fatty acids, low serum carnitine, and increased serum sarcosine. Clinical manifestations thus include fasting hypoglycemia, severe metabolic acidosis, hyperammonemia, sudden death, CNS anomalies, myopathy, and possible liver and cardiac involvement. Diagnosis of glutaric acidemia type II is confirmed by increased ethylmalonic, glutaric, 2- and 3-hydroxyglutaric, and other dicarboxylic acids in organic acid analysis, and glutaryl and isovaleryl and other acylcarnitines in tandem mass spectrometry studies. Enzyme deficiencies in skin fibroblasts can be confirmatory. Treatment of glutaric acidemia type II is similar to that for MCADD, except that riboflavin may be effective in some patients. Treatment for this disorder includes avoidance of fasting, frequent feeding, carnitine, riboflavin, and, during acute episodes, high-dose glucose
Short-Chain 3-Hydroxyacyl-CoA Dehydrogenase (SCHAD) Deficiency – Ketotic C8–C14 3-hydroxydicarboxylic aciduria is noted which corresponds with the following clinical features: recurrent myoglobinuria, ketonuria, hypoglycemia, encephalopathy, and cardiomyopathy. Avoidance of fasting is noted to be the current treatment.

Short/Medium-Chain 3-Hydroxyacyl-CoA Dehydrogenase (S/MCHAD) – Biochemical presentation includes a marked elevation of MCHADs and acylcarnitines. Liver failure and encephalopathy are common clinical features and avoidance of fasting is key to treatment.

Medium-Chain 3-Ketoacyl-CoA Thiolase (MCKAT) Deficiency – Biochemical presentation includes lactic aciduria, ketosis, and elevated urinary C4–C12 dicarboxylic aciduria (especially C10 and C12). Clinically, fasting intolerance, vomiting, dehydration, metabolic acidosis, liver dysfunction, and rhabdomyolysis are noted and avoidance of fasting is key to treatment.

2,4-Dienoyl-CoA Reductase Deficiency – Hyperlysinemia, low plasma carnitine, and 2-trans,4-cis decadienoylcarnitine in plasma and urine are noted biochemically. Clinical features include neonatal hypotonia, and respiratory acidosis. Treatment has not yet been established.