Fatty acid oxidation disorders are a group of rare, genetic, metabolic disorders caused by mutations in genes that encode enzymes involved in fatty acid metabolism.1 Six of these diseases are grouped as long chain fatty acid oxidation disorders (LCFAOD) and include carnitine palmitoyltransferase (CPT I or CPT II) deficiency, carnitine-acylcarnitine translocase (CACT) deficiency, very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiency, and trifunctional protein (TFP) deficiency.2
The clinical presentation of the diseases varies greatly from one patient to the next, but the most common comorbidities include hypoketotic hypoglycemia, hepatic dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy. Peripheral neuropathy and retinopathy are also seen in some subtypes.3
Hypoketotic hypoglycemia is defined as a decreased concentration of glucose in the blood due to the reduced concentration of ketone bodies.4
Normally, fatty acids are converted into ketones inside the mitochondria. Some of these ketones enter the Krebs cycle and produce energy in the form of ATP, while some are converted into glucose to feed the brain.5
When there is a deficiency in one of the enzymes that play a role in the transport of long chain fatty acids into the mitochondria or in one involved in their beta-oxidation once inside the mitochondria as in LCFAOD, the levels of ketones go down (hypoketotic) and they cannot be converted into glucose, causing hypoglycemia.3
The lack of ketone production also means that the body becomes dependent on glycogen stores, which further contributes to hypoglycemia.
Hypoketotic hypoglycemia can impair the function of the central nervous system and cause lethargy, seizures, apnea, or coma.3
The management strategy for hypoketotic hypoglycemia is to stop the attempted catabolism of fatty acids by cells by switching to a diet low in long chain fatty acids and supplementing the diet with medium-chain triglycerides.3
The inability of the liver to metabolize fatty acids in LCFAOD leads to hepatic steatosis or the accumulation of fats inside the liver. This can lead to hepatic encephalopathy, hepatomegaly, hyperammonemia, and liver failure.6
The symptoms of liver dysfunction include jaundice, pale stools, cholestasis, and axial hypotonia.6
With a strict nutritional plan that contains no long chain fatty acids and is supplemented with medium-chain triglycerides, hepatic problems usually resolve within a month.3
Cardiomyopathy develops as a result of fatty acids accumulating inside heart cells due to the absence of enzymes that are involved in their breakdown causing inflammation. This, in turn, leads to a misalignment in cardiac myofibrils and causes cardiac contractions to be inefficient.7
The deficiency in fatty acid oxidation also causes low energy levels that lead to inefficient cardiac contractions, heart muscle hypertrophy, and cardiomyopathy.7
Cardiomyopathy can lead to congestive heart failure and sudden death in infancy or early childhood in patients with LCFAOD.
The management strategies of cardiomyopathy include low-intensity aerobic exercise, β-blockers, calcium channel blockers, diuretics, vasoconstrictors, and angiotensin-converting enzyme inhibitors. In more severe cases, inotropic therapy, respiratory ventilation, mechanical cardiac support, and heart transplant may be necessary.3
Rhabdomyolysis and Skeletal Myopathy
In patients with LCFAOD, periods of fasting or prolonged exercise can lead to rhabdomyolysis. It is thought that this is caused by not enough ATP being delivered to the muscle cells, which disrupts cellular integrity and leads to cellular disintegration.8
Rhabdomyolysis can cause hypotonia, muscle weakness, and disrupted gait. Skeletal myopathy in LCFAOD tends to appear when patients are in their toddler years. They can also appear in childhood or adulthood.
Rhabdomyolysis can be prevented by avoiding intense or prolonged exercise.8
Peripheral Neuropathy and Retinopathy
Peripheral neuropathy and retinopathy can occur in patients with TFP deficiency and LCHAD deficiency.9
It is thought that they are the result of energy deficiency, unmetabolized intermediates, and docosahexaenoic acid deficiencies, which have a negative effect on brain development. Low docosahexaenoic acid levels can be caused by dietary over-restrictions, so this should be avoided.
Peripheral neuropathy is irreversible and is usually progressive. It cannot be reversed using high-caloric intake but long-chain triglyceride restrictions are recommended.9
It is thought that high levels of hydroxyacylcarnitines and hydroxy fatty acids in the plasma during metabolic crises may cause the destruction of retinal cells and lead to retinopathy.10
Peripheral neuropathy can be treated with physiotherapy or occupational therapy to reduce pain and increase function.
A strict diet supplemented with medium-chain triglycerides could slow the progression of retinopathy in patients with LCFAOD.3
- Vockley J, Burton B, Berry G, et al. Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: results from an open-label, long-term extension study. J Inherit Metab Dis. 2021;44(1):253-263. doi:10.1002/jimd.12313
- Knottnerus SJG, Bleeker JC, Wüst RCI, et al. Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle. Rev Endocr Metab Disord. 2018;19(1):93-106. doi:10.1007/s11154-018-9448-1
- Merritt JL II, MacLeod E, Jurecka A, Hainline B. Clinical manifestations and management of fatty acid oxidation disorders. Rev Endocr Metab Disord. 2020;21(4):479-493. doi:10.1007/s11154-020-09568-3
- Hypoketotic hypoglycemia. MedGen. Accessed June 25, 2021.
- Dhillon KK, Gupta S. Biochemistry, ketogenesis. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2021.
- Saudubray JM, Martin D, de Lonlay P, et al. Recognition and management of fatty acid oxidation defects: a series of 107 patients. J Inherit Metab Dis. 1999;22(4):488-502. doi:10.1023/a:1005556207210
- Cox GF. Diagnostic approaches to pediatric cardiomyopathy of metabolic genetic etiologies and their relation to therapy. Prog Pediatr Cardiol. 2007;24(1):15-25. doi:10.1016/j.ppedcard.2007.08.013
- Diekman EF, Visser G, Schmitz JPJ, et al. Altered energetics of exercise explain risk of rhabdomyolysis in very long-chain acyl-CoA dehydrogenase deficiency. PLoS One. 2016;11(2):e0147818. doi:10.1371/journal.pone.0147818
- Spiekerkoetter U. Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening. J Inherit Metab Dis. 2010;33(5):527-532. doi:10.1007/s10545-010-9090-x
Fletcher AL, Pennesi ME, Harding CO, Weleber RG, Gillingham MB. Observations regarding retinopathy in mitochondrial trifunctional protein deficiencies. Mol Genet Metab. 2012;106(1):18-24. doi:10.1016/j.ymgme.2012.02.015
Reviewed by Harshi Dhingra, MD, on 7/1/2021.