Long Chain Fatty Acid Oxidation Disorder (LCFAOD)


Long chain fatty acid cxidation disorder (LCFAOD) is a group of genetic metabolic diseases characterized by the accumulation of long chain fatty acids in the body causing damage to different organs and systems.1 

The diseases are caused by defects in the carnitine shuttle of long chain fatty acids into the mitochondria or the beta-oxidation of these fatty acids once inside the organelle.1

There are 6 main types of LCFAODs caused by a mutation in genes encoding for enzymes that are involved in long chain fatty acid metabolism.2 

Three of these genes, CPT1A, SLC25A20, and CPT2 encode for enzymes that are respectively involved in binding long chain fatty acids to carnitine, transporting the long chain fatty acid-carnitine complex inside the mitochondria, and removing the carnitine molecule from long chain fatty acids once inside the mitochondria so they can be metabolized.2

The most common of the LCFAOD, however, are mitochondrial trifunctional protein (MTP) deficiency, isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.

MTP, LCHAD Deficiency Complications

MTP is made up of three enzymes: long-chain enoyl-CoA hydratase, LCHAD, and long-chain ketoacyl-CoA thiolase, which play a role in the last three steps of fatty acid beta-oxidation in the mitochondria. Mutations in the HADHA gene causes defects in the LCHAD enzyme while mutations in both the HADHA and HADHB genes cause MTP deficiency.3

If left untreated, MTP and LCHAD deficiency have high morbidity and mortality rates. The diseases lead to long-term complications, such as rhabdomyolysis, cardiomyopathy, peripheral neuropathy, and retinopathy due to the accumulation of toxic β-oxidation intermediates.4

 A 2015 study that analyzed 14 Austrian patients with LCHAD deficiency found that around half of patients developed complications affecting different organ systems. These included cardiomyopathy, hepatopathy, retinopathy, and polyneuropathy.

The study showed that the diseases also caused pregnancy complications to the mother in some cases. These included HELLP syndrome, preeclampsia, and placental insufficiency.4 

According to another study published in 2018, the accumulation of toxic ß-oxidation intermediates due to MTP and LCHAD deficiency caused complications, such as recurrent metabolic derangement and rhabdomyolysis as well as cardiomyopathy, feeding difficulties, peripheral neuropathy, and retinopathy.5

The exact mechanism of how these complications develop is not well understood but it is thought that it could be due to the accumulation of 3-hydroxy fatty acid intermediate.6

VLCAD Deficiency Complications

VLCAD deficiency is caused by mutations in the ACADVL gene, which encodes for the enzyme that is involved in the first step of mitochondrial beta-oxidation of long chain fatty acids.3 

The VLCAD enzyme is one of the first enzymes in fatty acid oxidation. It plays a role in the supply of electrons to the respiratory chain. It also provides a pathway that allows the production of ketones. 

When there is a mutation in the ACADVL gene and the VLCAD enzyme does not function properly, there is a significant reduction in fatty acid oxidation. This has a detrimental impact on the ability to maintain cardiac output since the heart constantly uses fatty acids as a source of energy. It also impairs the ability to adapt to long term fasting and to generate energy for exercise since during periods of fasting, the liver normally uses acetyl CoA to generate ketone bodies and during exercise, skeletal muscles use long chain fatty acid oxidation to generate energy. This leads to cardiomyopathy, hepatomegaly, hypotonia, and intermittent hypoglycemia in patients with VLCAD deficiency.7

In the long-term, the disease can cause recurrent rhabdomyolysis and myoglobinuria, which may lead to acute renal failure.3

Management of Complications

The development of complications can be prevented by preventing catabolic episodes. 

Anaplerotic therapy with heptanoate can act as a substrate for the citric acid cycle and the electron transport chain and bypass the deficient fatty acid oxidation enzymes.4

Complications such as hypertrophic cardiomyopathy, congestive heart failure, hepatomegaly, and muscle weakness can be prevented with a diet containing 30% to 35% of total caloric intake as heptanoate.8 

Recurrent rhabdomyolysis caused by VLCAD deficiency should be treated with hydration and the alkalization of the urine.7 

Because acute episodes are usually triggered by long periods of fasting, these should be avoided. In infants, aged 0 to 6 months, there should not be more than four hours between feeds. For babies, aged 6 months to three years this can be increased to eight hours. After age 3, a fasting period of 8 to 12 hours should be tolerated by the patient.9 

In the case of an acute episode that requires hospitalization, 10% dextrose should be promptly administered intravenously.9

References

  1. Vockley J. Long-chain fatty acid oxidation disorders and current management strategies. Am J Manag Care. 2020;26(7 Suppl):S147-S154. doi:10.37765/ajmc.2020.88480
  2. 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
  3. Amaral AU, Wajner M. Recent advances in the pathophysiology of fatty acid oxidation defects: secondary alterations of bioenergetics and mitochondrial calcium homeostasis caused by the accumulating fatty acids. Front Genet. 2020;27;11:598976. doi:10.3389/fgene.2020.598976
  4. Karall D, Brunner-Krainz M, Kogelnig K, et al. Clinical outcome, biochemical and therapeutic follow-up in 14 Austrian patients with long-chain 3-hydroxy acyl coa dehydrogenase deficiency (LCHADD). Orphanet J Rare Dis. 2015;10: 21. doi:10.1186/s13023-015-0236-7
  5. Lotz-Havla AS, Röschinger W, Schiergens K, et al. Fatal pitfalls in newborn screening for mitochondrial trifunctional protein (MTP)/long-chain 3-hydroxyacyl-coa dehydrogenase (LCHAD) deficiency. Orphanet J Rare Dis. 2018;20;13(1):122. doi:10.1186/s13023-018-0875-6
  6. Kang E, Kim Y-M, Kang M, et al. Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening. BMC Pediatr. 2018;8;18(1):103. doi:10.1186/s12887-018-1069-z
  7. Leslie ND, Valencia CA, Strauss AW, Kejian Z. Very long-chain acyl-coenzyme A dehydrogenase deficiency. 2009 May 28. Updated 2021 May 13. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2021. 
  8. Roe CR, Sweetman L, Roe DS, David F, Brunengraber H. Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride. J Clin Invest. 2002;110(2):259-69. doi:10.1172/JCI15311
  9. Very long chain acyl coa dehydrogenase deficiency (LCAD). National Organization of Rare Disorders. 2020. Accessed June 15, 2021. 

Reviewed by Harshi Dhingra, MD, on 7/1/2021.

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