Long Chain Fatty Acid Oxidation Disorder (LC-FAOD)

Long chain fatty acid oxidation disorders (LCFAOD) are a group of disorders characterized by the body’s inability to break down long chain fatty acids. This leads to muscle symptoms like rhabdomyolysis, hypotonia, muscle weakness, and exercise intolerance. It can also cause cardiac symptoms, such as cardiomyopathy and arrhythmia. Finally, it can lead to hypoglycemia, steatohepatitis, and hepatomegaly.¹

There are 6 main types of LCFAODs that are each caused by a mutation in one of the genes that encodes enzymes that are essential for long chain fatty acid metabolism. Each type of disease is inherited in an autosomal recessive manner.²

Some of these enzymes are involved in the carnitine shuttle (carnitine palmitoyltransferase I and II, and carnitine-acyl-carnitine translocase), a mechanism by which long chain fatty acids are transported into the mitochondria.³ Others play a role in beta-oxidation and energy production (very-long-chain acyl-coenzyme A (CoA) dehydrogenase and trifunctional protein (TFP) enzyme complex).

Cause of Carnitine Palmitoyltransferase I (CPT I) Deficiency

Carnitine palmitoyltransferase I (CPT I) deficiency is the first type of LCFAOD.⁴ CPT I is required for the transport of long chain fatty acids inside the mitochondria to be broken down and be converted into energy. The disease is caused by mutations in the CPT1A gene, which encodes for CPT I.

The mitochondrial membrane is impermeable to long chain fatty acids, so they can only enter the organelle when they are bound to carnitine. CPT I binds long chain fatty acids to carnitine. Mutations in the CPT1A gene reduce or completely eliminate the activity of CPT I, thereby inhibiting the binding of long chain fatty acids to carnitine. This ultimately results in long chain fatty acids not being able to enter the mitochondria and leads to their accumulation, which is toxic. This problem also leads to energy deficiency.

Cause of Carnitine-Acyl-Carnitine Translocase (CACT) Deficiency

Carnitine-acyl-carnitine translocase (CACT) deficiency, the second type of LCFAOD is caused by mutations in the SLC25A20 gene.⁵ This enzyme encodes for CACT, which is located in the inner membrane of the mitochondria. Its role is to transport the long chain fatty acid-carnitine complex inside the mitochondria. 

Mutations in the SLC25A20 gene change the structure of the CACT protein and lead to CACT deficiency. As a result, long chain fatty acids cannot be transported to the mitochondria and metabolized resulting in energy deficiency and long chain fatty acid accumulation.

Cause of Carnitine Palmitoyltransferase II (CPT II) Deficiency

Carnitine palmitoyltransferase II  (CPT II) comes into play once the long chain fatty acid-carnitine complex enters the nucleus. The role of CPT II is to remove the carnitine molecule from long chain fatty acids so they are ready to be metabolized.^3,6

The gene that encodes CTP II is called the CPT2 gene. When there are mutations in this gene, the activity of CPT II is reduced. This leads to carnitine not being removed from long chain fatty acids, which cannot be metabolized as a result. Once again, they accumulate to toxic levels causing damage and there is a reduction in energy production.

Cause of Very-Long-Chain Acyl-Coenzyme A (CoA) Dehydrogenase (VLCAD) deficiency

Very-long-chain acyl-coenzyme A (CoA) dehydrogenase (VLCAD) deficiency is caused by mutations in the ACADVL gene, which encodes for the VLCAD enzyme. This enzyme is required for the beta-oxidation of fatty acids inside the mitochondria. Like with defects in enzymes that play a role in the carnitine shuttles, defects in the VLCAD enzyme result in energy deficiency and fatty acid accumulation that is toxic.⁷ 

Cause of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is caused by mutations in the HADHA gene. This gene encodes for part of the mitochondrial trifunctional protein (TFP) enzyme complex. This complex is made of three different enzymes, each of which plays a different role in long chain fatty acid metabolism inside the mitochondria.⁸ 

Mutations in the HADHA gene disrupt the function of the whole enzyme complex and lead to long chain fatty acid accumulation, as well as energy deficiency.

Cause of Trifunctional Protein (TFP) Deficiency

The last type of LCFAOD is trifunctional protein (TFP) deficiency and is caused by mutations in both the HADHA and HADHB genes. The HADHB gene encodes for the second enzyme in the TFP complex. Mutations in these two genes completely disrupt the function of the TFP complex leading to long chain fatty acid accumulation and energy deficiency.⁹

References

1. 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
2.  Understand what causes LC-FAOD and how it impacts the body. FAOD in Focus. Accessed June 4, 2021.
3. El-Gharbawy A, Vockley J. Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System. Pediatr Clin North Am. 2018;65(2):317-335. doi:10.1016/j.pcl.2017.11.006
4. Carnitine palmitoyltransferase I deficiency. Medline Plus. August 18, 2020. Accessed June 4, 2021. 
5. Carnitine-acylcarnitine translocase deficiency. Orphanet. February 2014. Accessed June 4, 2021.
6. Carnitine palmitoyltransferase II deficiency. Medline Plus. August 18, 2020. Accessed June 4, 2021. 
7. Very long-chain acyl-CoA dehydrogenase deficiency. Medline Plus. August 18, 2020. Accessed June 4, 2021. 
8. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Medline Plus. August 18, 2020. Accessed June 4, 2021. 
9. Mitochondrial trifunctional protein deficiency. Medline Plus. August 18, 2020. Accessed June 4, 2021. 

Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.

---

Ozge Ozkaya, MSc, PhD

Özge’s background is in research; she holds a MSc. in Molecular Genetics from the University of Leicester and a PhD. in Developmental Biology from the University of London. Özge worked as a bench scientist for six years in the field of neuroscience before embarking on a career in science communication. She worked as the research communication officer at MDUK, a UK-based charity that supports people living with muscle-wasting conditions, and then a research columnist and the managing editor of resource pages at BioNews Services before joining Rare Disease Advisor.