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.
Long chain fatty acid oxidation disorder (LCFAOD) is the name given to a group of rare autosomal recessive genetic disorders characterized by impaired fat metabolism resulting in acute crises of energy production and chronic energy deficiency.1
There are 6 types of LCFAOD. These are carnitine palmitoyltransferase (CPT1 or CPT2) 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
History of LCFAOD
The first report of a genetic fatty acid oxidation disorder (FAOD) dates to 1973.3 Since then other FAODs have been identified but little is known about the natural history of the disease.
LCFAOD is caused by mutations in genes that encode for mitochondrial enzymes that play a role in energy metabolism during times of fasting and physiologic stress. Each type of LCFAOD is caused by a mutation in a gene encoding for one of the enzymes that are essential for breaking down long chain fatty acids.1
CPT1 deficiency is caused by a mutation in the CPT1A gene causing long chain fatty acids not to be able to be processed in the first step in the carnitine shuttle, which brings them into the mitochondria. Key signs and symptoms usually appear in childhood and can include neurological problems.4
CACT deficiency is caused by a mutation in the SLC25A20 gene leading to the middle step of the carnitine shuttle, transporting the long chain fatty acid into the mitochondria being unable to function properly.5
CPT2 deficiency is caused by mutations in the CPT2 gene disrupting the last step in the carnitine shuttle, also preventing long chain fatty acids from entering the mitochondria to be broken down.6
VLCAD deficiency is caused by a mutation in the ACADVL gene encoding for an enzyme that is part of the long chain beta oxidation spiral, which processes long-chain fatty acids once they enter the mitochondria via the carnitine shuttle. When the VLCAD enzyme is not functioning properly, long-chain fatty acids are not broken down properly. This results in low energy and cell damage.7
TFP deficiency is caused by mutations in both the HADHA and HADHB genes. TFP is an enzyme complex involved in the last 3 steps of long-chain fatty acid breakdown. If the TFP complex is not working properly, long-chain fatty acids cannot be broken down and accumulate inside cells causing damage.8
LCHAD deficiency is caused by a mutation in the HADHA gene only, which encodes for one of the enzymes in the TFP complex. This also leads to long-chain fatty acid build-up and causes damage, as well as low energy production.9
Read more about LCFAOD etiology.
The clinical manifestations of LCFAOD include rhabdomyolysis induced by exercise, fasting or illness, liver dysfunction, such as severe hypoglycemia and hyperammonemia, and cardiomyopathy.1 Other symptoms include muscle weakness, hypotonia, and fatigue.
These symptoms usually appear soon after birth or in infancy, and can cause complications that can be life-threatening.
Patients with some types of LCFAOD may also develop retinopathy or peripheral neuropathy.2
Symptoms of a metabolic crisis in infants include neurologic distress that manifests as extreme sleepiness, coma, and Reye’s syndrome, changes in heart rhythm, muscle weakness, and changes in appetite or dietary requirements.10
Read more about LCFAOD symptoms.
In the US and some other countries, LCFAOD is identified through newborn screening. If newborn screening is positive, diagnostic blood tests assessing levels of plasma acylcarnitine are performed. Genetic testing can confirm the diagnosis and identify the type of LCFAOD for the patient.11
Invitae offers sponsored genetic testing for patients suspected of having LCFAOD in the US and Canada. The test screens 24 genes that are associated with beta-oxidation of fatty acids, carnitine shuttle, carnitine transport, ketogenesis, and other conditions that could lead to abnormal plasma acylcarnitine profiles. These genes are ACAD9, ACADM, ACADS, ACADSB, ACADVL, CPT1A, CPT2, ETFA, ETFB, ETFDH, FLAD1, HADH, HADHA, HADHB, HMGCL, HMGCS2, MLYCD, NADK2, SLC22A5, SLC25A20, SLC25A32, SLC52A1, SLC52A2, SLC52A3.12
Read more about LCFAOD diagnosis.
LCFAOD patients should avoid fasting. Supplementation of medium-chain triglyceride oil can also help since this does not require the typical steps of LCFAOD for metabolism.1
Medium, odd-chain fatty acids, like triheptanoin are also being studied as a potential therapeutic approach for LCFAOD. In 2020, the US Food and Drug Administration approved triheptanoin (Dojolvi™) as a calorie and fatty acid source for the treatment of children and adults with LCFAOD.13
Read more about LCFAOD treatment
- 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
- 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
- DiMauro S, DiMauro PM. Muscle carnitine palmityltransferase deficiency and myoglobinuria. Science. 1973;20;182(4115):929-31. doi:10.1126/science.182.4115.929
- Bennett MJ, Santani AB.Carnitine Palmitoyltransferase 1A Deficiency. GeneReviews. March 17, 2016. Accessed June 3, 2021.
- Carnitine-acylcarnitine translocase deficiency. Medline Plus. August 18, 2020. Accessed June 3, 2021.
- Deschauer M, Wieser T, Zierz S. Muscle carnitine palmitoyltransferase II deficiency: clinical and molecular genetic features and diagnostic aspects. Arch Neurol. 2005;62(1):37-41. doi:10.1001/archneur.62.1.37
- VLCAD deficiency. Genetic and Rare Diseases Information Center. Accessed June 3, 2021.
- Mitochondrial trifunctional protein deficiency. Medline Plus. August 18, 2020. Accessed June 3, 2021.
- Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Medline Plus. August 18, 2020. Accessed June 3, 2021.
- Understand What Causes LC-FAOD and How It Impacts the Body. FAOD in Focus. Accessed June 3, 2021.
- The Importance of Timely and Proper Diagnosis. FAOD in Focus. Accessed June 3, 2021.
- Long Chain Fatty Acid Oxidation Disorders. Invitae. Accessed June 3, 2021.
- Ultragenyx Announces U.S. FDA Approval of Dojolvi™ (UX007/triheptanoin), the First FDA-Approved Therapy for the Treatment of Long-chain Fatty Acid Oxidation Disorders. News Release. Ultragenyx Pharmaceutical. June 30, 2020.
Reviewed by Harshi Dhingra, MD, on 7/1/2021.