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 disorders (LCFAODs) are a group of autosomal recessive genetic diseases caused by mutations in different genes. Symptoms include rhabdomyolysis induced by exercise, fasting or illness, severe hypoglycemia, hyperammonemia, and cardiomyopathy, which usually appear soon after birth or in infancy and can be life-threatening.1
There are 6 types of LCFAODs each caused by a mutation in a different gene. These are the CPT1A, SLC25A20, CPT2, ACADVL, HADHA, and HADHB genes.
Each of these genes encodes for a different protein that is involved in long chain fatty acid metabolism. CPT1A, SLC25A20, and CPT2 encode for the carnitine palmitoyltransferase I (CPT I), carnitine-acyl-carnitine translocate (CACT), and carnitine palmitoyltransferase II (CPT II) proteins respectively, which are involved in the carnitine shuttle of long chain fatty acids inside the mitochondria to be used as a source of energy.
CPT I binds long chain fatty acids to carnitine so that CACT can transport the long chain fatty acid-carnitine complex across the mitochondrial membrane. CPT II then removes the carnitine molecule so long chain fatty acids can be metabolized once inside the mitochondria.
The enzymes that the ACADVL, HADHA, and HADHB genes encode are involved in the beta-oxidation of long chain fatty acids inside the mitochondria.
When there is a defect in any one of these genes, long chain fatty acids cannot be metabolized and accumulate causing damage. This also causes energy deficiency.2
Carnitine supplementation has been proposed as a therapeutic approach for LCFAODs. The idea is that supplementation could aid carnitine transportation of long chain fatty acids inside the mitochondria and improve fatty acid oxidation.2
However, the approach has not been well studied and is controversial. In case secondary carnitine deficiency develops, carnitine supplementation may be considered. But again, evidence for the efficacy of the approach is lacking.1
Carnitine supplementation may also not be safe because it could induce the accumulation of toxic intramitochondrial long-chain acyl-carnitine and -CoAs. Carnitine supplementation has also been associated with ventricular fibrillation and rhabdomyolysis and should not be used for the acute management of a metabolic crisis.3
Ketone Body Replacement Therapy
Ketone body replacement therapy is another approach that has been proposed as an addition to standard therapy.4
Ketone bodies are the product of the beta-oxidation of long chain fatty acids inside the mitochondria. They are converted into acetyl-CoA, which enters the Krebs cycle and are oxidized to create energy.
Since in LCFAODs long chain fatty acids cannot be converted into ketones, supplementing the body with ketone bodies could be a promising therapeutic approach.
Research has shown that this approach could have a positive effect on a wide range of LCFAOD symptoms including motor development, hepatomegaly, and leukodystrophy.
Triheptanoin is a highly purified, 7-carbon chain triglyceride that can be used as a source of calories and fatty acids to treat children and adults with LCFAODs in lieu of long chain fatty acids.5
Once ingested triheptanoin is broken down into free heptanoate, which can be metabolized by short- and medium-chain fatty acid oxidation enzymes thereby bypassing the enzyme that are deficient in LCFAODs. The resulting acetyl-CoA enters the tricarboxylic acid (TCA) cycle and produce ATP or is diverted to the liver for ketogenesis, while propionyl-CoA is converted into succinyl-CoA, which supplies TCA cycle intermediates that may be missing in LCFAODs. This provides energy for gluconeogenesis and increases blood glucose and liver glycogen stores.4
The US Food and Drug Administration (FDA) approved triheptanoin under the brand name Dojolvi marketed by Ultragenyx for the treatment of children and adults with LCFAODs in 2020.6
Ultragenyx tested the safety and efficacy of the treatment in three clinical trials. The first two trials evaluated the side effects of the treatment while the third study evaluated the potential benefits of the treatment. It tested whether Dojolvi was able to reduce muscle pain and increase heart function as well as the amount of energy in patients, ages 7 and older with a confirmed diagnosis of VLCAD deficiency, CPT II deficiency, LCHAD deficiency, and TFP deficiency.7
The trials showed that Dojolvi reduced the mean annualized rate and duration of major clinical events (rhabdomyolysis, hypoglycemia, or cardiomyopathy). The most common adverse events associated with the treatment were diarrhea, abdominal pain or discomfort, and vomiting. Most of these were mild to moderate. Three patients had serious adverse events, which were diverticulitis, ileus, rhabdomyolysis, possibly due to the treatment.8
- 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
- Spiekerkoetter U, Lindner M, Santer R, et al. Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. J Inherit Metab Dis. 2009;32(4):498-505. doi:10.1007/s10545-009-1126-8
- Sun A, Merritt II JL. Orphan drugs in development for long-chain fatty acid oxidation disorders: challenges and progress. Orphan Drugs: Research and Reviews. 2015;5:33-41. doi:10.2147/ODRR.S63061
- Merritt JL, MacLeod E, Jurecka A, Hainline B. Clinical manifestations and management of fatty acid oxidation disorders. Rev Endocr Metab Disord. 21,479–493 (2020). doi:10.1007/s11154-020-09568-3
- Ultragenyx announces US 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.
- Study of triheptanoin for treatment of long-chain fatty acid oxidation disorder (triheptanoin). ClinicalTrials.gov. March 20, 2017.
- 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
Article reviewed by Kyle Habet, MD, on July 1, 201.