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 (LCFAODs) is a group of autosomal recessive genetic metabolic disorders characterized by the failure of mitochondrial beta-oxidation of long chain fatty acids and their carnitine shuttle into the mitochondria.
This leads to rhabdomyolysis, liver dysfunction, and cardiomyopathy soon after birth and during infancy and can lead to coma and sudden death. In some instances, the symptoms of the disease appear in adolescence or adulthood.1
It is estimated that the mortality rate of LCFAODs is between 60% to 95%.2 With the introduction of fatty acid oxidase deficiency disorders in newborn screening programs in the US and other developed countries, the prognosis of the disease has improved dramatically.3
Types of Long Chain Fatty Acid Oxidation Disorders
There are 6 types of LCFAODs. 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.4
CPT1, CACT, and CPT2 play a role in the carnitine shuttle of long chain fatty acids into the mitochondria, whereas VLCAD and LCHAD, which are part of the TFP complex, are involved in the beta-oxidation of long chain fatty acids inside the mitochondria.
Prognosis of CPT1 Deficiency
CPT1 deficiency caused by a mutation in the CPT1A gene causes hypoketotic hypoglycemia, liver dysfunction, and rapid progression to liver failure. However, hypoglycemia in the neonate is rare.
A form of CPT1 deficiency, which is more prevalent in Arctic populations, is seen in association with impaired fasting intolerance and greater infant mortality.3
Prognosis of CACT Deficiency
In its most severe cases, CACT deficiency, caused by mutations in the SLC25A20 gene, which changes the structure of the CACT protein leads to severe cardiomyopathy in the neonate as well as ventricular dysrhythmias, hypoglycemia, and hyperammonemia, which can lead to sudden death.
Even with newborn screening, the disease has a poor prognosis with patients experiencing developmental delays, seizures, and complications even with treatment, which are associated with high mortality.3
Prognosis of CPT2 Deficiency
A rare and severe form of this disease can cause death within the first few days of life. Affected infants have congenital problems such as dysmorphic facies, renal dysgenesis, and neuronal migration malformations. They often experience hypotonia, cardiomyopathy, arrhythmias, and seizures.
More commonly, the disease affects adolescents or adults. These patients have exercise intolerance and episodes of rhabdomyolysis, which are associated with a risk of renal failure.5
The disease is caused by mutations in the CPT2 gene.
Prognosis of VLCAD Deficiency
The prognosis of VLCAD deficiency is much less certain. Infants usually present with cardiomyopathy and may experience sudden death. Other complications include dilated cardiomyopathy, hepatomegaly, and hypotonia. If they survive past age 1, patients have hypoketotic hypoglycemia and rhabdomyolysis. The disease is caused by mutations in the ACADVL gene.6
Prognosis of LCHAD and TFP Deficiency
The prognosis of these two types of LCFAODs is the worst. They cause two additional symptoms, which are progressive pigmentary retinopathy and progressive peripheral neuropathy.
Most patients present with hypoketotic hypoglycemia. Others may have hypotonia, liver disease, or failure to thrive. Affected babies may also cause problems to the mother during pregnancy such as hemolysis, elevated liver enzymes, and low platelets.6
LCHAD deficiency is caused by mutations in the HADHA gene while for a patient to have TFP deficiency, they must have a mutation in both the HADHA and HADHB genes.
Newborn screening tests are done for carnitine update defects, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, trifunctional protein (TFP) deficiency, and very-long-chain acyl-coenzyme A (CoA) dehydrogenase (VLCAD) deficiency.7
Early diagnosis through newborn screening can ensure the necessary dietary restrictions and supplementations are implemented and can dramatically improve prognosis.
However, genotype/phenotype correlations are not certain, and in most cases, enzyme activity does not always correlate with disease severity.6
Other Factors That Can Improve Prognosis
Dietary management of the disease to avoid catabolism can have a positive impact on prognosis. Patients’ diet can also be supplemented with medium-chain fat and this can also have a positive effect on prognosis.6
Lifestyle changes such as avoiding fasting and severe exercise, especially in the case of late-onset phenotype can reduce rhabdomyolysis and improve prognosis.
Triheptanoin (Dojolvi™) is a calorie and fatty acid source for the treatment of children and adults with LCFAOD approved by the US Food and Drug Administration (FDA) in 2020.8
- 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
- Vockley J, Marsden D, McCracken E, et al. Long-Term Major Clinical Outcomes in Patients With Long Chain Fatty Acid Oxidation Disorders Before and After Transition to Triheptanoin Treatment—A Retrospective Chart Review. Mol Genet Metab. 2015;116(0): 53–60. doi:10.1016/j.ymgme.2015.06.006
- Merritt JL, Norris M, Kanungo S. Fatty acid oxidation disorders. Ann Transl Med. 2018;6(24): 473. doi:10.21037/atm.2018.10.57
- 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
- Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet. 2006;15;142C(2):77-85. doi:10.1002/ajmg.c.30087
- Wilcken B. Fatty acid oxidation disorders: outcome and long-term prognosis. J Inherit Metab Dis. 2010;33(5):501-6. doi: 10.1007/s10545-009-9001-1
- Treatment of fatty acid oxidation disorders. March of Dimes. January 2014. Accessed June 7, 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.