Long Chain Fatty Acid Oxidation Disorder (LCFAOD)


Long chain fatty acid oxidation disorders (LCFAOD) are a group of autosomal recessive genetic metabolic disorders characterized by the inability to metabolize fatty acids.1

There are 6 types of LCFAODs based on the causative genetic mutation, which either affects the ability of long chain fatty acids to enter the mitochondria or their beta oxidation once inside the mitochondria.2

The addition of fatty acid oxidation disorders to newborn screening programs in the US and other developed countries, has significantly increased the ability to diagnose LCFAODs early.3

There is currently no cure for LCFAODs and treatment options focus on dietary restriction and supplementations to reduce the risk of complications and life-threatening events.

Diagnostic Guidelines

The US Health Resources and Services Administration (HRSA)’s Maternal and Child Health Bureau commissioned the American College of Medical Genetics (ACMG) in 2002 to develop recommendations about which disorders should be included in newborn screening programs.4

In 2006, the ACMG published recommendations on inclusion criteria of genetic diseases to the programs. These included very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) and long-chain L-3-OH acyl-CoA dehydrogenase (LCHAD) deficiency, 2 types of LCFAODs.5 Later, other types of of LCFAODs were also added to the newscreen program.

Recommendations for the diagnostic workup of an abnormal newborn screening result have also been developed by a workgroup of experts. The workgroup developed ACTion (ACT) sheets and diagnostic algorithms to be used by healthcare professionals to follow-up a positive newborn screen.6 ACT sheets and algorithms are available for carnitine palmitoyltransferase 1 (CPT 1) deficiency, carnitine palmitoyltransferase 2 (CPT 2) or carnitine-acylcarnitine translocase (CACT) deficiency, LCHAD deficiency and trifunctional protein (TFP) deficiency among others and are updated on a regular basis.7

Management Guidelines

Management guidelines are based on diet and supplementation especially in case of metabolic crisis. Treatment recommendations have to be disease-specific.8

Chronic Management

Chronic management is based on diets that limit dependence on long chain fats as a source of energy. 

The dietary composition of infants should consist of medium-chain triglyceride (MCT), long chain fat, and supplements providing 40% to 45% of the energy intake. 

In severe cases of VLCAD, long chain fats should be restricted to 10% and MCT to 30% of the energy intake. In moderate or mild forms of the disease, half of the fat calories should come from MCT and half from long chain fats. Around 15% of energy intake should come from proteins.9

In children older than age 1 and in adults, 10% to 20% of total energy intake should come from long chain fats, while the rest come from MCT.

Genetic Metabolic Dietitians International (GMDI) provides a sample diet for a 2-week old patient with VLCAD deficiency. According to this, the infant’s total energy requirement is 410 kcal, 45% of which will come from fats (185 kcal) and 50% of these will be long chain fat (92 kcal). Since breast milk contains 4.6 g fat per 100 cc, the infant would need to consume 220 cc of breast milk. Half of the fat calories should be as MCT corresponding to 11 g. Around 12% to 15% of calories should come from protein and the diet should be supplemented with essential fatty acids, docosahexaenoic acid (DHA), and L-carnitine as necessary.2

Fasting Period

Most guidelines recommend that a maximum of 8 to 10 hours of overnight fasting is safe for most patients with regular meals and snacks during the day and before bed. However, as a general guideline infants, aged 0 to 4 months should be fed at least every 4 hours, and an extra hour can be left between feeds for every month thereafter. Cornstarch therapy may be necessary for some patients to prevent overnight hypoglycemia.2

Exercise

Children with VLCAD deficiency can take part in physical education or sports. However, it is recommended that they have a snack, such as a low-fat granola bar, whole grain bread, cereals or cornstarch, before exercise and during long exercises. MCT oil should be given 30 to 45 minutes before strenuous exercise and should be supplemented with carbohydrates and fluids every 2 hours.2 

Acute Management

Recommendations on the acute management of metabolic crisis vary greatly and there is no clear consensus. Because this occurs as a result of available glucose being depleted, glucose should be supplied to the body but the exact amount is not clear and depends on many factors such as the age of the patient, their level of stress, and any residual enzyme activity.11 However, in case of illness, a sick day protocol should be implemented. This includes increased fluid and caloric intake to prevent catalysis or, in more severe cases, intravenous dextrose solution containing 10% dextrose.11

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. Marsden D, Bedrosian DL, Vockley J. Impact of newborn screening on the reported incidence and clinical outcomes associated with medium- and long-chain fatty acid oxidation disorders. Genet Med. 23,816–829 (2021). doi:10.1038/s41436-020-01070-0
  4. 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
  5. Watson M, Mann M, Lloyd-Puryear M, et al. Executive summary. Genet Med. 8, 1–11(2006). doi:10.1097/01.gim.0000223891.82390.ad
  6. Lindner M, Hoffmann GF, Matern D. Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting. J Inherit Metab Dis. 2010;33(5):521-6. doi:10.1007/s10545-010-9076-8
  7. ACT Sheets and Algorithms. American College of Medical Genetics and Genomics. Accessed June 14, 2021.
  8. 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
  9. Roe CR, Roe DS, Wallace M, Garritson B. Choice of oils for essential fat supplements can enhance production of abnormal metabolites in fat oxidation disorders. Mol Genet Metab. 2007;92(4):346-50. doi:10.1016/j.ymgme.2007.07.012
  10. Very long chain acyl coa dehydrogenase deficiency (VLCADD) OMIM #201475. Genetic Metabolic Dietitians International.  Accessed June 14, 2021.
  11. Vockley J. Long-chain fatty acid oxidation disorders and current management strategies.  AJMC. August 14, 2020. doi.org/10.37765/ajmc.2020.88480

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

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