Long Chain Fatty Acid Oxidation Disorder (LCFAOD)


Long chain fatty acid oxidation disorder (LCFAOD) is the name given to a group of autosomal recessive genetic metabolic disorders characterized by the body’s inability to metabolize long chain fatty acids. This leads to the accumulation of long chain fatty acids and energy deficiency, which cause damage to different organs and systems in the body.1

There are 6 different types of LCFAODs caused by mutations in genes that encode for different enzymes that all play a role in long chain fatty acid metabolism. Some of these genes (CPT1A, SLC25A20, and CPT2) encode for enzymes that are involved in the carnitine shuttle of the long chain fatty acids into the mitochondria, while others (ACADVL, HADHA, and HADHB ) encode for enzymes that play a role in their beta oxidation once inside the mitochondria.2

Read more about Long chain fatty acid oxidation disorder etiology.

The symptoms of different types of LCFAODs overlap and include rhabdomyolysis induced by exercise, fasting, illness, severe hypoglycemia, hyperammonemia, cardiomyopathy, muscle weakness, hypotonia, and fatigue.1 

Long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency, two types of LCFAOD can also cause additional symptoms including retinopathy and peripheral neuropathy.2

Because the symptoms of each LCFAOD are similar to each other, the differential diagnosis of one type of disease includes the other types.

There are also other disorders, symptoms of which may be similar to those of LCFAOD. These include medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, glutaricaciduria II (GA II), and Reye syndrome.3

Acyl-CoA Dehydrogenase (MCAD) Deficiency

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common of the fatty acid oxidation disorders. It is caused by mutations in the ACADM gene encoding for the medium-chain acyl-CoA dehydrogenase enzyme, which normally catabolizes medium chain fatty acids.

Symptoms of MCAD deficiency include lethargy, emesis, hepatomegaly, seizures, coma, or sudden death due to cardiorespiratory arrest. These symptoms can be caused by hypoketotic hypoglycemia due to longer periods of fasting, illness, and metabolic stress, such as surgery. Secondary symptoms of the disease may include lasting muscle pain and weakness, exercise intolerance, aphasia, and attention deficit disorder due to damage to the brain during a metabolic crisis. 

Clinical findings of the disease may include fatty infiltration of the liver, secondary carnitine deficiency, and elevated levels of urinary organic acids.4

MCAD deficiency can be differentiated from LCFAODs, such as very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and late-onset carnitine palmitoyltransferase 2 (CPT II), deficiency based on in vitro fatty acid oxidation rate studies. Accordingly, the oxidation rate ratio of oleate over myristate is less than 0.6 in VLCAD disorder, between 0.7–1.3 in late-onset CPT II deficiency, and more than 1.3 in MCAD deficiency.5 

Genetic testing that identifies a mutation in the ACADM can help confirm a diagnosis of MCAD deficiency.4

Glutaricaciduria II (GA II)

Glutaricaciduria II (GA II), also known as multiple acyl-CoA dehydrogenase deficiency or ethylmalonic-adipic aciduria, is a genetic metabolic disorder that is characterized by impaired fatty acid oxidation and amino acid metabolism.6 

It can be caused by the deficiency of either 1 of 2 enzymes, which are normally involved in the recycling of  the acyl-CoA dehydrogenases, electron transfer flavoprotein, or electron transfer flavoprotein dehydrogenase. The disease can also be caused by mutations in genes encoding for enzymes involved in the uptake of riboflavin inside cells or their metabolism into flavin adenine dinucleotide.

Symptoms vary greatly depending on the age of onset and severity of the disease. In the neonatal form of the disease, patients may or may not have congenital abnormalities. Those with congenital abnormalities may present with macrocephaly, cardiomyopathy, and unusual facial features. 

Newborns with the disease who do not have any congenital abnormalities may present with severe hypoglycemia, respiratory distress, hypotonia, hepatomegaly, cardiomyopathy, and renal abnormalities.

In late-onset GA II, symptoms can appear anytime from childhood to adulthood and include muscle weakness, intermittent emesis, and hypoglycemia.

Diagnosis can be reached based on glutaric aciduria and molecular genetic testing.7 

Reye Syndrome

Reye syndrome is a condition of unknown etiology characterized by hepatic steatosis and acute encephalopathy. The symptoms of the disease include sudden and persistent emesis, elevated hepatic transaminase levels, severe disorientation, seizures, and coma.8

When urine and blood test results are not indicative of fatty acid oxidation disorders, Reye syndrome may be suspected. The syndrome can be triggered in infants and children by the use of aspirin to treat illnesses or infections such as influenza or chickenpox.9

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. Very long chain acyl co dehydrogenase deficiency (LCAD). National Organization for Rare Disorders. 2020. Accessed June 16, 2021.
  4. Medium chain acyl coa dehydrogenase deficiency. National Organization for Rare Disorders. 2018. Accessed June 16, 2021.
  5. Sim KG, Hammond J, Wilcken B. Strategies for the diagnosis of mitochondrial fatty acid beta-oxidation disorders. Clin Chim Acta. 2002;323(1-2):37-58. doi: 10.1016/s0009-8981(02)00182-1
  6. Sahai I, Garganta CL, Bailey J, et al. Newborn screening for glutaric aciduria-II: the new england experience. JIMD Rep. 2014; 13: 1–14. doi:10.1007/8904_2013_262
  7. Glutaric aciduria type II. National Organization for Rare Disorders. 2019. Accessed June 16, 2021.
  8. Reye syndrome. National Organization for Rare Disorders. 2020. Accessed June 16, 2021.
  9. Reye’s syndrome. Mayo Clinic. Accessed June 16, 2021.

Article reviewed by Harshi Dhingra, MD, on July 1, 2021.

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