Fatty Acid Oxidation Defects

 

Background

Defects of fatty acid oxidation are a group of very rare inborn errors of metabolism. The most common of these disorders, medium-chain-acyl-CoA dehydrogenase (MCAD) deficiency, occurs in 1:10,000 births.

                 
Fatty acids provide an important alternative source of fuel for the body, especially when glucose supplies are low (e.g., when fasting). 

 Fatty acids can be used directly for fuel by tissues including the heart, skeletal muscle, and gut. When oxidized by the liver to ketone bodies, fatty acids also provide a critical energy source for brain, especially when glucose is in short supply. Thus, a deficiency in the enzymes used for fatty acid beta-oxidation can be dangerous during hypoglycemic states.

 

Fatty Acid Metabolism

Fatty acids go through several steps of metabolism: a FFA (free fatty acid) in the cytoplasm is conjugated to coenzyme A to make fatty acyl-CoA, which then passes through the mitochondrial membranes via the “carnitine shuttle” (that is, conjugated to carnitine).

Once inside the mitochondrial matrix, the fatty acyl-CoA molecule detaches from carnitine and undergoes beta-oxidation, creating many molecules of acetyl-CoA which can be used as intermediates in the Krebs cycle or can go on to form ketone bodies.

Click HERE to view diagrams of the process of
fatty acid transport and oxidation.

Inside the mitochondria, different enzymes perform the job of beta-oxidation depending on how long the fatty acid is; for instance, medium-length fatty acids are oxidized by medium-chain-acyl-CoA dehydrogenase (MCAD), and very long fatty acids are oxidized by very long chain acyl-CoA dehydrogenase (VLCAD).

When one of these enzymes is missing, fatty acids of the corresponding length accumulate in body tissues.

There are as many fatty acid oxidation defect syndromes as there are enzymes involved.

Click HERE for a list of the syndromes
and which fatty acids accumulate. 

 

Presentatio

Because fatty acids are not utilized for fuel in great amounts when glucose is plentiful, fatty acid oxidation defects can be asymptomatic when the patient is not fasting and is under no increased metabolic demand (illness, trauma, vigorous exercise, etc.).

In infants and young children, fatty acids begin to be significantly oxidized after 12 hours of fasting, and in older children after 16-24 hours of fasting.

When this occurs, the classic presentation of a fatty acid oxidation deficiency is fasting hypoglycemia WITHOUT the expected accompanying increase in serum ketones. Even the first episode of hypoglycemia in these syndromes can be lethal; in fact, some deaths previously attributed to SIDS are actually thought to have been due to fasting hypoglycemia due to a fatty acid oxidation defect.

In many of these syndromes, including VLCAD deficiency, prolonged fasting can also lead to heart failure, liver failure, and skeletal muscle rhabdomyolosis due to fatty acid buildup in these tissues. MCAD deficiency is often described as having presenting symptoms similar to Reye’s syndrome (lethargy, hypotonia, persistent vomiting, hepatomegaly).

 

Diagnosis

As recommended by the American Academy of Family Physicians, all states include MCAD deficiency screening on their newborn screen. Some states, including Illinois, screen for other enzyme deficiencies as well.

In a fatty acid oxidation enzyme deficiency, fatty acids of the corresponding length will usually be elevated in the bloodstream. Because the hypoglycemia seen in fatty acid oxidation defects can be lethal and the buildup of fatty acids in tissue can cause organ failure, early diagnosis is imperative.

Click BELOW for the Illinios Department of Public Health Fact Sheet for Fatty Acid Oxidation Defects & Neonatal Screening

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Treatment

Treatment for fatty acid oxidation defects is centered on the avoidance of fasting. Some sources recommend keeping the patient’s blood sugar above 120 at all times.

Avoidance of fasting is often sufficient to prevent symptoms unless the patient experiences an acute illness, trauma, or other catabolic state.

In these instances, patients must be given a high-volume, low-fat, high-carbohydrate diet. In some such cases, patients must be hospitalized and given IV dextrose until the acutely increased metabolic demand diminishes.

Overall, prognosis for MCAD deficiency and most other fatty acid oxidation defects is excellent when caught at an early age and managed appropriately.

 

Resources & Support

Early identification on part of the provider and adequate education, follow up and support for famlies is crucial for these types of disorders. 

Listed below are various resources & sources of support for professionals and families alike:

 

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 NNSGRC is a project of the University of Texas Health Science Center at San Antonio (UTHSCSA) and serves as a focal point for national newborn screening and genetics activities and resources for professionals and families.

 

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FOD is a worldwide resource for families, friends, clinicians, researchers and others who would like to support, educate and provide a forum for the sharing of ideas and concerns for those whose lives have been touched by
a Fatty acid Oxidation Disorder.

 

References

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  4. Roe CR, Ding J. Mitochondrial fatty acid oxidation disorders. In: Metabolic and molecular bases of inherited disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 2001. p.2297.
  5. Spiekerkoetter U, Wood PA. Mitochondrial fatty acid oxidation disorders: pathophysiological studies in mouse models. J Inherit Metab Dis. 2010 October; 33(5): 539–546.
  6. Stanley CA, Hale DE, Coates PM, Hall CL, Corkey BE, Yang W, Kelley RI, Gonzales EL, Williamson JR, Baker L. Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels. Pediatr Res. 1983;17(11):877.
  7. Stanley CA, Hale DE. Genetic disorders of mitochondrial fatty acid oxidation. Curr Opin Pediatr. 1994;6(4):476.
  8. Sunehag A, Haymond MW. Etiology of hypoglycemia in infants and children. Up to Date. 2011 June; accessed 12/14/12.
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  10. Waisbren SE. Expanded Newborn Screening: Information and Resources for the Family Physician. Am Fam Physician. 2008 Apr 1;77(7):987-994.
  11. Wilcken B. Fatty acid oxidation disorders: outcome and long-term prognosis. J Inherit Metab Dis. 2010 Oct;33(5):501-6. doi: 10.1007/s10545-009-9001-1. Epub 2010 Jan 5.