Fatty acids are the preferred energy source for the heart and an important energy source for skeletal muscle during prolonged exertion. Also, during fasting, the bulk of the body's energy needs must be supplied by fat metabolism. Using fat as an energy source requires catabolizing adipose tissue into free fatty acid and glycerol. The free fatty acid is metabolized in the liver and peripheral tissue via β-oxidation into acetyl CoA; the glycerol is used by the liver for triglyceride synthesis or for gluconeogenesis. Primary disorders of carnitine are discussed in Carnitine Deficiency, but secondary carnitine deficiency is a secondary biochemical feature of many organic acidemias and fatty acid oxidation defects. For a more complete listing of fatty acid and glycerol metabolism disorders, see Table Disorders of Fatty Acid, Very Long-Chain Fatty Acid, and Glycerol Metabolism.
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Disorders of the β-Oxidation Cycle
In these processes, there are numerous inherited defects, which typically manifest during fasting with hypoglycemia and acidosis; some cause cardiomyopathy and muscle weakness.
Acetyl CoA is generated from fatty acids through repeated β-oxidation cycles. Sets of 4 enzymes (an acyl dehydrogenase, a hydratase, a hydroxyacyl dehydrogenase, and a lyase) specific for different chain lengths (very long chain, long chain, medium chain, and short chain) are required to catabolize a long-chain fatty acid completely. Inheritance for all fatty acid oxidation defects is autosomal recessive.
Medium-chain acyl dehydrogenase deficiency (MCADD):
This deficiency is the most common defect in the β-oxidation cycle and has been incorporated into expanded neonatal screening in many states.
Clinical manifestations typically begin after 2 to 3 mo of age and usually follow fasting (as little as 12 h). Patients have vomiting and lethargy that may progress rapidly to seizures, coma, and sometimes death (which can also appear as SIDS). During attacks, patients have hypoglycemia, hyperammonemia, and unexpectedly low urinary and serum ketones. Metabolic acidosis is often present but may be a late manifestation.
Diagnosis is by detecting medium-chain fatty acid conjugates of carnitine in plasma or glycine in urine or by detecting enzyme deficiency in cultured fibroblasts; however, DNA testing can confirm most cases.
Treatment of acute attacks is with 10% dextrose IV at 1.5 times the fluid maintenance rate (see Maintenance requirements); some clinicians also advocate carnitine supplementation during acute episodes. Prevention is a low-fat, high-carbohydrate diet and avoidance of prolonged fasting. Cornstarch therapy is often used to provide a margin of safety during overnight fasting.
Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD):
This deficiency is the 2nd most common fatty acid oxidation defect. It shares many features of MCADD, but patients may also have cardiomyopathy; rhabdomyolysis, massive creatine kinase elevations, and myoglobinuria with muscle exertion; peripheral neuropathy; and abnormal liver function. Mothers with an LCHADD fetus often have HELLP syndrome (hemolysis, elevated liver enzymes, low platelets—see Diagnosis) during pregnancy.
Diagnosis is based on the presence of excess long-chain hydroxy acids on organic acid analysis and on the presence of their carnitine conjugates in an acylcarnitine profile or glycine conjugates in an acylglycine profile. LCHADD can be confirmed by enzyme study in skin fibroblasts.
Treatment during acute exacerbations includes hydration, high-dose glucose, bed rest, urine alkalinization, and carnitine supplementation. Long-term treatment includes a high-carbohydrate diet, medium-chain triglyceride supplementation, and avoidance of fasting and strenuous exercise.
Very long-chain acyl-coA dehydrogenase deficiency (VLCADD):
This deficiency is similar to LCHADD but is commonly associated with significant cardiomyopathy.
Glutaric acidemia type II:
A defect in the transfer of electrons from the coenzyme of fatty acyl dehydrogenases to the electronic transport chain affects reactions involving fatty acids of all chain lengths (multiple acyl-coA dehydrogenase deficiency); oxidation of several amino acids is also affected.
Clinical manifestations thus include fasting hypoglycemia, severe metabolic acidosis, and hyperammonemia.
Diagnosis is by increased ethylmalonic, glutaric, 2- and 3-hydroxyglutaric, and other dicarboxylic acids in organic acid analysis, and glutaryl and isovaleryl and other acylcarnitines in tandem mass spectrometry studies. Enzyme deficiencies in skin fibroblasts can be confirmatory.
Treatment is similar to that for MCADD, except that riboflavin may be effective in some patients.
Disorders of Glycerol Metabolism
Glycerol is converted to glycerol-3-phosphate by the hepatic enzyme glycerol kinase; deficiency results in episodic vomiting, lethargy, and hypotonia.
Glycerol kinase deficiency is X-linked; many patients with this deficiency also have a chromosomal deletion that extends beyond the glycerol kinase gene into the contiguous gene region, which contains the genes for congenital adrenal hypoplasia and Duchenne muscular dystrophy. Thus, patients with glycerol kinase deficiency may have one or more of these disease entities.
Symptoms begin at any age and are usually accompanied by acidosis, hypoglycemia, and elevated blood and urine levels of glycerol.
Diagnosis is by detecting an elevated level of glycerol in serum and urine and is confirmed by DNA analysis.
Treatment is with a low-fat diet, but glucocorticoid replacement is critical for those with adrenal hypoplasia.
Last full review/revision February 2010 by Chin-To Fong, MD
Content last modified September 2013