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Beta-Oxidation Cycle Disorders

By

Matt Demczko

, MD, Sidney Kimmel Medical College of Thomas Jefferson University

Last full review/revision Oct 2021
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Topic Resources

In these processes, there are numerous inherited defects, which typically manifest during fasting with hypoglycemia and metabolic acidosis Metabolic Acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3−), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly subnormal... read more ; some cause cardiomyopathy and muscle weakness.

Acetyl CoA is generated from fatty acids through repeated beta-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 fatty acids completely. Inheritance for all fatty acid oxidation defects is autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more .

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Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

This deficiency is the most common defect in the beta-oxidation cycle.

Clinical manifestations typically begin after 2 to 3 months of age and usually follow fasting (as little as 12 hours). Patients have vomiting and lethargy that may progress rapidly to seizures, coma, and sometimes death (which can also appear as sudden infant death syndrome). 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 of MCADD 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. MCADD is now included in routine neonatal screening Screening Tests for Newborns Screening recommendations for newborns vary by clinical context and state requirements. Blood typing is indicated when the mother has type O or Rh-negative blood or when minor blood antigens... read more in all states in the US.

Treatment of acute attacks is with 10% dextrose IV at 1.5 times the fluid maintenance rate (see Maintenance requirements Maintenance requirements Dehydration is significant depletion of body water and, to varying degrees, electrolytes. Symptoms and signs include thirst, lethargy, dry mucosa, decreased urine output, and, as the degree... read more ); 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 3-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 Diagnosis Preeclampsia is new-onset or worsening of existing hypertension with proteinuria after 20 weeks gestation. Eclampsia is unexplained generalized seizures in patients with preeclampsia. Diagnosis... read more (hemolysis, elevated liver enzymes, and low platelet count) during pregnancy.

Diagnosis of LCHADD 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 or by genetic testing. LCHADD is now included in routine neonatal screening Screening Tests for Newborns Screening recommendations for newborns vary by clinical context and state requirements. Blood typing is indicated when the mother has type O or Rh-negative blood or when minor blood antigens... read more in all states in the US.

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 of glutaric acidemia type II 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. DNA analysis can be confirmatory.

Treatment of glutaric acidemia type II is similar to that for MCADD, except that riboflavin may be effective in some patients.

More Information

The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

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