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Beta-Oxidation Cycle Disorders

By

Matt Demczko

, MD, Sidney Kimmel Medical College of Thomas Jefferson University

Last full review/revision Apr 2020| Content last modified Apr 2020
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In these processes, there are numerous inherited defects, which typically manifest during fasting with hypoglycemia and metabolic acidosis; some cause cardiomyopathy and muscle weakness.

Beta-oxidation cycle disorders (see the table) are among the fatty acid and glycerol metabolism disorders.

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.

Table
icon

Fatty Acid Transport and Mitochondrial Oxidation Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Comments

Systemic primary carnitine deficiency (212140*)

Plasma membrane carnitine transport OCTN2

Biochemical profile: High urinary carnitine excretion despite very low plasma carnitine, absence of significant dicarboxylic aciduria

Clinical features: Hypoketotic hypoglycemia, fasting intolerance with hypotonia, depressed central nervous system, apnea, seizures, dilated cardiomyopathy, developmental delay

Treatment: L-Carnitine

Long-chain fatty acid transport deficiency (603376*)

Biochemical profile: Low to normal free carnitine; during acute episodes, elevated plasma C8–C18 acylcarnitine esters

Clinical features: Episodic acute liver failure, hyperammonemia, encephalopathy

Treatment: Liver transplantation

Carnitine palmitoyltransferase I (CPT-I) deficiency (255120*)

CPT-I

Biochemical profile: Normal to elevated total and free plasma carnitine, no dicarboxylic aciduria

Clinical features: Fasting intolerance, hypoketotic hypoglycemia, hepatomegaly, seizures, coma, elevated creatine kinase

Treatment: Avoidance of fasting; frequent feeding; during acute episodes, high-dose glucose; replacement of long-chain dietary fat with medium-chain fat

Carnitine/acylcarnitine translocase deficiency (212138*)

Carnitine/acylcarnitine translocase

Biochemical profile: Low total plasma carnitine, with most conjugated to long-chain fatty acids; elevated C16 carnitine ester

Clinical features: In the neonatal form, fasting intolerance with hypoglycemic coma, vomiting, weakness, cardiomyopathy, arrhythmia, mild hyperammonemia

In the mild form, recurrent hypoglycemia with no cardiac involvement

Treatment: Avoidance of fasting; frequent feeding; if plasma level is low, carnitine; during acute episodes, high-dose glucose

Carnitine palmitoyltransferase II (CPT-II) deficiency (255110*, 600649* [infantile form], 608836* [lethal neonatal form])

CPT-II

Biochemical profile: Elevated C16 carnitine ester

In the classical muscle form, carnitine usually normal

In the severe form, low total plasma carnitine, with most conjugated to long-chain fatty acids

Clinical features: In the classical muscle form, presentation in adulthood with muscle pain and episodic myoglobinuria and weakness after prolonged exercise, fasting, intercurrent illness, or stress

In the severe form, presentation in neonatal period or infancy with hypoketotic hypoglycemia, cardiomyopathy, arrhythmia, hepatomegaly, coma, or seizures

Treatment: Avoidance of fasting; frequent feeding; if plasma level is low, carnitine; during acute episodes, high-dose glucose

VLCAD

Biochemical profile: Elevated saturated and unsaturated C14–C18 acylcarnitine esters, elevated urinary C6–C14 dicarboxylic acids

Clinical features: In the VLCAD-C type, arrhythmia, hypertrophic cardiomyopathy, sudden death

In the VLCAD-H type, recurrent hypoketotic hypoglycemia, encephalopathy, mild acidosis, mild hepatomegaly, hyperammonemia, elevated liver enzymes

Treatment: Avoidance of fasting; high-carbohydrate diet; carnitine; medium-chain triglycerides; during acute episodes, high-dose glucose

LCHAD

Biochemical profile: Elevated saturated and unsaturated C16–C18 acylcarnitine esters, elevated urinary C6–C14 3-hydroxydicarboxylic acids

Clinical features: Fasting-induced hypoketotic hypoglycemia, exercise-induced rhabdomyolysis, cardiomyopathy, cholestatic liver disease, retinopathy, maternal HELLP syndrome

Treatment: Avoidance of fasting; high-carbohydrate diet; carnitine; medium-chain triglycerides; during acute episodes, high-dose glucose

For retinopathy, docosahexanoic acid possibly useful

Mitochondrial trifunctional protein (TFP) deficiency (609015*)

Mitochondrial TFP

Biochemical profile: Similar to LCHAD deficiency

Clinical features: Liver failure, cardiomyopathy, fasting hypoglycemia, myopathy, sudden death

Treatment: Similar to that for LCHAD deficiency

Alpha-subunit

Beta-subunit

MCAD

Biochemical profile: Elevated saturated and unsaturated C8–C10 acylcarnitine esters; elevated urinary C6–C10 dicarboxylic acids, suberylglycine, and hexanoylglycine; low free carnitine

Clinical features: Episodic hypoketotic hypoglycemia after fasting, vomiting, hepatomegaly, lethargy, coma, acidosis, sudden infant death syndrome, Reye-like syndrome

Treatment: Avoidance of fasting; frequent feeding, including bedtime snacks; high-carbohydrate diet; carnitine; during acute episodes, high-dose glucose

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency (201470*)

SCAD

Biochemical profile: In the neonatal form, intermittent ethylmalonic aciduria

In the chronic form, low muscle carnitine

Clinical features: In the neonatal form, neonatal acidosis, vomiting, growth and developmental delay

In the chronic form, progressive myopathy

Treatment: Avoidance of fasting

Glutaric aciduria type II (231680*)

Electron transfer flavoprotein (ETF)

Biochemical profile: Elevated urinary ethylmalonic, glutaric, 2-hydroxyglutaric, 3-hydroxyisovaleric, and C6–C10 dicarboxylic acids and isovalerylglycine; elevated glutarylcarnitine, isovalerylcarnitine, and straight-chain acylcarnitine esters of C4, C8, C10, C10:1, and C12 fatty acids; low serum carnitine; increased serum sarcosine

Clinical features: Fasting hypoketotic hypoglycemia, acidosis, sudden death, central nervous system anomalies, myopathy, possibly liver and cardiac involvement

Treatment: Avoidance of fasting; frequent feeding; carnitine; riboflavin; during acute episodes, high-dose glucose

Alpha-subunit

Beta-subunit

ETF:ubiquinone oxidoreductase (ETF:QO)

Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency (601609*)

SCHAD

Biochemical profile: Ketotic C8–C14 3-hydroxydicarboxylic aciduria

Clinical features: Recurrent myoglobinuria, ketonuria, hypoglycemia, encephalopathy, cardiomyopathy

Treatment: Avoidance of fasting

Short/medium-chain 3-hydroxyacyl-CoA dehydrogenase (S/MCHAD) deficiency

S/MCHAD

Biochemical profile: Marked elevation of MCHADs and acylcarnitines

Clinical features: Liver failure, encephalopathy

Treatment: Avoidance of fasting

Medium-chain 3-ketoacyl-CoA thiolase (MCKAT) deficiency (602199*)

MCKAT

Biochemical profile: Lactic aciduria, ketosis, elevated urinary C4–C12 dicarboxylic aciduria (especially C10 and C12)

Clinical features: Fasting intolerance, vomiting, dehydration, metabolic acidosis, liver dysfunction, rhabdomyolysis

Treatment: Avoidance of fasting

2,4-Dienoyl-CoA reductase deficiency (222745*)

2,4-Dienoyl-CoA reductase

Biochemical profile: Hyperlysinemia, low plasma carnitine, 2-trans,4-cis decadienoylcarnitine in plasma and urine

Clinical features: Neonatal hypotonia, respiratory acidosis

Treatment: Not established

* For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man® (OMIM®) database.

HELLP = hemolysis, elevated liver enzymes, and low platelet count.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

This deficiency is the most common defect in the beta-oxidation cycle and has been incorporated into expanded neonatal screening in many states.

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.

Treatment of acute attacks is with 10% dextrose IV at 1.5 times the fluid maintenance rate (see Dehydration in Children : 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 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 (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.

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.

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