In beta-oxidation cycle disorders, 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.
See also Approach to the Patient With a Suspected Inherited Disorder of Metabolism and testing for suspected inherited disorders of metabolism.
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.
Порушення транспорту жирних кислот і мітохондріального окислення
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 |
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (201475*) | 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 |
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (600890*) | 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 | ||
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (201450*) | 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. | ||
Дефіцит середньоланцюгової ацил-КоА-дегідрогенази (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 unexpected infant death). 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 in all states in the United States.
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.
Дефіцит довголанцюгової 3-гідроксиацил-КоА-дегідрогенази (LCHADD)
This deficiency is the second 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. A mother whose fetus has LCHADD often has HELLP syndrome (hemolysis, elevated liver function tests, 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 in all states in the United States.
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.
Дефіцит дуже довголанцюгової ацил-КоА-дегідрогенази (VLCADD)
This deficiency is similar to LCHADD but is commonly associated with significant cardiomyopathy.
Глутарова ацидемія II типу
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.
Додаткова інформація
The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
Online Mendelian Inheritance in Man (OMIM) database: Complete gene, molecular, and chromosomal location information
