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Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

Abstract
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes involved in mitochondrial fatty acid β-oxidation. Fatty acid β-oxidation fuels hepatic ketogenesis, which provides a major source of energy once hepatic glycogen stores become depleted during prolonged fasting and periods of higher energy demands. MCAD deficiency is the most common disorder of fatty acid β-oxidation and one of the most common inborn errors of metabolism. Most children are now diagnosed through newborn screening. Clinical symptoms in a previously apparently healthy child with MCAD deficiency include hypoketotic hypoglycemia and vomiting that may progress to lethargy, seizures, and coma triggered by a common illness. Hepatomegaly and liver disease are often present during an acute episode. Children appear normal at birth and – if not identified through newborn screening – typically present between age three and 24 months, although presentation even as late as adulthood is possible. The prognosis is excellent once the diagnosis is established and frequent feedings are instituted to avoid any prolonged periods of fasting.The diagnosis of MCAD deficiency is established in a proband with confirmatory biochemical testing results and biallelic pathogenic variants in ACADM identified on molecular genetic testing. Diagnostic testing is typically initiated after either a positive newborn screening result or suggestive biochemical testing in a previously healthy individual who develops symptoms. Biochemical and molecular diagnostic methods for MCAD deficiency are sensitive enough to identify asymptomatic affected individuals without needing provocative tests. Assays to determine residual enzyme activity are possible but not routinely necessary and not clinically available in many regions.Treatment of manifestations: The most important intervention is giving simple carbohydrates by mouth (e.g., glucose tablets or sweetened, non-diet beverages) or IV if needed to reverse catabolism and sustain anabolism. Prevention of primary manifestations: The mainstay is avoidance of fasting: infants require frequent feedings; toddlers could be placed on a relatively low-fat diet (e.g., <30% of total energy from fat) and could receive 2 g/kg of uncooked cornstarch at bedtime to ensure sufficient glucose overnight. Agents/circumstances to avoid: Hypoglycemia (e.g., from excessive fasting); infant formulas that contain medium-chain triglycerides as the primary source of fat. Evaluation of relatives at risk: If the ACADM pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs and offspring of the proband. If the ACADM pathogenic variants in the family are not known, plasma acylcarnitine and urine acylglycine analysis can be used to clarify the disease status.MCAD deficiency is inherited in an autosomal recessive manner. At conception, the sibs of an affected individual are at a 25% risk of being affected, a 50% risk of being asymptomatic carriers, and a 25% risk of being unaffected and not carriers. Because of the high carrier frequency for the ACADM c.985A>G pathogenic variant in individuals of northern European origin, carrier testing should be discussed with reproductive partners of individuals with MCAD deficiency. Once both ACADM pathogenic variants have been identified in an affected family member, prenatal molecular genetic testing for a pregnancy at increased risk and preimplantation genetic diagnosis for MCAD deficiency are possible.

Publisher

University of Washington, Seattle
Seattle (WA)

Language

eng

PubMed ID

20301597

Citation

Merritt JL, Chang IJ: Medium-Chain Acyl-Coenzyme a Dehydrogenase Deficiency.GeneReviews®. Edited by Adam MP, et al: University of Washington, Seattle, 1993, Seattle (WA).
Merritt JL, Chang IJ. Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. Edited by Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993.
Merritt JL & Chang IJ. (1993). Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. Edited by Adam MP & Ardinger HH & Pagon RA, et al. In GeneReviews®. Seattle (WA): University of Washington, Seattle;
Merritt JL, Chang IJ. Edited by Adam MP, et al. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993.
* Article titles in AMA citation format should be in sentence-case
TY - CHAP T1 - Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency BT - GeneReviews® A1 - Merritt,J Lawrence,2nd AU - Chang,Irene J, Y1 - 1993/// PY - 2019/6/27/pubmed PY - 2019/6/27/medline PY - 2010/3/20/entrez KW - MCAD Deficiency KW - MCAD Deficiency KW - Medium-chain specific acyl-CoA dehydrogenase, mitochondrial KW - ACADM KW - Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency N2 - CLINICAL CHARACTERISTICS: Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes involved in mitochondrial fatty acid β-oxidation. Fatty acid β-oxidation fuels hepatic ketogenesis, which provides a major source of energy once hepatic glycogen stores become depleted during prolonged fasting and periods of higher energy demands. MCAD deficiency is the most common disorder of fatty acid β-oxidation and one of the most common inborn errors of metabolism. Most children are now diagnosed through newborn screening. Clinical symptoms in a previously apparently healthy child with MCAD deficiency include hypoketotic hypoglycemia and vomiting that may progress to lethargy, seizures, and coma triggered by a common illness. Hepatomegaly and liver disease are often present during an acute episode. Children appear normal at birth and – if not identified through newborn screening – typically present between age three and 24 months, although presentation even as late as adulthood is possible. The prognosis is excellent once the diagnosis is established and frequent feedings are instituted to avoid any prolonged periods of fasting. DIAGNOSIS/TESTING: The diagnosis of MCAD deficiency is established in a proband with confirmatory biochemical testing results and biallelic pathogenic variants in ACADM identified on molecular genetic testing. Diagnostic testing is typically initiated after either a positive newborn screening result or suggestive biochemical testing in a previously healthy individual who develops symptoms. Biochemical and molecular diagnostic methods for MCAD deficiency are sensitive enough to identify asymptomatic affected individuals without needing provocative tests. Assays to determine residual enzyme activity are possible but not routinely necessary and not clinically available in many regions. MANAGEMENT: Treatment of manifestations: The most important intervention is giving simple carbohydrates by mouth (e.g., glucose tablets or sweetened, non-diet beverages) or IV if needed to reverse catabolism and sustain anabolism. Prevention of primary manifestations: The mainstay is avoidance of fasting: infants require frequent feedings; toddlers could be placed on a relatively low-fat diet (e.g., <30% of total energy from fat) and could receive 2 g/kg of uncooked cornstarch at bedtime to ensure sufficient glucose overnight. Agents/circumstances to avoid: Hypoglycemia (e.g., from excessive fasting); infant formulas that contain medium-chain triglycerides as the primary source of fat. Evaluation of relatives at risk: If the ACADM pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs and offspring of the proband. If the ACADM pathogenic variants in the family are not known, plasma acylcarnitine and urine acylglycine analysis can be used to clarify the disease status. GENETIC COUNSELING: MCAD deficiency is inherited in an autosomal recessive manner. At conception, the sibs of an affected individual are at a 25% risk of being affected, a 50% risk of being asymptomatic carriers, and a 25% risk of being unaffected and not carriers. Because of the high carrier frequency for the ACADM c.985A>G pathogenic variant in individuals of northern European origin, carrier testing should be discussed with reproductive partners of individuals with MCAD deficiency. Once both ACADM pathogenic variants have been identified in an affected family member, prenatal molecular genetic testing for a pregnancy at increased risk and preimplantation genetic diagnosis for MCAD deficiency are possible. PB - University of Washington, Seattle CY - Seattle (WA) UR - https://www.unboundmedicine.com/medline/citation/20301597/GeneReviews®:_Medium-Chain_Acyl-Coenzyme_A_Dehydrogenase_Deficiency L2 - https://www.ncbi.nlm.nih.gov/books/NBK1424 DB - PRIME DP - Unbound Medicine ER -