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Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency.

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GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
2000 Apr 20 [updated 2015 Mar 5].

Excerpt

CLINICAL CHARACTERISTICS:

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes involved in mitochondrial fatty acid β-oxidation, which fuels hepatic ketogenesis, a major source of energy once hepatic glycogen stores become depleted during prolonged fasting and periods of higher energy demands. In a typical clinical scenario, a previously healthy child with MCAD deficiency presents with hypoketotic hypoglycemia, vomiting, and lethargy triggered by a common illness. Seizures may occur. Hepatomegaly and liver disease are often present during an acute episode, which can quickly progress to coma and death. Children are normal at birth and – if not identified through newborn screening – typically present between ages three and 24 months; later presentation, even into adulthood, is possible. The prognosis is excellent once the diagnosis is established and frequent feedings are instituted to avoid any prolonged period of fasting.

DIAGNOSIS/TESTING:

Diagnosis of MCAD deficiency requires the integrated interpretation of multiple analyses, including consideration of the clinical status of the affected individual (i.e., acutely symptomatic vs asymptomatic) at the time of sample collection. Initial testing should include plasma acylcarnitine analysis, urine organic acid analysis, and urine acylglycine analysis and their proper interpretation. Further confirmatory testing can be by identification of biallelic pathogenic variants in ACADM or additional biochemical genetic testing (i.e., determination of fatty acid β-oxidation flux in fibroblasts or measurement of MCAD enzyme activity in leukocytes, fibroblasts or other tissues).

MANAGEMENT:

Treatment of manifestations: Most important 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. Prevention of secondary complications: Weight control measures including proper nutrition and exercise. 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: Evaluate plasma acylcarnitines and urine acylglycines in sibs and parents to permit early diagnosis and treatment of previously asymptomatic at-risk family members.

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. The risk of being affected could be 50% if one of the parents is also affected. Because asymptomatic parents and sibs may have MCAD deficiency, biochemical evaluation and/or molecular genetic testing should be offered to both parents and all sibs. Because of the high carrier frequency for the ACADM p.Lys304Glu pathogenic variant in individuals of northern European origin, carrier testing should be offered to reproductive partners of individuals with MCAD deficiency. Prenatal testing for pregnancies at 25% or higher risk is possible by biochemical methods or, if both parental pathogenic allelic variants are known, by molecular genetic testing.

Copyright © 1993-2015, University of Washington, Seattle. All rights reserved.

PMID:
20301597
[PubMed]
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