Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency - PubMed

In: GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.

2000 Apr 20 [updated 2024 Sep 26].

Clinical characteristics: Individuals with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency typically appear normal at birth, and many are diagnosed through newborn screening programs. Symptomatic individuals experience hypoketotic hypoglycemia in response to either prolonged fasting (e.g., weaning the infant from nighttime feedings) or during intercurrent and common infections (e.g., viral gastrointestinal or upper respiratory tract infections), which typically cause loss of appetite and increased energy requirements when fever is present. Untreated severe hypoglycemic episodes can be accompanied by seizures, vomiting, lethargy, coma, and death. Metabolic decompensation during these episodes can result in elevated liver transaminases and hyperammonemia. Individuals with MCAD deficiency who have experienced the effects of uncontrolled metabolic decompensation are also at risk for chronic myopathy. Early identification and avoidance of prolonged fasting can ameliorate these findings. However, children with MCAD deficiency are at risk for obesity after initiation of treatment due to the frequency of feeding.

Diagnosis/testing: The diagnosis of MCAD deficiency is established in a proband through biochemical testing (prominent accumulation of C8-acylcarnitine (octanoylcarnitine) with lesser elevations of C6-, C10-, and C10:1-acylcarnitines and elevated C8/C2 and C8/C10 ratios) AND/OR by identification of biallelic pathogenic variants in ACADM by molecular genetic testing OR by significantly reduced activity of MCAD activity in blood or cultured skin fibroblasts. Because of its relatively high sensitivity, ACADM molecular genetic testing can obviate the need for enzymatic testing, which is available only in limited academic centers.

Management: Treatment of manifestations: For routine daily treatment, fasting should be avoided and may require frequent feeding (every 2-3 hours) in infancy, overnight feeding, a bedtime snack, or 2 g/kg of uncooked cornstarch to maintain blood glucose levels during sleep. A normal, healthy diet containing no more than 30% of total energy from fat is recommended. All individuals with MCAD deficiency should avoid skipping meals and weight loss diets that recommend fasting. Prolonged or intense exercise should be covered by adequate carbohydrate intake and hydration. Intravenous glucose is recommended for surgical procedures that require several hours of fasting. Weight control measures such as regular education about proper nutrition and recommended physical exercise should be discussed to help avoid obesity. Standard treatment for developmental delay / aphasia, attention-deficit/hyperactivity disorder, and muscle weakness. For acute inpatient treatment, IV administration of glucose should be initiated immediately with 10% dextrose with appropriate electrolytes at a rate of 1.5 times maintenance rate or at 10-12 mg glucose/kg/minute to achieve and maintain a blood glucose level higher than 5 mmol/L, or between 120 and 170 mg/dL. Address electrolyte and pH imbalances with intravenous fluid management and initiate appropriate treatment for what triggered the metabolic stress.

Surveillance: Infants should establish care with a biochemical genetics clinic including a metabolic dietitian as soon as possible following a positive newborn screen. A metabolic dietician should be involved to ensure proper nutrition in terms of quality and quantity. Affected infants should be seen in team clinic in two to three months, then every six to 12 months if otherwise clinically well; however, the frequency of routine follow-up visits is individualized based on comfort level of the affected persons, their families, and health care providers. Routine assessments for growth, acquisition of developmental milestones, neurobehavioral issues, and secondary carnitine deficiency are recommended.

Agents/circumstances to avoid: Hypoglycemia; infant formulas, coconut oil, and other manufactured foods containing medium-chain triglycerides as the primary source of fat; popular high-fat/low-carbohydrate diets; alcohol consumption, in particular acute alcohol intoxication (e.g., binge drinking), which can elicit metabolic decompensation; aspirin.

Pregnancy management: Pregnant women who have MCAD deficiency must avoid catabolism. This is supported by several case reports describing carnitine deficiency, acute liver failure, and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) in pregnant women with MCAD deficiency.

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 and preimplantation genetic testing for MCAD deficiency are possible.

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