Medium chain acyl-CoA dehydrogenase deficiency

Medium chain acyl-CoA dehydrogenase deficiency (MCADD), also known as MCAD deficiency, is one of the most common inherited disorders of fatty acid oxidation. It is caused by mutations in the ACADM gene, which encodes the medium chain acyl-CoA dehydrogenase enzyme. This enzyme is essential for the breakdown (beta-oxidation) of medium-chain fatty acids (6 to 12 carbons in length) within the mitochondria. When the body relies on fat for energy — such as during fasting, illness, or prolonged exercise — individuals with MCADD cannot adequately metabolize these fatty acids, leading to a dangerous energy deficit and accumulation of toxic metabolic intermediates. The condition primarily affects the metabolic and neurological systems. Key clinical features include hypoketotic hypoglycemia (low blood sugar with inappropriately low ketone production), lethargy, vomiting, seizures, and in severe cases, coma or sudden death. Liver dysfunction with hepatomegaly and elevated liver enzymes may also occur during metabolic crises. The most common disease-causing variant is c.985A>G (p.K329E) in the ACADM gene, which accounts for approximately 80% of alleles in affected individuals of Northern European descent. Symptoms typically present between 3 months and 2 years of age, often triggered by a common childhood illness or prolonged fasting. MCADD is now included in newborn screening programs in many countries, which has dramatically improved outcomes by enabling early diagnosis and preventive management. Treatment centers on avoidance of prolonged fasting, ensuring adequate caloric intake (particularly carbohydrates) during illness, and emergency management protocols with intravenous glucose during metabolic crises. With early diagnosis through newborn screening and adherence to dietary precautions, the prognosis is generally excellent, and most individuals can lead normal, healthy lives. L-carnitine supplementation may be considered in some cases, though its routine use remains debated.

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