Medium Chain Acyl-CoA Dehydrogenase Deficiency

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is the commonest fatty acid beta oxidation disorder, an autosomal recessive condition due to variants in ACADM (1p31), with a prevalence of about 1 in 10,000 to 20,000 (higher in people of Northern European descent). The common variant c.985A>G (p.K329E) is homozygous in about 80 to 90% of clinically presenting cases in Europeans.

During fasting and illness, mitochondrial oxidation of medium chain fatty acids is impaired, causing failure of ketogenesis, hypoketotic hypoglycaemia, accumulation of toxic medium chain acylcarnitines and hepatic dysfunction.

• Typically presents between 3 months and 3 years (earlier in neonates) after prolonged fasting, gastroenteritis, vomiting, or poor feeding; most are well between episodes
• Acute episode: vomiting, lethargy, hypotonia, seizures, coma, hypoketotic hypoglycaemia, hepatomegaly, hyperammonaemia, raised transaminases and coagulopathy (Reye like syndrome); cardiorespiratory arrest and sudden death (about 20 to 25% of first episodes were fatal before newborn screening)
• Adults: may present with episodes following alcohol, fasting, pregnancy or prolonged exercise, with rhabdomyolysis
• Long term outcomes with prevention: normal growth and development, but some have mild neurological sequelae after severe episodes

1. Newborn screening by tandem mass spectrometry: elevated octanoylcarnitine (C8; above about 0.3 micromol/L) with elevated C6, C10 and C10:1 and an elevated C8/C10 ratio (above 5 to 10).
2. Confirmatory: plasma acylcarnitine profile, urinary organic acids (hexanoylglycine, suberylglycine, phenylpropionylglycine), and ACADM sequencing (the K329E variant and others).
3. During an acute episode: hypoglycaemia with inappropriately low or absent ketones (urinary ketones low or negative), raised free fatty acid to ketone ratio, mild hyperammonaemia, elevated liver enzymes, and uric acid.
4. Fibroblast enzyme assay if genotype is uncertain. Fasting tests are contraindicated.

• Prevention of fasting: limit fasting according to age (up to 4 to 6 hours in the first months of life, 8 hours at 6 to 12 months, 10 to 12 hours in older children and adults, with a safe overnight fast limit of about 12 hours after age 2 years); frequent feeds, and uncooked cornstarch (1 to 2 g/kg) at bedtime for older children who cannot go through the night.
• Sick day regimen: during febrile illness, vomiting or poor intake, give frequent high carbohydrate drinks (10 to 15% glucose polymer solution, about 2 mL/kg/hour) every 2 to 3 hours including at night; if oral intake fails or vomiting persists, go to hospital promptly for IV 10% dextrose with electrolytes at 1.5 to 2 times maintenance (glucose infusion rate 6 to 8 mg/kg/min) until clinically well and eating; check glucose, ketones and electrolytes.
• Acute decompensation: IV dextrose bolus 2 mL/kg of 10% for hypoglycaemia, then glucose infusion, correction of electrolytes, avoidance of lipid emulsion infusions (including propofol in prolonged use), and ICU care for coma or cardiac involvement.
• Dietary guidance: avoid medium chain triglyceride (MCT) oil and ketogenic diets; a normal diet with moderately restricted fat in infants is not required (some use a mild fat restriction to 25 to 30% of energy).
• Carnitine supplementation: controversial; some give 50 to 100 mg/kg/day orally when free carnitine is low.
• Education: emergency letter, wrist band, and avoiding prolonged exercise without carbohydrate and alcohol in adults.
• Genetic counselling: 25% recurrence risk; test siblings (as asymptomatic siblings are at risk).