Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency

Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is an autosomal recessive disorder of mitochondrial fatty acid oxidation due to biallelic variants in HADHA, most often the common c.1528G>C (p.Glu510Gln) variant. It causes hypoketotic hypoglycaemia, cardiomyopathy, rhabdomyolysis, pigmentary retinopathy and peripheral neuropathy, and is associated with maternal liver disease in pregnancy.

Pathophysiology. The mitochondrial trifunctional protein catalyses the last three steps of long chain fatty acid oxidation, and HADHA encodes its alpha subunit with the LCHAD domain. Loss of activity causes accumulation of long chain 3-hydroxyacylcarnitines, which are toxic to retina, liver, heart and muscle.

Retinopathy and neuropathy progress despite good metabolic control.

Fatty acid oxidation is the main energy source during fasting, so illness is dangerous.

• Hypoketotic hypoglycaemia with encephalopathy in infancy
• Hepatic dysfunction, cholestasis and hepatomegaly
• Cardiomyopathy and arrhythmia, which can cause sudden death
• Muscle weakness, rhabdomyolysis with fasting or exercise
• Pigmentary retinopathy with chorioretinal atrophy, progressive visual loss and myopia
• Peripheral neuropathy
• Failure to thrive
• Mothers carrying an affected foetus: acute fatty liver of pregnancy, and HELLP syndrome
• Metabolic crises with infection, with lactic acidosis

• Acylcarnitine profile: raised C16-OH, C18-OH and C18:1-OH, with low free carnitine. Newborn screening can detect the disease.
• HADHA sequencing with deletion and duplication analysis; p.Glu510Gln is tested first.
• Enzyme activity of LCHAD in fibroblasts.
• Glucose, ketones, ammonia, lactate, creatine kinase and liver tests during illness.
• Urine organic acids: raised 3-hydroxydicarboxylic acids.
• Echocardiography, ECG, and ophthalmology (including electroretinography).
• Nerve conduction studies when neuropathy is suspected.

Differential diagnosis.

• Mitochondrial trifunctional protein deficiency (HADHB)
• Very long chain acyl-CoA dehydrogenase deficiency and CPT II deficiency
• Medium chain acyl-CoA dehydrogenase deficiency
• Other causes of hypoketotic hypoglycaemia
• Acute fatty liver of pregnancy and HELLP syndrome from other causes

• Diet: restrict long chain fat to 25 to 30% of energy, supplement with medium chain triglycerides 10 to 20% of energy, or triheptanoin up to 35% of daily calories in 4 divided doses, and give frequent meals. Cornstarch 1 to 2 g/kg at night in older children to prevent fasting.
• Fasting limits: maximum fasting of 3 to 4 hours in infants under 6 months, 6 hours at 6 to 12 months, and 8 hours in toddlers and children, with night feeds or gastrostomy if needed.
• Essential fatty acids: docosahexaenoic acid 60 to 100 mg daily, and linoleic acid by diet.
• Acute illness: emergency regimen of 10% dextrose with an infusion of 8 to 10 mg/kg/min, no fat or lipid emulsions, and admission for any vomiting or fever.
• Cardiomyopathy: enalapril 0.1 mg/kg daily increasing to 0.5 mg/kg daily, and furosemide 1 mg/kg once or twice daily for fluid overload.
• Rhabdomyolysis: intravenous glucose, hydration with urine output at least 2 mL/kg/hour, and monitoring of potassium and creatinine.
• Retinopathy and neuropathy: ophthalmology review every 6 to 12 months, low vision support and neuropathic pain treatment with gabapentin 100 mg three times daily increasing to 600 mg three times daily (adults).
• Carnitine: use is controversial and should be limited to specialist care.
• Drug avoidance: propofol infusions and prolonged fasting.
• Pregnancy: a woman carrying an affected foetus is at risk of acute fatty liver of pregnancy and HELLP syndrome, so monitor liver tests and blood pressure at least every 2 weeks from 28 weeks, and deliver if liver dysfunction develops.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis available.

Special groups.

• Mothers with a family history: perform foetal genotyping or test partners and plan monitoring for acute fatty liver of pregnancy.

Monitoring. Growth, creatine kinase and acylcarnitines every 3 months in childhood. Echocardiography every 6 to 12 months, ophthalmology review every 6 to 12 months, and dietary review at each visit.

Referral and escalation. Refer to clinical genetics, metabolic medicine, cardiology and ophthalmology. Emergency for hypoglycaemia, encephalopathy, arrhythmia or maternal liver dysfunction in pregnancy.