Long chain acyl-CoA dehydrogenase deficiency

🧬 Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a rare autosomal recessive disorder of fatty acid metabolism that prevents effective energy production from long-chain fats, particularly during fasting or metabolic stress. It is one of the key causes of acute fatty liver of pregnancy (AFLP) and neonatal hypoglycaemia syndromes.

🧠 About

• Inherited defect in fatty acid β-oxidation due to LCHAD enzyme deficiency, part of the mitochondrial trifunctional protein complex.
• Prevents the body from converting long-chain fats into energy, especially during periods of fasting, illness, or stress.
• Can present in neonates, infants, or children with metabolic decompensation, and may cause maternal complications in pregnancy (AFLP or HELLP).

🧬 Aetiology

• Autosomal recessive disorder due to mutations in the HADHA gene encoding long-chain 3-hydroxyacyl-CoA dehydrogenase.
• The defective enzyme prevents β-oxidation of long-chain fatty acids, leading to accumulation of toxic intermediates and energy deficiency in cardiac, skeletal muscle, and hepatic tissues.
• Carrier mothers may develop acute fatty liver of pregnancy when carrying an affected fetus.

⚠️ Clinical Features

• 🫀 Cardiomyopathy and skeletal myopathy.
• 🩸 Hypoketotic hypoglycaemia — low glucose without compensatory ketone production.
• 👁️ Pigmentary retinopathy and possible progressive vision loss.
• 🧒 Hepatomegaly, liver dysfunction, and recurrent vomiting in infants.
• ⚡ Metabolic crises triggered by fasting, infection, or cold exposure.
• ❗ Some cases present as sudden infant death syndrome (SIDS).
• 🤰 Mothers may experience AFLP or HELLP syndrome in pregnancy.

🧪 Investigations

• 🎯 Tandem mass spectrometry (MS/MS): detects abnormal acylcarnitine profile (↑ long-chain 3-hydroxyacylcarnitines C14–C18).
• 🧫 Urine organic acid analysis: elevated 3-hydroxy-dicarboxylic acids.
• 🧬 Genetic testing: confirms HADHA pathogenic variants.
• 💉 Liver function tests: may show elevated transaminases during crises.
• 🔬 Newborn screening: detects fatty acid oxidation defects via acylcarnitine profiling in many countries.

🧩 Differential Diagnosis

• Reye’s syndrome — both present with microvesicular fatty liver and hypoglycaemia, but Reye’s is usually post-viral and linked to aspirin use.
• Other fatty acid oxidation defects (MCAD, VLCAD deficiencies).

💊 Management

• 🍽️ Dietary management:
  • Low long-chain fat intake (13–39% of calories).
  • High medium-chain triglyceride (MCT) diet to bypass the metabolic block.
  • Protein above the age-specific reference intake.
  • Supplementation with essential fatty acids (linoleic, arachidonic, α-linolenic, and DHA).
• 🍼 Infants: frequent feeding to avoid fasting; bedtime complex carbohydrate snack in children and adults.
• 💧 Emergency care: IV glucose during illness or fasting to prevent hypoglycaemia.
• 🩺 Supplements: MCT oil or triheptanoin, carnitine if deficient.
• 🫁 Exercise: moderate, regular exercise; avoid prolonged or intense exertion.
• 🫀 Cardiac management: standard treatment for cardiomyopathy; monitor ECG and echocardiogram regularly.
• 🧠 Developmental support: occupational and physiotherapy if motor delay or muscle weakness occurs.
• 🤰 Maternal implications: carrier testing and pre-pregnancy counselling; monitor for signs of AFLP or HELLP in future pregnancies.

📚 References

• Spiekerkoetter U et al. Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. GeneReviews (updated 2021).
• Schwartz M et al. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical features and diagnosis. J Inherit Metab Dis. 2009;32(2):205–212.

💡 Teaching tip: In infants with recurrent hypoglycaemia, hepatomegaly, or cardiac dysfunction — always consider fatty acid oxidation defects. In mothers presenting with AFLP or HELLP, test the baby for LCHAD deficiency, as early dietary management is life-saving.