🧬 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
💡 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.
