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Reference Material
Overview of Fatty Acid Metabolism Disorders
| Deficiency/Impairment | Accumulated Substance | Clinical Features |
|---|---|---|
| Medium-chain acyl-CoA dehydrogenase deficiency | Medium-chain fatty acids (acyl-CoAs) | Hypoketotic hypoglycemia, Liver dysfunction, Encephalopathy (lethargy, seizures, coma) |
| Long-chain hydroxyacyl-CoA dehydrogenase deficiency | Long-chain fatty acids | Cardiomyopathy, Peripheral neuropathy, Retinopathy, Skeletal myopathy, Rhabdomyolysis |
| Primary Carnitine Deficiency (Defective carnitine transporter) |
Long-chain fatty acids | Weakness, Lethargy, Dilated cardiomyopathy, Hypotonia |
| Carnitine palmitoyltransferase II deficiency | Long-chain acylcarnitines | Cardiomyopathy, Skeletal myopathy, Rhabdomyolysis, Hepatomegaly |
1. Fatty Acid Synthesis & Degradation
- Synthesis: Requires transport of citrate from mitochondria to cytosol. Predominantly occurs in liver, lactating mammary glands, adipose tissue.
Mnemonic: "Sytrate" = synthesis. - Degradation (Long-chain fatty acid): Requires carnitine-dependent transport into mitochondrial matrix.
Mnemonic: Carnitine = carnage of fatty acids.
2. Detailed Disorder Breakdown
Medium-chain acyl-CoA dehydrogenase deficiency
- Defect: Breakdown of medium-chain fatty acids.
- Pathophysiology: Deficiency → defective breakdown → elevated fatty acyl-CoA in blood → hypoketotic hypoglycemia.
- Triggers: Prolonged fasting, infection, exercise.
- Clinical: Vomiting, Lethargy, Seizures, Coma, Cardiopulmonary collapse.
- Labs: Hypoglycemia, ↓ Ketones, Hyperammonemia, Hyperuricemia, Metabolic acidosis.
- Treatment: Avoid fasting states.
- Complications: Fatty liver disease, Sudden death.
Long-chain hydroxyacyl-CoA dehydrogenase deficiency
- Defect: Long-chain fatty acid oxidation.
- Pathophysiology: Defective breakdown → toxic fatty acid intermediates → hypoketotic hypoglycemia.
- Clinical: Poor feeding, Growth faltering, Irritability, Lethargy. Onset in first few years.
- Labs: Hypoglycemia, ↓ Ketones, Hyperammonemia, Metabolic acidosis, ↑ 3-hydroxydicarboxylic acids in urine.
Primary Carnitine Deficiency
- Defect: Defective plasma-membrane carnitine transporter → renal loss + impaired uptake.
- Pathophysiology: Impaired entry of long-chain fatty acids into mitochondria → ↓ Energy/Ketones → Hypoketotic Hypoglycemia. Toxic accumulation of long-chain fatty acids in cytosol.
- Clinical: Weakness, Liver dysfunction, Dilated cardiomyopathy.
- Labs: ↓ Glucose, ↓ Ketones, Very low plasma carnitine.
Carnitine palmitoyltransferase II deficiency
- Defect: Impaired long-chain fatty acid oxidation in mitochondria.
- Pathophysiology: Carnitine cannot be removed from long-chain fatty acids → no oxidation. Accumulation of acylcarnitines.
- Clinical: Hepatomegaly, Cardiomyopathy, Muscle damage.
- Labs: Hypoglycemia, ↓ Ketones, ↓ Total/Free carnitine, ↑ Acylcarnitines, ↑ ALT/AST.
- Treatment: Diet low in long-chain fatty acids, high in medium-chain fatty acids + carbohydrates.