A 34-year-old woman with a family history of metabolic disorder presents with recurrent episodes of hypoketotic hypoglycemia, hepatomegaly, and muscle weakness. Genetic testing reveals a deficiency in a mitochondrial enzyme involved in fatty acid oxidation. Which is the most common enzymatic defect causing this clinical presentation?

Explanation

## Most Common Fatty Acid Oxidation Disorder **Key Point:** Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid oxidation, accounting for approximately 1 in 6,000 to 1 in 17,000 live births in developed countries. ## Clinical Features of MCAD Deficiency **High-Yield:** The classic presentation includes: - Hypoketotic hypoglycemia (the hallmark — low glucose WITHOUT appropriate ketone elevation) - Hepatomegaly with fatty infiltration - Recurrent episodes triggered by fasting, illness, or metabolic stress - Elevated dicarboxylic acids in urine (characteristic finding) - Normal development if diagnosed early and managed with frequent feeds ## Biochemical Mechanism **Clinical Pearl:** MCAD catalyzes the first oxidation step of medium-chain fatty acids (C6–C10). Its deficiency prevents the β-oxidation of medium-chain substrates, leading to: 1. Impaired energy production during fasting → hypoglycemia 2. Inability to generate ketones adequately (hypoketotic state) 3. Accumulation of unmetabolized medium-chain fatty acids → dicarboxylic aciduria ## Comparison with Other Acyl-CoA Dehydrogenase Deficiencies | Deficiency | Frequency | Chain Length | Key Clinical Feature | Ketone Status | | --- | --- | --- | --- | --- | | **MCAD** | **Most common** | **C6–C10** | **Hypoketotic hypoglycemia** | **Low** | | LCAD | Rare | C12–C18 | Cardiomyopathy, myopathy | Hyperketotic | | VLCAD | Uncommon | C14–C20+ | Cardiomyopathy, neonatal presentation | Variable | | SCAD | Very rare | C2–C4 | Developmental delay, metabolic acidosis | Normal/high | **Mnemonic:** **MCAD = Most Common Acyl-CoA Deficiency** — remember this is the #1 inherited FAO disorder in clinical practice. ## Diagnostic Clues - **Urine organic acids:** Elevated hexanoylglycine, suberylglycine (dicarboxylic acids) - **Plasma acylcarnitines:** Elevated C6–C10 acylcarnitines - **Genetic testing:** Mutations in ACADM gene (most common: A985G) - **Newborn screening:** Now included in expanded newborn screening panels ## Management - Frequent feeding (every 3–4 hours, avoid prolonged fasting) - Cornstarch supplementation for sustained glucose release - Avoidance of fasting during illness - Genetic counseling (autosomal recessive inheritance) [cite:Stryer's Biochemistry 8e Ch 23; Harrison 21e Ch 417]