A 3-year-old child presents with recurrent episodes of hypoketotic hypoglycemia, hepatomegaly, and developmental delay. Urine organic acid analysis shows elevated dicarboxylic acids. Which feature best distinguishes medium-chain acyl-CoA dehydrogenase (MCAD) deficiency from long-chain acyl-CoA dehydrogenase (LCAD) deficiency?

Question

Accepted Answer

A. MCAD deficiency shows elevated C6–C10 acylcarnitines; LCAD shows elevated C12–C18 acylcarnitines on tandem mass spectrometry. ## Distinguishing MCAD from LCAD Deficiency

### Pathophysiology of Fatty Acid Oxidation Defects

Both MCAD and LCAD are disorders of β-oxidation, but they impair oxidation of different chain lengths, leading to distinct metabolite accumulation patterns and clinical presentations.

### Key Biochemical Difference

**High-Yield:** The cardinal discriminator is the **acylcarnitine profile on tandem mass spectrometry (MS/MS)**:

| Feature | MCAD Deficiency | LCAD Deficiency |
|---------|-----------------|------------------|
| **Substrate blocked** | Medium-chain (C6–C10) fatty acids | Long-chain (C12–C18) fatty acids |
| **Elevated acylcarnitines** | C6, C8, C10 (especially C8) | C12, C14, C16, C18 |
| **Urine organic acids** | Hexanoate, octanoate, decanoate | Elevated dicarboxylic acids (but longer chain) |
| **Primary presentation** | Hypoketotic hypoglycemia + encephalopathy | Cardiomyopathy, skeletal myopathy, lipid storage |
| **Age of onset** | 3 months–2 years (often after viral illness) | Neonatal or early infancy |

**Key Point:** MS/MS acylcarnitine profiling is the gold standard for diagnosis and allows precise differentiation by chain length of accumulated acyl-CoA species.

### Clinical Context

MCAD is the most common fatty acid oxidation disorder in Caucasians (1:6,000–1:10,000); LCAD is rarer but more severe, with cardiac involvement being a hallmark feature.

**Clinical Pearl:** A child presenting with **hypoketotic hypoglycemia + normal ketones during fasting** suggests MCAD, whereas **progressive cardiomyopathy + lipid storage in muscle** points to LCAD.

### Why MS/MS Acylcarnitine Profile is Diagnostic

The specific pattern of elevated acylcarnitines reflects the exact enzymatic block:
- **MCAD block** → C6–C10 accumulate (cannot be oxidized further)
- **LCAD block** → C12–C18 accumulate (cannot enter the β-oxidation spiral)

This is measured directly and unambiguously in newborn screening and diagnostic panels.

Answer

B. MCAD deficiency is autosomal recessive; LCAD is X-linked recessive

Answer

C. MCAD deficiency presents with hypoketotic hypoglycemia triggered by fasting; LCAD presents with cardiomyopathy and skeletal myopathy

Answer

D. MCAD deficiency manifests after 6 months of age; LCAD manifests in the neonatal period

Explanation

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