A 2-week-old Indian neonate born to consanguineous parents is detected on newborn screening to have elevated plasma phenylalanine (>20 mg/dL) and normal pterins. Which of the following is the most common cause of this biochemical phenotype?

## Differential Diagnosis of Hyperphenylalaninemia **Key Point:** Elevated plasma phenylalanine with **normal pterins** (tetrahydrofolate, dihydropteridine) indicates a defect in phenylalanine metabolism itself, not in cofactor synthesis. Phenylalanine hydroxylase (PAH) deficiency accounts for >99% of cases with this biochemical profile. ### Classification of Hyperphenylalaninemia ```mermaid flowchart TD A["Elevated Plasma Phenylalanine"]:::outcome --> B{"Pterins Normal?"}:::decision B -->|Yes| C["Phenylalanine Hydroxylase Pathway Defect"]:::action B -->|No| D["Cofactor Synthesis Defect"]:::action C --> E["PAH Deficiency<br/>Most Common"]:::outcome C --> F["Dihydropteridine Reductase Deficiency<br/>Rare"]:::outcome D --> G["Tetrahydrofolate Reductase Deficiency"]:::outcome D --> H["GTP Cyclohydrolase Deficiency"]:::outcome ``` ### Biochemical Pathways **High-Yield:** The hydroxylation of phenylalanine to tyrosine requires: - **Enzyme:** Phenylalanine hydroxylase (PAH) - **Cofactor:** Tetrahydrofolate (BH₄) - **Location:** Liver (>90% of activity) When pterins are **normal**, the cofactor is intact → defect is in the enzyme itself (PAH). ### Comparison of Hyperphenylalaninemia Causes | Cause | Plasma Phe | Pterins | Neurotransmitters | Frequency | | --- | --- | --- | --- | --- | | **PAH deficiency** | ↑↑ (>20 mg/dL) | Normal | Normal (early) | >99% of cases | | Dihydrofolate reductase deficiency | ↑ | Low | ↓ (neurological crisis) | Rare | | Tetrahydrofolate reductase deficiency | ↑ | Low | ↓↓ (severe) | Very rare | | GTP cyclohydrolase deficiency | ↑ | Low | ↓ (variable) | Rare | ### Clinical Features of Classical PKU **Clinical Pearl:** The "mousy" or "musty" odor of urine is due to phenylacetic acid accumulation. This is a classic bedside sign that should prompt immediate testing. **Mnemonic:** **PHEN-OH** = **P**henylalanine **H**ydroxylase deficiency → **O**dor in urine (mousy), **H**yperphenylalanemia ### Why PAH Deficiency Is Most Common 1. **Enzyme frequency:** PAH is a large gene (35 kb) with >1,000 known mutations; carrier frequency is ~1 in 50–60 2. **Cofactor-independent defect:** Pterins are normal, ruling out the rarer cofactor synthesis disorders 3. **Consanguinity:** Autosomal recessive inheritance is common in Indian populations due to consanguineous marriages **Warning:** Do not confuse PAH deficiency with cofactor defects. The normal pterins are the key discriminator—they rule out all tetrahydrofolate synthesis defects.