A 3-year-old boy presents with developmental delay, musty odor of urine, and light skin pigmentation. His sibling was diagnosed with phenylketonuria (PKU) at newborn screening. Which single biochemical finding best distinguishes PKU from alkaptonuria?

Explanation

## Distinguishing PKU from Alkaptonuria ### Key Biochemical Difference **Key Point:** PKU is a defect in phenylalanine hydroxylase (converting phenylalanine → tyrosine), whereas alkaptonuria is a defect in homogentisate 1,2-dioxygenase (downstream in tyrosine catabolism). The plasma amino acid profile is the critical discriminator. ### Comparison Table | Feature | PKU | Alkaptonuria | | --- | --- | --- | | **Enzyme defect** | Phenylalanine hydroxylase | Homogentisate 1,2-dioxygenase | | **Plasma phenylalanine** | ↑↑↑ (>20 mg/dL) | Normal | | **Plasma tyrosine** | Normal or low | Normal | | **Urinary homogentisic acid** | Normal | ↑↑↑ (dark on standing) | | **Urinary phenylpyruvate** | ↑↑↑ (musty odor) | Normal | | **Urine darkening** | No | Yes (oxidation of HGA) | | **Ochronosis** | Absent | Present (>30 years) | | **Arthritis** | Absent | Present (>30 years) | ### Why This Discriminates **High-Yield:** Elevated plasma phenylalanine with normal tyrosine is pathognomonic for PKU. In alkaptonuria, phenylalanine is normal because the block is downstream—the problem is in tyrosine catabolism, not its synthesis. Tyrosine levels remain normal because it is still produced from other sources (diet, protein breakdown). **Clinical Pearl:** PKU presents early (3–6 months) with developmental delay and musty urine odor. Alkaptonuria is often asymptomatic in childhood and presents with ochronosis (dark pigmentation of connective tissue) and arthritis in adulthood. ### Mnemonic **PHEN-KEY:** **PHEN**ylalanine ↑ = **KEY** to PKU diagnosis. Alkaptonuria = **HGA** (homogentisic acid) in urine.