A 6-month-old female infant presents with poor feeding, vomiting, and lethargy that worsens after milk feeds. On examination, she has hepatomegaly and a musty odor to her urine. Newborn screening was not performed. Serum amino acid analysis shows elevated phenylalanine (1200 µmol/L; normal <120 µmol/L) and elevated tyrosine. Urine organic acids show phenylpyruvate. Which of the following is the most appropriate immediate management?

Explanation

## Diagnosis: Classic Phenylketonuria (PKU) ### Clinical Recognition **Key Point:** This infant presents with the classic triad of untreated PKU: developmental delay/lethargy, hepatomegaly, and the pathognomonic **musty or "mousy" odor** of the urine (due to phenylacetate and phenylpyruvate accumulation). The markedly elevated serum phenylalanine (>10× normal) with elevated tyrosine and urinary phenylpyruvate confirms the diagnosis. ### Pathophysiology Classic PKU results from deficiency of the enzyme **phenylalanine hydroxylase (PAH)**, which normally converts phenylalanine to tyrosine. Without this enzyme: 1. Phenylalanine accumulates in blood and urine 2. Alternative transamination pathway produces phenylpyruvate and phenylacetate (causing the musty odor) 3. Tyrosine becomes conditionally essential 4. Accumulation of phenylalanine and its metabolites causes intellectual disability, seizures, eczema, and light skin pigmentation if untreated ### Immediate Management Algorithm ```mermaid flowchart TD A[Confirmed elevated Phe + phenylpyruvate]:::outcome --> B[Discontinue regular milk feeds]:::action B --> C[Start Phe-restricted formula]:::action C --> D[Perform BH4 loading test]:::action D --> E{BH4-responsive?}:::decision E -->|Yes| F[Add sapropterin therapy]:::action E -->|No| G[Continue Phe-restricted diet alone]:::action F --> H[Regular monitoring of Phe levels]:::action G --> H ``` ### Why Option 2 is Correct **High-Yield:** The immediate management triad for classic PKU is: 1. **Dietary restriction** of phenylalanine (specialized amino acid formula without Phe) 2. **BH4 loading test** to determine if the patient has BH4-responsive PKU (a subset where PAH retains some cofactor-dependent activity) 3. **Conditional sapropterin therapy** only if BH4-responsive phenotype is confirmed **Clinical Pearl:** Not all PKU patients are BH4-responsive. The loading test (typically 20 mg/kg/day for 3–7 days with repeat Phe measurement) identifies the ~30% of classic PKU patients who may benefit from sapropterin monotherapy or as adjunctive therapy. Premature sapropterin without testing wastes time and resources in non-responsive patients. **Key Point:** Immediate dietary intervention is non-negotiable and must begin within days of diagnosis to prevent further neurological damage. Discontinuing milk (high Phe content) and starting a Phe-free or low-Phe formula is the foundation of all PKU management. ### Monitoring - Serum phenylalanine levels should be checked weekly initially, then monthly - Target Phe level: 2–6 mg/dL (120–360 µmol/L) in infants; up to 10 mg/dL in older children - Dietary compliance is critical for normal neurodevelopment [cite:Harrison 21e Ch 397]