In phenylketonuria (PKU), which of the following metabolic consequences occurs due to accumulation of phenylalanine and its alternative metabolic products?

Explanation

## Metabolic Consequences of Phenylketonuria (PKU) **Key Point:** In PKU, phenylalanine accumulates because phenylalanine hydroxylase is deficient or absent. Excess phenylalanine is shunted into alternative catabolic pathways, producing phenylpyruvate and phenyllactate. ### Alternative Metabolism of Phenylalanine in PKU ```mermaid flowchart TD A[Excess Phenylalanine]:::outcome --> B[Transamination]:::action B --> C[Phenylpyruvate]:::outcome C --> D[Reduction]:::action D --> E[Phenyllactate]:::outcome C --> F[Oxidation]:::action F --> G[Phenylacetate]:::outcome E --> H[Urinary Excretion]:::action H --> I[Musty/Mousy Odor]:::outcome ``` **High-Yield:** The characteristic "musty" or "mousy" odor of urine in PKU patients is pathognomonic and results from phenylpyruvate and phenyllactate accumulation. This is a classic clinical sign used historically for screening before newborn screening programs. ### Why Other Pathways Are NOT Primarily Affected | Pathway | Why Not Primarily Affected in PKU | | --- | --- | | **Dopamine/Epinephrine synthesis** | Requires tyrosine, which is DEPLETED in PKU (not synthesized from phenylalanine). This leads to decreased, not increased, catecholamine synthesis. | | **Serotonin synthesis** | While tryptophan hydroxylase can be competitively inhibited by excess phenylalanine, this is a secondary effect. The primary metabolic derangement is accumulation of phenylalanine metabolites. | | **Melanin synthesis** | Requires tyrosine. In PKU, tyrosine is deficient, leading to HYPOPIGMENTATION (fair skin, light hair), not hyperpigmentation. | **Clinical Pearl:** Untreated PKU causes intellectual disability, light skin pigmentation, eczema, and behavioral problems. Early dietary restriction of phenylalanine prevents these complications. The musty odor is a historical diagnostic clue that has been largely replaced by tandem mass spectrometry newborn screening. **Mnemonic:** **PKU → Phenyl Products** — Phenylalanine accumulation → Phenylpyruvate and Phenyllactate → Musty urine odor.