Epidemiology

Etiology

Most commonly due to a defect of the liver enzyme phenylalanine hydroxylase (PAH) → impaired conversion of phenylalanine to tyrosine → tyrosine becomes nutritionally essential (classical PKU)
Less commonly
- Tetrahydrobiopterin deficiency (malignant PKU): due to tetrahydrobiopterin deficiency (a cofactor of phenylalanine metabolism), caused by a deficiency in dihydropteridine reductase (normally reduces dihydrobiopterin to BH4), resulting in:
  - Hyperphenylalaninemia due to ↓ conversion of phenylalanine to tyrosine → ↓ synthesis of catecholamines (BH4 is a cofactor for phenylalanine hydroxylase and tyrosine hydroxylase)
  - ↓ Synthesis of serotonin (BH4 is a cofactor for tryptophan hydroxylase) → deficiencies of neurotransmitters
  - Symptom severity varies between affected individuals.

Phenylketonuria

Mnemonic

Musty → having a stale, moldy, or damp smell → MOLD-E

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Newborn Screening (Blood phenylalanine): Universal screening via heel prick 24-72 hours after birth. Measures Phe levels using tandem mass spectrometry. This is the primary screening test.
Serum Amino Acid Analysis: The confirmatory test. Shows ↑ Phenylalanine and ↓ Tyrosine levels in the plasma, confirming the diagnosis and establishing the severity.
Urinary Pteridine Analysis: Performed after a confirmed high Phe level to differentiate between PAH deficiency (classic PKU) and BH4 deficiency. Abnormal pterin profile indicates a defect in BH4 synthesis or regeneration.
Urinary Ferric Chloride Test: A historical, now obsolete, test. Urine turns a blue-green color in the presence of phenylpyruvic acid. Not used for screening or diagnosis today.

Low phenylalanine and high tyrosine diet
BH4 deficiency: supplementation of BH4 and possibly levodopa and 5-hydroxytryptophan