Epidemiology
Etiology
Pathophysiology
- 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.
- 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:
Clinical features
Phenylketonuria
Link to originalMnemonic
Musty → having a stale, moldy, or damp smell → MOLD-E
- Blue eyes, light skin, pale hair
- Due to a lack of melanin
Diagnostics
- Newborn screening: direct measurement of serum phenylalanine levels on 2nd–3rd day after birth (phenylalanine levels are normal at birth because of circulating maternal PAH)
- ↑ Phenylketones in urine
- Hyperphenylalaninemia
Treatment
- Low phenylalanine and high tyrosine diet
- BH4 deficiency: supplementation of BH4 and possibly levodopa and 5-hydroxytryptophan