Untreated: severe brain damage with intellectual disability, seizures, spasticity, movement disorder.
Treatment does not generally reverse neurologic symptoms that have already occurred.
- Summary
Deficiency of phenylalanine hydroxylase causes phenylketonuria (PKU), which is characterised by intellectual disability due to accumulating phenylalanine und metabolites as well as neurotransmitter deficiencies, and lighter skin and hair colour due to reduced melanin production. Affected children are asymptomatic at birth and have normal development when treated from birth.
PKU was one of the first neurogenetic diseases identified (Følling 1934), the first successfully treated inherited metabolic disease (diet: Bickel 1953), and instrumental for the introduction of neonatal population screening (dried blood spots: Guthrie 1963).
- TypeDisease
- Gene product
- Disease group(s)
Clinical
Variants
- PKU: requires diet (differences in disease severity/Phe tolerance: severe PKU = homozygous null mutation, mild PKU = at least one hypomorphic/residual function mutation)
- MHP: mild hyperphenylalaninemia, does not require diet therapy (Phe <600 µmol/l in Germany, <400 µmol/l in the UK, <360 µmol/l in the USA)
- BH4-responsive PKU: reduction of Phe levels after BH4 supplementation in many patients with mild PKU (stabilization/activation of mutant protein).
Genetics
Loss of function effect, >1100 pathogenic variants with different residual activities, genotype may allow prediction of severity and BH4 responsiveness. PAH mutation database: https://www.biopku.org
Incidence
In Europe up to 1:4,400 (Ireland), average ~1:8,000
Diagnosis, Investigations
Newborn screening (filter paper card), AA (plasma): ↑Phe, n–↓Tyr
Differential diagnosis
Disorders of tetrahydrobiopterin (BH4 cofactor) metabolism; DNAJC12 deficiency
Treatment
Phe-restricted diet, supplementation of essential amino acids + micronutrients.
BH4 supplementation in mild PKU with BH4 responsiveness (not all patients).
Exact recommendations differ between countries:- D/A/CH: treatment if Phe > 600 µM, target range age 0-6: 40–240 µmol/l,
age 7-12: 40-360 µmol/l, age 12-18: 40-600 µmol/l; adult 40-1200 µmol/l - UK: treatment if Phe > 600 µM,
target range: 120-360 µmol/l, school-age or older: 120-480 µmol/l - USA: treatment if Phe > 360 µM, target range 120–360 µmol/l throughout life
- “European” (ESPKU): treatment if Phe > 360 µM,
target range age 0-12: 120–360 µmol/l, from age 12 incl. adults: 120–600 µmol/l
- D/A/CH: treatment if Phe > 600 µM, target range age 0-6: 40–240 µmol/l,
Prognosis
Normal development and intelligence with immediate and efficient treatment.