Last edited 09/2021 and last reviewed 09/2021

Phenylketonuria is an inborn error of metabolism where phenylalanine hydroxylase is deficient. Thus there is an inability to convert phenylalanine into tyrosine which results in the accumulation of phenylalanine and its metabolic products in body fluids.

  • is an autosomal recessive mendelian disorder (OMIM 261600) characterized by an increase of phenylalanine in blood and body fluids (1)
    • phenylketonuria manifests itself as increased phenylalanine concentration in blood (hyperphenylalaninemia (HPA))
    • 98% of HPA is due to mutations in the gene coding for phenylalanine hydroxylase (PAH) enzyme
    • 2% of HPA is due to a defect in tetrahydrobiopterin (BH4) metabolism which is an essential co-factor for the activity of PAH
    • incidence of PKU due to mutations in the PAH gene is about 1 in 10,000 in individuals of European and Oriental Asian origin

PKU patients, who are deficient in phenylalanine hydroxylase (PAH), and patients with BH4 deficiency, are unable to convert phenylalanine from the diet

  • PAH hydroxylates phenylalanine through an oxidative reaction with tetrahydrobiopterin (BH4) as co-factor to form tyrosine
  • deficiency for either PAH or BH4 can result in high blood phenylalanine concentrations, which are toxic to the brain and can lead to neurological and behavioural disorders such as lower intelligence, decreased mental concentration, slowed reaction time, depression and phobias
    • other possible features of this condition include light pigmentation and mousy odour
  • dietary restrictions in order to minimize phenylalanine intake are difficult to maintain and often cause other deficiencies.

Carrier detection and prenatal diagnosis is possible using DNA analysis

Sapropterin dihydrochloride is a synthetic form of cofactor BH4 (2)

  • excess of cofactor activates residual PAH enzyme, improving phenylalanine metabolism and decreasing phenylalanine concentrations in the blood of PKU patients
  • in patients with BH4 deficiency, sapropterin provides an effective alternative to BH4
  • PKU patients treated with sapropterin must continue their restricted phenylalanine diet and undergo regular clinical assessment (monitoring of blood phenylalanine and tyrosine concentrations, nutrient intake and psychomotor development)


  • Somaraju UR, Merrin M. Sapropterin dihydrochloride for phenylketonuria. Cochrane Database Syst Rev. 2015;2015(3):CD008005. Published 2015 Mar 27. doi:10.1002/14651858.CD008005.pub4
  • Dubois EA, Cohen AF. Sapropterin. Br J Clin Pharmacol. 2010;69(6):576-577. doi:10.1111/j.1365-2125.2010.03643.x