treatment

Last edited 09/2021 and last reviewed 10/2021

A low phenylalanine diet should be instituted before the end of the first month of life to ensure normal intellectual development. Guidance recommend that a low phenylalanine diet should be continued throughout adult life (1).

The diet for PKU can be very complicated to follow and is often considered to be unpalatable

• it issometimes difficult for people to adhere to the diet strictly, if at all.
• researchers have investigated other potential therapies which would facilitate compliance to treatment (2). Supplementation of the diet with tyrosine is one such therapy which has been studied in PKU
  • a systematic review concluded (3)
    • from the available evidence no recommendations can be made about whether tyrosine supplementation should be introduced intoroutine clinical practice

NICE have stated (4):

• sapropterin is recommended as an option for treating hyperphenylalaninaemia that responds to sapropterin (response as defined in the summary of product characteristics) in people with phenylketonuria (PKU), only if they are:

  • under 18 and a dose of 10 mg/kg is used, only using a higher dose if target blood phenylalanine levels cannot be achieved at 10 mg/kg
  • aged 18 to 21 inclusive, continuing the dose they were having before turning 18 or at a maximum dose of 10 mg/kg
  • pregnant (from a positive pregnancy test until birth)

Notes (5,6):

• 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
  • dietary restrictions in order to minimize phenylalanine intake are difficult to maintain and often cause other deficiencies
• sapropterin dihydrochloride is a synthetic form of cofactor tetrahydrobiopterin (BH4)
  • 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)

Reference:

• 1) Recommendations on the dietary management of phenylketonuria. Report of Medical Research Council Working Party on Phenylketonuria. Arch Dis Child. (1993) 68(3):426-7.
• 2) Pietz J, Landwehr R, Kutscha A, Schmidt H, de Sonneville L,Trefz FK. Effect of high-dose tyrosine supplementation on brainfunction in adults with phenylketonuria. Journal of Pediatrics1995;127(6):936-43.
• 3) Remmington T, Smith SRemmington T, Smith S. Tyrosine supplementation for phenylketonuria. Cochrane Database of Systematic Reviews 2021, Issue 1. Art. No.: CD001507. DOI: 10.1002/14651858.CD001507.pub4.
• 4) NICE (September 2021). Sapropterin for treating hyperphenylalaninaemia in phenylketonuria
• 5) Dubois EA, Cohen AF. Sapropterin. Br J Clin Pharmacol. 2010;69(6):576-577. doi:10.1111/j.1365-2125.2010.03643.x
• 6) 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