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Synonyms: phenylalanine hydroxylase deficiency, oligophrenia/idiotica/imbecilitas phenylpyruvica, Følling's disease, type I hyperphenylalaninaemia

Phenylketonuria (PKU) is an inborn error of amino acid metabolism (the most common in the UK) caused by absent or virtually absent phenylalanine hydroxylase (PAH) enzyme activity. This enzyme converts dietary phenylalanine to tyrosine. The products of this metabolic pathway are important in the formation of catecholamines, neurotransmitters and melanin.

High plasma concentrations of phenylalanine lead to the formation of the byproducts phenylpyruvic acid and phenylethylamine, which are thought to be neurotoxic above a threshold concentration. If untreated, the condition leads to general learning disability, usually developing in the first year of life. The condition is eminently treatable through dietary manipulation and is screened for by heel-prick blood taken from all babies born in the UK. The condition can cause damage to the unborn children of mothers affected by the condition and, to avoid this complication, must be carefully managed during pregnancy.

Type I, or classical, PKU

  • Inherited in an autosomally recessive fashion. The gene locus is on the long arm of chromosome 12[1].
  • There are multiple allelic forms of the dysfunctional gene and many patients are compound heterozygotes for two of these.

Type II

  • There are cases of hyperphenylalaninaemia (HPA) where up to 5% of enzyme activity is retained, due to less critical mutations in the enzyme's sequence, or differing phenotypical expression.
  • These patients tend to have less serious disease that presents later in life and their optimal treatment is less clear-cut.

Malignant PKU

  • There is a variety of PKU due to a deficiency in the synthesis or metabolism of the enzyme's co-factor tetrahydrobiopterin (THB), important for the hydroxylation of tyrosine and tryptophan.
  • Such patients tend to develop more severe neurological disease that is not fully responsive to dietary manipulation.
This article concentrates on type I, or classical, PKU. More than 950 gene variants have now been identified[2]. Further information on the other variants is available from the National Society for Phenylketonuria[3].
  • One study estimated the prevalence per 10,000 live births in South East England was 1.14 among white, 0.11 among black and 0.29 among Asian ethnic groups[4].
  • There is marked variation between different ethnic groups. Turkey is the country with the highest incidence at around 1 in 2,600 live births. High incidence of the disease is also found in the Yemenite Jewish population[5]as well as in parts of Northern and Eastern Europe, Italy and China[6].
  • Although screening programmes have largely eliminated the burden of neurological dysfunction caused by the disease,a study in 2008 suggested that there were likely to be a large number of people with PUK living in the UK who were born before the national screening scheme was instituted[7].
  • The disease should therefore still form part of the differential diagnosis of developmental delay or general learning disability in children presenting at any age.
  • Most children appear normal at birth and diagnosis usually occurs through an abnormal result in the heel-prick blood assay.
  • Children tend to be very fair with pale blue eyes if compared to siblings or general family colouring.
  • In undetected cases, children often give off a musty or 'mousey' odour.
  • Progressive developmental delay and general learning disability are the usual modes of presentation in those not detected by screening.
  • Diagnosed children who cease dietary manipulation may show deterioration in motor skills and cognitive function (IQ falling by about 10 points); there may be MRI evidence of demyelination.
  • Other presentations in infancy or later childhood include:
    • Recurrent vomiting.
    • Unusual musty/'mousey' odour.
    • Eczematous skin eruptions, scleroderma-like skin lesions and other dermatological abnormalities.
    • Seizures.
    • Self-mutilation.
    • Severe behavioural disturbance.
    • Untreated older children may be hyperactive with rhythmic rocking and writhing movements classically affecting the hands, face and tongue.
  • Heel-prick blood should be assayed for phenylalanine (or subjected to indirect Guthrie assay) in all UK-born newborns.
  • This test should be carried out at >12 hours after birth.
  • Blood levels of phenylalanine above a threshold value (usually around 120 μmol/L) suggest the diagnosis and prompt re-testing and/or formal assay by a specialist laboratory and assessment by a metabolic disease service.
  • Tyrosine and THB assay may form part of specialist investigations.
  • The disease may be detected during aminoaciduria screening for older children with developmental delay or general learning disability.
  • Children being treated for the condition may be prone to nutritional deficiencies due to the special diet. Those who are ill or have other blood test abnormalities may need assay/assessment of iron, vitamins, selenium, protein, essential fatty acids and other nutrient levels.
  • MRI scan may be used to detect demyelination and other abnormalities in older, treated children who become unwell after stopping or complying poorly with dietary manipulation.
  • Genetic testing may be appropriate where genetic counselling is required, to determine the status of at-risk relatives and for prenatal testing[8].

Children with PKU should be managed in a specialist metabolic/paediatric clinic. The cornerstones of therapy are dietary protein restriction combined with dietary substitution of proteins containing a balanced mixture of amino acids, including a generous supply of tyrosine. Regular assay of plasma phenylalanine level, along with levels of its metabolites, are used to assess and monitor response to therapy.

  • Careful weaning is very important in PKU. Dietary phenylalanine intake is severely restricted and the diet is supplemented with phenylalanine-free amino acids and special low-protein foods[9].
  • The degree to which dietary phenylalanine must be restricted remains controversial. The diet should be monitored to ensure that growth and nutritional status are not affected and deficiency of phenylalanine or tyrosine does not develop. The diet should also be adjusted to allow for illness and activity[8]. The optimal duration of dietary restriction necessary to avoid the adverse effects of HPA is unclear[10].
  • Some authorities consider that the diet (which is difficult to adhere to and often not popular with older children) can be discontinued in later childhood but others advocate lifelong dietary adjustment.
  • There is some limited evidence that there are subtle differences in IQ between those who stop the diet after childhood and those who maintain it[10].
  • There are currently insufficient data to draw conclusions regarding the short-term or long-term use of protein substitutes in PKU[11].
  • There is evidence of short-term benefit from using sapropterin in some patients with sapropterin-responsive forms of PKU; blood phenylalanine concentration is lowered and protein tolerance increased[12]. See further details in the editor's note below.
  • Definitive evidence of benefit for tyrosine supplementation is lacking but it is widely used and biochemically plausible as a potentially beneficial intervention[13].
  • Aspartame, a common sweetening agent, should be avoided, as it is a rich source of phenylalanine.
  • Supplementation of iron, vitamins and minerals may be necessary for those on the diet.
  • There is some evidence that the diet causes deficiency of essential fatty acids, which can have an adverse effect on bone mineral density[14].
  • Treatment is still thought to bring benefits in children or adults with intellectual disability  who were not diagnosed in infancy.
  • It is very important that pregnant PKU patients who are not strictly adherent to their diet should resume it. Studies suggest that untreated PKU in pregnancy is associated with microcephaly, intellectual disability and attention deficit hyperactivity disorder[15]

Editor's note

Dr Sarah Jarvis, 28th September 2021

Sapropterin for treating hyperphenylalaninaemia in phenylketonuria - NICE guidance

Sapropterin is a synthetic version of the naturally occurring 6R-BH4, which is a cofactor of the hydroxylases for phenylalanine, tyrosine and tryptophan. It is used, in conjunction with a protein-restricted diet, for people whose PKU has been shown to respond to it. The aim of treatment is to maintain satisfactory blood phenylalanine levels to reduce PKU symptoms and complications, and potentially allow a less restricted diet.
The National Institute for Health and Care Excellence (NICE) has issued new guidance on the above treatment[16]. It recommends that patients in the groups below with PKU and hyperphenylalaninaemia that responds to sapropterin should be identified as defined in the summary of product characteristics. In such patients, sapropterin is recommended as an option for patients who 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).

For patients already receiving treatment outside the terms of this guidance, treatment may continue until they and their NHS clinician consider it appropriate to stop.

  • Developmental delay or intellectual disability developing in later life due to non-adherence to diet.
  • Epilepsy.
  • Severe behavioural disturbance.
  • Congenital anomaly and intellectual disability in offspring of untreated PKU mothers.
  • Skin lesions (eczematous or scleroderma-like).
  • Subtle deficiencies in attention and organisational planning abilities may affect some treated sufferers. This is thought to be due to poorly controlled phenylalanine levels.
  • Agoraphobia, low self-esteem and other psychological disturbance can affect some patients, usually if not on a special diet.
  • Worsening intellectual disability and developmental delay in infancy and childhood if untreated.
  • Long-term outlook is excellent in those who adhere to dietary and other therapies.
  • Overall intelligence is normal or near-normal, although some of those affected may encounter significant educational challenges.
  • Vigilance in the heel-prick blood testing programme for newborns.
  • Adherence to dietary and other manipulations prevents serious complications of the disease; it should be instituted and supported by healthcare staff and family from an early age.
  • Careful management of pregnant women with PKU protects against disease in the newborn.

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Further reading and references

  1. Phenylketonuria, PKU; Online Mendelian Inheritance in Man (OMIM)

  2. Blau N; Genetics of Phenylketonuria: Then and Now. Hum Mutat. 2016 Jun37(6):508-15. doi: 10.1002/humu.22980. Epub 2016 Mar 18.

  3. National Society for Phenylketonuria

  4. Hardelid P, Cortina-Borja M, Munro A, et al; The birth prevalence of PKU in populations of European, South Asian and sub-Saharan African ancestry living in South East England. Ann Hum Genet. 2008 Jan72(Pt 1):65-71. doi: 10.1111/j.1469-1809.2007.00389.x.

  5. Bercovich D, Elimelech A, Yardeni T, et al; A mutation analysis of the phenylalanine hydroxylase (PAH) gene in the Israeli population. Ann Hum Genet. 2008 May72(Pt 3):305-9. doi: 10.1111/j.1469-1809.2007.00425.x. Epub 2008 Feb 19.

  6. Mei L, Song P, Kokudo N, et al; Current situation and prospects of newborn screening and treatment for Phenylketonuria in China - compared with the current situation in the United States, UK and Japan. Intractable Rare Dis Res. 2013 Nov2(4):106-14. doi: 10.5582/irdr.2013.v2.4.106.

  7. Murphy GH, Johnson SM, Amos A, et al; Adults with untreated phenylketonuria: out of sight, out of mind. Br J Psychiatry. 2008 Dec193(6):501-2. doi: 10.1192/bjp.bp.107.045021.

  8. Mitchell JJ; Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [Updated 2013 Jan 31]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews.

  9. MacDonald A, Evans S, Cochrane B, et al; Weaning infants with phenylketonuria: a review. J Hum Nutr Diet. 2012 Apr25(2):103-10. doi: 10.1111/j.1365-277X.2011.01199.x. Epub 2011 Aug 8.

  10. Poustie VJ, Wildgoose J; Dietary interventions for phenylketonuria. Cochrane Database Syst Rev. 2010 Jan 20(1):CD001304. doi: 10.1002/14651858.CD001304.pub2.

  11. Yi SH, Singh RH; Protein substitute for children and adults with phenylketonuria. Cochrane Database Syst Rev. 2008 Oct 8(4):CD004731.

  12. Somaraju UR, Merrin M; Sapropterin dihydrochloride for phenylketonuria. Cochrane Database Syst Rev. 2012 Dec 1212:CD008005. doi: 10.1002/14651858.CD008005.pub3.

  13. Webster D, Wildgoose J; Tyrosine supplementation for phenylketonuria. Cochrane Database Syst Rev. 2010 Aug 4(8):CD001507. doi: 10.1002/14651858.CD001507.pub2.

  14. Lage S, Bueno M, Andrade F, et al; Fatty acid profile in patients with phenylketonuria and its relationship with bone mineral density. J Inherit Metab Dis. 2010 Dec33 Suppl 3:S363-71. doi: 10.1007/s10545-010-9189-0. Epub 2010 Sep 10.

  15. Waisbren SE, Rohr F, Anastasoaie V, et al; Maternal Phenylketonuria: Long-term Outcomes in Offspring and Post-pregnancy Maternal Characteristics. JIMD Rep. 201521:23-33. doi: 10.1007/8904_2014_365. Epub 2015 Feb 25.

  16. Sapropterin for treating hyperphenylalaninaemia in phenylketonuria; NICE Technology appraisal guidance, September 2021