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Phenylketonuria (PKU)

PKU is a rare, lifelong metabolic condition limiting the body’s ability to break down dietary protein, which can cause brain damage and lead to cognitive, behavioural and emotional problems.1-3

EU-PKU-00220 December 2021

What is PKU?

For people with PKU, simply eating foods like meat, fish, eggs or even bread can damage their brain and how it functions.1-3 PKU is a rare genetic condition that affects around one in every 10,000 babies born across Europe.1 People with PKU inherit a deficiency in the enzyme phenylalanine hydroxylase (PAH).1 PAH is required to metabolise phenylalanine (Phe), an amino acid found in protein-containing foods.1,2 Loss of PAH activity results in increased levels of Phe in the blood and toxic concentrations in the brain, which can affect patients’ cognitive function and cause behavioural, social and emotional problems.2,3

PKU is an autosomal recessive disease, which means that if both parents are carriers of the PKU gene, their baby has a one in four chance of having the condition.1,4

Symptoms of PKU

The burden of PKU is substantial. High or unstable blood Phe levels in PKU can cause a variety of signs and symptoms.3 In children, PKU can damage IQ and cause problems with memory, attention and impulse control, as well as social difficulties and decreased self-esteem.3 Even with dietary intervention, adults with PKU can experience cognitive, psychiatric and behavioural problems.5-7 These can include; lower IQ than the general population; impairments in executive function (the set of cognitive abilities critical to perform everyday life activities) such as attention, cognitive flexibility and inhibitory control; and depression, anxiety and stress.5-7 Symptoms like these can impact on independence, interpersonal relationships, and educational and career goals.3,5,8-11 People with PKU also have a higher prevalence of physical comorbidities than the general population, including obesity, renal insufficiency with hypertension and osteoporosis.12

Diagnosing PKU

Early diagnosis and treatment are essential for preventing neurological damage in people with PKU.1,13 Since the 1960s, the condition has been detected by screening newborn babies using a heel prick blood test, enabling treatment to start soon after birth in many countries.14

Managing PKU

PKU is a lifelong disorder that requires management from birth and throughout adulthood.1,13 The goal of treatment is to lower blood Phe to the right level for normal brain function.1,13 Reducing natural Phe intake with a restricted diet is the basis of management to maintain Phe levels in the recommended range.1,13 Phe metabolism can also be increased with medical treatment.1,13 Natural proteins are avoided by cutting out foods like meat, fish, eggs, nuts and cheese.2 Other basic foods such as bread, flour and pasta are replaced by special low protein ‘medical’ versions, and patients take Phe-free amino acid supplements to meet their nutritional needs.13 The diet can be extremely hard to follow and compliance is often poor.2 Even with early and continuous dietary intervention, people with PKU can experience cognitive, behavioural and emotional problems.3 This can lead to a cycle of decline, where the symptoms of PKU make it increasingly difficult for patients to adhere to treatment – which requires executive functioning abilities like planning, organisation and impulse control.3,15

Achieving the recommended blood Phe goals is challenging for people with PKU, and levels tend to rise with age.3 Everyone with PKU should have lifelong, systematic follow-up in specialised metabolic centres to manage the health risks of the condition.1,13

  1. van Spronsen FJ et al. Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol 2017;5(9):743-56.
  2. Blau N et al. Phenylketonuria. Lancet 2010;376(9750):1417-27.
  3. Enns GM et al. Suboptimal outcomes in patients with PKU treated early with diet alone: revisiting the evidence. Mol Genet Metab 2010;101:99-109.
  4. NORD. Phenylketonuria. Available at: https://rarediseases.org/rare-diseases/phenylketonuria/. Last accessed June 2022.
  5. Bilder DA et al. Systematic review and meta-analysis of neuropsychiatric symptoms and executive functioning in adults with phenylketonuria. Dev Neuropsychol 2016;41(4):245-60.
  6. Jahja R et al. Cognitive profile and mental health in adult phenylketonuria: A PKU-COBESO study. Neuropsychology 2017;31(4):437-47.
  7. Clacy A et al. Depression, anxiety, and stress in young adults with phenylketonuria: Associations with biochemistry. J Dev Behav Pediatr 2014;35(6):388-91.
  8. Christ SE, et al. Executive function in early-treated phenylketonuria: Profile and underlying mechanisms. Mol Genet Metab 2010;99(suppl 1):S22-S32.
  9. Gentile JK et al. Psychosocial aspects of PKU: Hidden disabilities – A review. Mol Genet Metab 2010;99(suppl 1):S64-S67.
  10. Bone A et al. A neuropsychiatric perspective of phenylketonuria I: Overview of phenylketonuria and its neuropsychiatric sequelae. Psychosomatics 2012;53(6):517-23.
  11. Brumm VL et al. Psychiatric symptoms and disorders in phenylketonuria. Mol Genet Metab 2010;99(suppl 1):S59-S63.
  12. Burton B et al. Prevalence of comorbid conditions among adult patients diagnosed with phenylketonuria. Mol Genet Metab 2018;125(3): 228-34.
  13. van Wegberg AMJ et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12(1):162.
  14. Berry SA et al. Newborn screening 50 years later: access issues faced by adults with PKU. Genet Med 2013;15(8):591-99.
  15. Vockley J et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med 2014;16(2):188-200.

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