Phenylketonuria (PKU) : Introduction to PKU for Primary Care Clinicians

Phenylketonuria (PKU) is a rare autosomal recessive inborn error of metabolism caused by deficiency of the enzyme phenylalanine hydroxylase, which normally converts phenylalanine to tyrosine. In its absence, phenylalanine accumulates to toxic levels, leading to progressive brain damage and intellectual disability if untreated.

In the UK, PKU is detected through newborn blood spot screening on day 5, enabling early diagnosis and dietary intervention. While patients under specialist metabolic care are usually well managed, primary care clinicians play an important role in:

Ensuring newborn screening is completed and results acted upon promptly.
Recognising potential signs in undiagnosed or poorly controlled children (e.g. developmental delay, fair complexion, musty odour).
Supporting families with dietary management, especially during intercurrent illness, adolescence, and pregnancy.
Being aware of contraindications (notably aspartame-containing products) and the need for close coordination with metabolic teams.

Aspect	Key Information
What is PKU?	A rare autosomal recessive disorder where phenylalanine cannot be broken down due to deficiency of phenylalanine hydroxylase → toxic accumulation → brain damage if untreated.
Prevalence	~1 in 10,000 births in the UK. Higher in Europeans (1:10,000), lower in African Americans (1:50,000 ↓).
Clinical Presentation	Newborns: Normal at birth. Untreated (3–6 months): Musty odor, fair skin/hair/eyes ↓, eczema, vomiting, developmental delay. Severe untreated: Intellectual disability, seizures, microcephaly, behavioral problems.
Diagnosis	Newborn screening: Phenylalanine ≥240 μmol/L ↑ at day 5. Confirmatory: Plasma amino acids, genetic testing (PAH gene).
Treatment	Lifelong low-phenylalanine diet: Avoid high-protein foods. PKU formula: Phenylalanine-free amino acid supplement. New therapies: Sapropterin (BH4) for responsive patients, pegvaliase for adults.
Management Goals	Maintain plasma phenylalanine 120–360 μmol/L (children), 120–600 μmol/L (adults). Regular blood monitoring and specialist dietary adjustments.
Prognosis	With early treatment: Normal IQ and development (subtle cognitive issues possible). Without treatment: Severe intellectual disability, seizures, permanent brain damage.
Primary Care Role	Ensure newborn screening, recognize undiagnosed cases, support families with dietary management, coordinate with metabolic specialists.
Key Contraindications	Avoid aspartame (diet sodas, medications, supplements) due to phenylalanine content ↑.
Special Considerations	Pregnancy: Strict dietary control to prevent fetal brain/heart defects. Adolescence: Risk of poor adherence ↓, needs extra support.

With early and lifelong treatment, most patients achieve normal development and quality of life. However, lapses in adherence—particularly during adolescence or pregnancy—can result in significant complications.

[1](https://www.genomicseducation.hee.nhs.uk/documents/phenylketonuria/)

[2](https://www.mayoclinic.org/diseases-conditions/phenylketonuria/symptoms-causes/syc-20376302)

[3](https://www.nhs.uk/conditions/phenylketonuria/)

[4](https://rarediseases.org/rare-diseases/phenylketonuria/)

[5](https://my.clevelandclinic.org/health/diseases/17816-phenylketonuria)

[6](https://bestpractice.bmj.com/topics/en-gb/867)

[7](https://phw.nhs.wales/services-and-teams/screening/newborn-bloodspot-screening-wales/files/clinical-referal-guidelines-2020/pku-clinical-referral-guideline-final-draft-2020-pdf/)

[8](https://www.gov.uk/government/publications/pku-suspected-description-in-brief/phenylketonuria-pku-detailed-information)

[9](https://www.mayoclinic.org/diseases-conditions/phenylketonuria/diagnosis-treatment/drc-20376308)

[10](https://nwknowledgenow.nhs.uk/wp-content/uploads/2024/03/GuidancePKUJuly2024_PPMO_Dietetics.pdf)

[11](https://phescreening.blog.gov.uk/wp-content/uploads/sites/152/2021/07/PKU-overview.pdf)

[12](https://www.ncbi.nlm.nih.gov/books/NBK535378/)

[13](https://www.nichd.nih.gov/health/topics/pku/conditioninfo/diagnosed)

[14](https://medlineplus.gov/lab-tests/phenylketonuria-pku-screening/)

[15](https://emedicine.medscape.com/article/947781-clinical)

[16](https://medlineplus.gov/genetics/condition/phenylketonuria/)

[17](https://www.ncbi.nlm.nih.gov/books/NBK1504/)

[18](https://www.cedars-sinai.org/health-library/diseases-and-conditions---pediatrics/p/phenylketonuria-pku-in-children.html)

[19](https://pmc.ncbi.nlm.nih.gov/articles/PMC4724370/)

[20](https://www.sciencedirect.com/science/article/pii/S1096719225001167)