Phenylketonuria (PKU)

Phenylketonuria (PKU) is a genetic condition caused by mutations of the phenylalanine hydroxylase (PAH) gene.¹ If left untreated or if the condition is poorly managed, the disease can lead to elevated blood phenylalanine concentrations and neurological symptoms, including learning disabilities, developmental delay, epilepsy, behavioral problems, depression and anxiety disorders.¹ Symptoms are usually progressive and become more apparent as a child grows.² 

What is phenylalanine? 

Phenylalanine is an essential amino acid used in protein synthesis.³ The absence of PAH activity leads to increased concentrations of phenylalanine in the blood and toxic concentrations in the brain.²

PAH activity is predominantly associated with the liver, requiring tetrahydrobiopterin (BH₄) and molecular oxygen for its action.³ PAH catalyzes the stereospecific hydroxylation of L-phenylalanine.³ However, in PKU, mutations in the PAH gene prevent the metabolization of phenylalanine, leading to elevated blood concentration levels.⁴  

Hyperphenylalaninaemia (HPA) can be caused by either mutations in the PAH gene locus resulting in PKU, or from mutations in several loci which affect BH₄ synthesis and generation, resulting in non-PKU HPA.³  

Left untreated, PKU is associated with growth failure, microcephaly, seizures, and intellectual impairment caused by the accumulation of toxic by-products of phenylalanine. Decreased or absent PAH activity can also lead to a deficiency of tyrosine and its downstream products, including melanin, L-thyroxine, and the catecholamine neurotransmitters.³

The estimated global prevalence of PKU is 1 in 23,930 live births⁵ and in the US there are thought to be ~16,500 people living with PKU.⁶   

Prevalence data was estimated for 64 countries from a literature search and reports from a national screening centres: the estimated number of PKU subjects was 360,466.⁵ The data suggests a large degree of geographic variability in disease prevalence, with the highest prevalence in Italy (1 in every 4,000 births) and the lowest in Thailand (1 in 227,273 births).⁵ The variability in geographic prevalence is thought to be explained by migration patterns, rates of reproductive relationships between closely related individuals (consanguinity), and genetic reserves in different countries.^5,7

In terms of disease severity, it is estimated that 62% of patients have classic PKU, 22% have mild PKU, and 16% have mild HPA.⁵

PKU classification is based on pre-treatment blood Phe concentrations:⁵

• Severe classic PKU: >1,200 µmol/L
• Mild PKU: 600–1,200 µmol/L
• Mild HPA: 120–600 µmol/L

Most newborns with PKU do not show any symptoms, but signs of the condition emerge after a few months.⁸ Children with untreated PKU can have:⁹

• Impaired brain development
• Intellectual disability
• Behavior problems
• Microcephaly
• Epilepsy

Those treated late or never treated are at risk of developing severe behavioral or psychiatric challenges such as anxiety, depression and phobias in their 20s and 30s.⁹

Other physical signs and symptoms can include:⁹

• Distinct musty body odor (due to excessive excretion of phenylalanine and its metabolites)
• Skin conditions such as eczema
• Decreased skin and hair pigmentation (resulting from tyrosinase inhibition due to elevated phenylalanine levels)

Additional physical problems that may occur in adulthood include exaggerated deep tendon reflexes, tremors, hemiplegia, or paraplegia.⁹

PKU diagnosis typically occurs during newborn screening programs in the first few weeks of life.¹⁰ This involves taking a small blood sample from the baby within a few days of birth and conducting a blood amino acid analysis to assess phenylalanine levels.¹¹ Patients with increased phenylalanine levels (>120 μmol/L), and therefore a diagnosis of PKU, are further screened for BH₄ responsiveness, and in Europe this is done via BH₄ loading.² A marked normalization (within 8 hours) in phenylalanine concentrations indicates BH₄ deficiency, whereas very little or no reduction in phenylalanine indicates BH₄-non-responsive PKU.²  

A diagnosis made after the neonatal period is often referred to as either ‘late diagnosis’ or ‘untreated PKU’. Late diagnosis refers to children diagnosed between the ages of 3 months and 7 years.¹² Untreated PKU refers to patients untreated by the age of 7.¹² Diagnosis after the neonatal period usually happens after a patient presents with developmental delay or other PKU-related symptoms and is confirmed following plasma amino acids analysis.¹²

Left untreated, the natural history of PKU involves progressive irreversible neurological impairment during infancy and childhood.¹¹ Disease severity positively correlates with blood phenylalanine levels, such that higher levels are associated with greater cognitive impairment.^11,13  

While there is no cure, the effects of PKU can be mitigated by low protein diets aimed at restricting dietary intake of phenylalanine to the minimum level required for normal growth.¹⁰ These dietary restrictions should be adhered to reduce further irreversible damage. If this restriction is implemented promptly after neonatal diagnosis, intellectual disability can be prevented;¹⁰ however, neurophysiological and neuropsychological impairments may persist, even in treated PKU patients.¹⁰ Notably, if the diet is relaxed during childhood, this can adversely affect IQ as the child gets older.¹³ In many adults, dietary management may be ineffective due to long-term non-adherence or inadequate phenylalanine-lowering effects.¹⁴  

In addition to low protein diets, PKU can be managed using phenylalanine-free amino acid supplements.¹⁴

Given that the primary management approach for PKU is dietary restriction, an important impact of the disease for patients is adhering to the strict dietary regime, which confers a significant patient burden.¹⁵ While dietary compliance in infancy is typically very good, non-compliance increases with age due to many reasons, such as lack of access to specific foods, socializing, palatability, work, and embarrassment.^16–18 

In one survey, PKU respondents reported that they feel distress when their symptoms are trivialised or dismissed as being unrelated to PKU by healthcare professionals.¹⁹ It is believed that a negative response by a healthcare professional could represent a barrier to care.¹⁹

In terms of broader practical, social, and psychological issues of PKU, a large UK survey found that problems described included struggle to maintain focus, experience anxiety or depression, gastrointestinal symptoms, social exclusion and difficulties with relationships. Children also encounter educational difficulties.²⁰  

PKU can have a particularly marked impact on women before, during, and after pregnancy, given that high blood phenylalanine levels during pregnancy can have a teratogenic effect on the developing fetus.²⁰ A survey showed women with PKU are concerned about pregnancy, and two-thirds of those who have had at least 1 pregnancy reported it to be stressful and difficult.²⁰  

There are also unique considerations for parents of children with PKU. When diagnosed with PKU, parents must assume immediate responsibility for the management of the disease and prevention of neurological damage which can carry a significant burden and often psychological stress.²¹ Parents of children with PKU emphasize the importance of gaining control of disease management and minimizing the impact of PKU on the child to ensure that they can live a normal life.²¹

1. de Groot MJ, Hoeksma M, Blau N, et al. Mol Genet Metab 2010;99:S86–S89. 
2. Blau N, van Spronsen FJ, Levy HL. Lancet 2010;376:1417–1427. 
3. Williams RA, Mamotte CD, Burnett JR. Clin Biochem Rev 2008;29(1):31–41. 
4. van Spronsen FJ, van Wegberg AM, Ahring K, et al. Lancet Diabetes Endocrinol 2017;5:743–756. 
5. Hillert A, Anikster Y, Belanger-Quintana A, et al. Am J Hum Gen 2020;107(2):234–250.
6. Sellos-Moura M, Glavin F, Lapidus D, et al. BMC Health Serv Res 2020;20(1):183. 
7. Shoraka HR, Haghdoost AA, Baneshi MR, et al. Clin Exp Pediatr 2020;63(2):34–43.
8. Phenylketonuria (PKU). Available at: https://www.mayoclinic.org/diseases-conditions/phenylketonuria/symptoms-causes/syc-20376302. Accessed April 2023. 
9. Mitchell JJ, Trakadis YJ, Scriver CR. Genet Med 2011;13(8):697–707. 
10. Al Hafid N, Christodoulou J. Transl Pediatr 2015;4(4):304–317. 
11. Strisciuglio P, Concolino D. Metabolites 2014;4:1007–1017.
12. van Wegberg AMJ, MacDonald A, Ahring K, et al. Orphanet J Rare Dis 2017;12(1):162.
13. Waisbren SE, Noel K, Fahrbach K, et al. Mol Gen Metab 2007;92:63–70.
14. Trefz KF, Muntau A, Kohlscheen K, et al. Orphanet J Rare Dis 2019;14:181. 
15. Nardecchia F, Manti F, Chiarotti F, et al. Mol Genet Metab 2015;115(2–3):84–90. 
16. Walkowiak D, Bukowska-Posadzy A, Kałużny Ł, et al. Adv Clin Exp Med 2019;28:1385–1391.
17. Cazzorla C, Bensi G, Biasucci G, et al. Mol Gen Metab Rep 2018;16:39–45.
18. Ford S, O’Driscoll M, MacDonald A. Mol Gen Metab Rep 2019;21:100527.
19. Ford S, O’Driscoll M, MacDonald A. Mol Gen Metab Rep 2018;17:57–63.
20. Ford S, O’Driscoll M, MacDonald A. Mol Gen Metab Rep 2018;17:64–68.
21. Carpenter K, Wittkowski A, Hare DJ, et al. J Genetic Couns 2018;27:1074–1086.