Scientific Knowledge & Personal Nutrition Stories for Rare Metabolic Conditions

Phenylketonuria (PKU) is a genetic disorder that affects how the body processes an amino acid called phenylalanine (Phe). This condition is caused by mutations in the PAH gene, which encodes the enzyme phenylalanine hydroxylase (PAH)¹. In simple terms, we will explore the scientific aspects of PKU, including the genetics behind it, the role of the PAH enzyme, and how its dysfunction leads to serious health issues.

What is an Autosomal Recessive Mutation?

Autosomal recessive inheritance means that a person must inherit two mutated copies of a gene—one from each parent—to develop a disorder like PKU. If a person has only one mutated gene, they are considered a carrier and do not show symptoms of the disease. In PKU, both parents are healthy carriers of the mutation, which means they have one normal and one mutated copy of the PAH gene. The chance of having an affected child is 25% for each pregnancy if both parents are carriers (Fig. 1).

Figure 1: Autosomal recessive inheritance. Image created with BioRender.

How Can One Base Change Affect an Enzyme?

A single base change in the DNA sequence can lead to a missense mutation, where one amino acid in the PAH enzyme is altered. This small change can disrupt the enzyme’s ability to fold correctly or function properly. Many mutations cause the PAH protein to misfold or destabilize, leading to its degradation before it can perform its function ^2,3. As a result, individuals with PKU have significantly reduced PAH activity, leading to high levels of Phe in their blood.

Effects of Various Mutations on the PAH Enzyme

Different mutations in the PAH gene can lead to varying degrees of enzyme dysfunction:

• Classic PKU: Caused by severe mutations that result in less than 1% residual PAH activity. This leads to very high Phe levels (≥1200 μmol/L or >13 mg/dL)⁴.
• Mild Hyperphenylalaninemia (HPA): Associated with mutations that allow for some residual PAH activity (1-5%), resulting in moderate Phe levels (600-1200 μmol/L or 6-13 mg/dL)⁵.
• Non-PKU HPA: Involves mutations with more than 5% residual PAH activity and lower Phe levels (<600 μmol/L or 6 mg/dL) but still requires monitoring⁶.

The Role of the PAH Enzyme

The PAH enzyme is crucial for converting Phe into another amino acid called tyrosine. When PAH is not functioning, Phe accumulates in the blood because it cannot be metabolized effectively. This excess Phe can cross the blood-brain barrier and lead to neurological damage, affecting cognitive function and behavior. Symptoms of untreated PKU can include learning disabilities, behavioral problems, and physical symptoms like lighter skin and hair due to reduced melanin production^1,7,8.

The Role of Tetrahydrobiopterin (BH4)

Tetrahydrobiopterin (BH4) is a cofactor necessary for the PAH enzyme’s activity. Mutations in PCBD1, QDPR, GCH1, and PTS genes cause a deficiency in BH4. This deficiency leads to elevated Phe levels because even if the enzyme is present, it cannot function without this cofactor. In some cases, patients with BH4 deficiencies may be misdiagnosed with PKU if their elevated Phe levels are not correctly attributed to their underlying condition^9,10. More on this subject will be covered in a future post on hyperphenylalaninemia.

Curiosities About PKU

Interestingly, there are documented cases of individuals with PKU who do not experience adverse effects from high Phe levels. These rare cases may involve unique genetic factors that allow for better regulation or metabolism of Phe. Research into these mechanisms could provide insights into potential therapies for managing PKU^11,12. Additionally, there have been instances where adults developed symptoms resembling PKU later in life. These cases often involve other metabolic disorders or environmental factors that trigger elevated Phe levels despite previously normal metabolism^13,14. Understanding these occurrences could lead to improved diagnostic methods and treatments.

Conclusion

PKU is a complex genetic disorder that highlights how small changes at the molecular level can have significant impacts on health. By understanding the role of the PAH enzyme and how its dysfunction leads to elevated phenylalanine levels, we can better appreciate the importance of early diagnosis and dietary management in affected individuals. Continued research into rare cases and alternative metabolic pathways will enhance our understanding and treatment options for this condition. By raising awareness about PKU and its implications, we can contribute to better outcomes for those affected by this disorder.

References

1.            van Spronsen, F. J. et al. Phenylketonuria. Nature Reviews Disease Primers 2021 7:1 7, 1–19 (2021).

2.            Pey, A. L., Desviat, L. R., Gámez, A., Ugarte, M. & Pérez, B. Phenylketonuria: Genotype–phenotype correlations based on expression analysis of structural and functional mutations in PAH. Human Mutation 21, 370–378 (2003).

3.            Gersting, S. W. et al. Loss of Function in Phenylketonuria Is Caused by Impaired Molecular Motions and Conformational Instability. Am J Hum Genet 83, 5–17 (2008).

4.            Williams, R. A., Mamotte, C. D. & Burnett, J. R. Phenylketonuria: An Inborn Error of Phenylalanine Metabolism. Clin Biochem Rev 29, 31–41 (2008).

5.            Waters, P. J. How PAH gene mutations cause hyper-phenylalaninemia and why mechanism matters: Insights from in vitro expression. Human Mutation 21, 357–369 (2003).

6.            Elhawary, N. A. et al. Genetic etiology and clinical challenges of phenylketonuria. Human Genomics 16, 22 (2022).

7.            Blau, N., Van Spronsen, F. J. & Levy, H. L. Phenylketonuria. The Lancet 376, 1417–1427 (2010).

8.            Van Wegberg, A. M. J. et al. The complete European guidelines on phenylketonuria: Diagnosis and treatment. Orphanet Journal of Rare Diseases 12, (2017).

9.            Tetrahydrobiopterin Deficiency – Symptoms, Causes, Treatment | NORD. https://rarediseases.org/rare-diseases/tetrahydrobiopterin-deficiency/.

10.         Nyhan, W. L., Hoffmann, G. F., Al-Aqeel, A. I. & Barshop, B. A. Hyperphenylalaninemia and defective metabolism of tetrahydrobiopterin. in Atlas of Inherited Metabolic Diseases (CRC Press, 2019).

11.         van Vliet, D. et al. Can untreated PKU patients escape from intellectual disability? A systematic review. Orphanet Journal of Rare Diseases 13, 149 (2018).

12.         van Vliet, D. et al. Untreated PKU Patients without Intellectual Disability: What Do They Teach Us? Nutrients 11, 2572 (2019).

13.         Tufekcioglu, Z. et al. Adult-onset phenylketonuria with rapidly progressive dementia and parkinsonism. Neurocase 22, 273–275 (2016).

14.         Rosini, F., Rufa, A., Monti, L., Tirelli, L. & Federico, A. Adult-onset phenylketonuria revealed by acute reversible dementia, prosopagnosia and parkinsonism. J Neurol 261, 2446–2448 (2014).ribute to better outcomes for those affected by this disorder.