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Phenylketonuria

Nature Reviews Disease Primers volume 7, Article number: 36 (2021) Cite this article

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Abstract

Phenylketonuria (PKU; also known as phenylalanine hydroxylase (PAH) deficiency) is an autosomal recessive disorder of phenylalanine metabolism, in which especially high phenylalanine concentrations cause brain dysfunction. If untreated, this brain dysfunction results in severe intellectual disability, epilepsy and behavioural problems. The prevalence varies worldwide, with an average of about 1:10,000 newborns. Early diagnosis is based on newborn screening, and if treatment is started early and continued, intelligence is within normal limits with, on average, some suboptimal neurocognitive function. Dietary restriction of phenylalanine has been the mainstay of treatment for over 60 years and has been highly successful, although outcomes are still suboptimal and patients can find the treatment difficult to adhere to. Pharmacological treatments are available, such as tetrahydrobiopterin, which is effective in only a minority of patients (usually those with milder PKU), and pegylated phenylalanine ammonia lyase, which requires daily subcutaneous injections and causes adverse immune responses. Given the drawbacks of these approaches, other treatments are in development, such as mRNA and gene therapy. Even though PAH deficiency is the most common defect of amino acid metabolism in humans, brain dysfunction in individuals with PKU is still not well understood and further research is needed to facilitate development of pathophysiology-driven treatments.

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Fig. 1: Phenylalanine metabolism and PKU.
Fig. 2: The prevalence of PAH deficiency and different PAH deficiency phenotypes worldwide.
Fig. 3: Timeline of milestones in the understanding and treatment of PKU.
Fig. 4: Pathological manifestations in PKU.
Fig. 5: Proposed algorithm for screening and diagnosis of PKU and monitoring treatment efficacy.

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Acknowledgements

The authors thank D. Abeln for giving his thoughts from the perspective of a parent.

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Authors and Affiliations

  1. Beatrix Children’s Hospital, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands

    Francjan J. van Spronsen

  2. University Children’s Hospital in Zurich, Zurich, Switzerland

    Nenad Blau

  3. Department of Molecular and Medical Genetics and Department of Pediatrics, Oregon Health & Science University, Oregon, USA

    Cary Harding

  4. University Hospital of Padova, Padova, Italy

    Alberto Burlina

  5. Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA

    Nicola Longo

  6. University of Amsterdam, Department of Pediatrics, Division of Metabolic Disorders, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Annet M. Bosch

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  1. Francjan J. van Spronsen
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  3. Cary Harding
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  4. Alberto Burlina
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Contributions

Introduction (F.J.v.S., N.B., C.H., A.B., N.L. and A.M.B.); Epidemiology (N.B.); Mechanisms/pathophysiology (C.H. and F.J.v.S.); Diagnosis, screening and prevention (N.B. and A.B.); Management (F.J.v.S.); Quality of life (F.J.v.S. and A.M.B.); Outlook (F.J.v.S. and N.L.).

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Correspondence to Francjan J. van Spronsen.

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Competing interests

F.J.v.S. has been a member of scientific advisory boards for defects in amino acid metabolism of APR, Agios, Arla Food International, BioMarin, Eurocept Int, Lucana, Moderna TX, Nutricia, Rivium, Homoly and Nestlé-Codexis; his institute has received research grants from Alexion, Biomarin, Codexis, Nutricia, SoBi and Vitaflo; his institute has received grants from patient organizations ESPKU, Metakids, NPKUA, Stofwisselkracht, Stichting PKU research and the Tyrosinemia Foundation; and his institute has received honoraria as consultant and speaker from APR, Pluvia, Biomarin, MendeliKABS and Nutricia. N.B. has received honoraria and/or consulting fees from BioMarin, Pharmaceuticals, Censa, Nestlé Pharmaceuticals and Homology Medicines. C.H. has received consulting fees, speaker fees, and travel and research support from BioMarin, Cydan Development Inc., Dimension Therapeutics, Horizon Pharma, Pfizer, Rubius Therapeutics, StrideBio and Synlogic. A.B. has received advisory board honoraria, speaker fees and travel support from Biomarin Pharmaceuticals, Nutricia, Cambrooke, PIAM, APR, Sanofi Genzyme and Takeda. N.L. has received consulting fees from Aeglea, BioMarin, Censa Pharmaceuticals, Dimension Therapeutics, Genzyme/Sanofi, Hemoshear, Horizon, Lumos Pharma, Moderna, Mitobridge, Pfizer, Retrophin and Stealth Therapeutics, and has conducted contracted research for Aeglea, BioMarin, Genzyme/Sanofi, Horizon, Lumos Pharma, Protalix, Retrophin, Shire, Stealth Therapeutics and Ultragenyx. A.M.B. has received a speaker fee from Nutricia and has been a member of advisory boards for Biomarin.

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Nature Reviews Disease Primers thanks T. Coskun, L. Desviat, H. Levy, A. MacDonald and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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van Spronsen, F.J., Blau, N., Harding, C. et al. Phenylketonuria. Nat Rev Dis Primers 7, 36 (2021). https://doi.org/10.1038/s41572-021-00267-0

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