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Phenylketonuria: Current Treatments and Future Developments

  • Uta Lichter-KoneckiEmail author
  • Jerry Vockley
Leading Article


Phenylalanine hydroxylase (PAH) deficiency is an inborn error of metabolism that results in elevated phenylalanine levels in blood. The classical form of the disease with phenylalanine level > 1200 µmol/L in blood is called phenylketonuria (PKU) and is associated with severe intellectual disability when untreated. In addition, phenylalanine levels above the therapeutic range in pregnant female patients lead to adverse fetal effects. Lowering the plasma phenylalanine level prevents intellectual disability, maintaining the level in the therapeutic range of 120–360 µmol/L is associated with good outcome for patients as well as their pregnancies. Patient phenotypes are on a continuous spectrum from mild hyperphenylalaninemia to mild PKU, moderate PKU, and severe classic PKU. There is a good correlation between the biochemical phenotype and the patient’s genotype. For over four decades the only available treatment was a very restrictive low phenylalanine diet. This changed in 2007 with the approval of cofactor therapy which is effective in up to 55% of patients depending on the population. Cofactor therapy typically is more effective in patients with milder forms of the disease and less effective in classical PKU. A new therapy has just been approved that can be effective in all patients with PAH deficiency regardless of their degree of enzyme deficiency or the severity of their phenotype. This article reviews the mainstay therapy, adjunct enzyme cofactor therapy, and the newly available enzyme substitution therapy for hyperphenylalaninemia. It also provides an outlook on emerging approaches for hyperphenylalaninemia treatment such as recruiting the microbiome into the therapeutic endeavor as well as therapies under development such as gene therapy.


Compliance with Ethical Standards


No financial assistance was obtained to prepare this publication.

Conflict of interest

ULK and JV have participated in clinical trials sponsored by BioMarin Pharmaceuticals, manufacturer of sapropterin and pegvaliase. JV is funded for research on PKU by the National Institutes of Health. JV has served as a consultant for Homology Pharmaceuticals, Moderna Pharmaceuticals, Synlogic Pharmaceuticals, ATG gene therapies, and Kaleido Pharmaceuticals.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, School of MedicineCenter for Rare Disease Therapy, UPMC Children’s Hospital of PittsburghPittsburghUSA

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