Advertisement

Drugs

pp 1–6 | Cite as

Phenylketonuria: Current Treatments and Future Developments

  • Uta Lichter-KoneckiEmail author
  • Jerry Vockley
Leading Article

Abstract

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.

Notes

Compliance with Ethical Standards

Funding

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.

References

  1. 1.
    Kaufman S. Phenylketonuria: biochemical mechanisms, 1–32. In: Agranoff BW, Aprison MH (eds): Adv Neurochem, 1976, vol 2. Plenum Press, New York.Google Scholar
  2. 2.
    Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, Bodamer OA, Brosco JP, Brown CS, Burlina AB, Burton BK, Chang CS, Coates PM, Cunningham AC, Dobrowolski SF, Ferguson JH, Franklin TD, Frazier DM, Grange DK, Greene CL, Groft SC, Harding CO, Howell RR, Huntington KL, Hyatt-Knorr HD, Jevaji IP, Levy HL, Lichter-Konecki U, Lindegren ML, Lloyd-Puryear MA, Matalon K, MacDonald A, McPheeters ML, Mitchell JJ, Mofidi S, Moseley KD, Mueller CM, Mulberg AE, Nerurkar LS, Ogata BN, Pariser AR, Prasad S, Pridjian G, Rasmussen SA, Reddy UM, Rohr FJ, Singh RH, Sirrs SM, Stremer SE, Tagle DA, Thompson SM, Urv TK, Utz JR, van Spronsen F, Vockley J, Waisbren SE, Weglicki LS, White DA, Whitley CB, Wilfond BS, Yannicelli S, Young JM. Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol Genet Metab. 2014;112:87–122 (PMID: 24667081).CrossRefGoogle Scholar
  3. 3.
    Bickel H, Gerrard J, Hickmans EM. Influence of phenylalanine intake on phenylketonuria. Lancet. 1953;265(6790):812–3.CrossRefGoogle Scholar
  4. 4.
    Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics. 1963;32:338–43.Google Scholar
  5. 5.
    Mabry CC, Denniston JC, Nelson TL, Son CD. Maternal phenylketonuria. A cause of mental retardation in children without the metabolic defect. N Engl J Med. 1963;269:1404–8.CrossRefGoogle Scholar
  6. 6.
    Williamson ML, Koch R, Azen C, Chang C. Correlates of intelligence test results in treated phenylketonuric children. Pediatrics. 1981;68(2):161–7.Google Scholar
  7. 7.
    Kaufman S. An evaluation of the possible neurotoxicity of metabolites of phenylalanine. J Pediatr. 1989;114:895–900.CrossRefGoogle Scholar
  8. 8.
    Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA, American College of Medical Genetics and Genomics Therapeutics Committee. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16(2):188–200 (Erratum in: Genet Med. 2014;16(4):356.).CrossRefGoogle Scholar
  9. 9.
    Acosta P, Yannicelli S. in The Ross Metabolic Formula System Nutrition Support Protocols. ed 4. Columbus: Ross Products Division/Abbot Laboratories; 2001. Protocol 1 – phenylketonuria (PKU).Google Scholar
  10. 10.
    Güttler F, Wamberg E. On indications for treatment of the hyperphenylalaninemic neonate. Acta Paediatr Scand. 1977;66(3):339–44.CrossRefGoogle Scholar
  11. 11.
    MacLeod EL, Gleason ST, van Calcar SC, Ney DM. Reassessment of phenylalanine tolerance in adults with phenylketonuria is needed as body mass changes. Mol Genet Metab. 2009;98(4):331–7.CrossRefGoogle Scholar
  12. 12.
    Walter JH, White FJ. Blood phenylalanine control in adolescents with phenylketonuria. Int J Adolesc Med Health. 2004;16(1):41–5 (PMID: 15148857).CrossRefGoogle Scholar
  13. 13.
    Pietz J, Kreis R, Rupp A, Mayatepek E, Rating D, Boesch C, Bremer HJ. Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest. 1999;103(8):1169–78.CrossRefGoogle Scholar
  14. 14.
    Bartholomé K, Byrd DJ, Kaufman S, Milstien S. Atypical phenylketonuria with normal phenylalanine hydroxylase and dihydropteridine reductase activity in vitro. Pediatrics. 1977;59(5):757–61.Google Scholar
  15. 15.
    Schaub J, Däumling S, Curtius HC, Niederwieser A, Bartholomé K, Viscontini M, Schircks B, Bieri JH. Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis. Arch Dis Child. 1978;53(8):674–6.CrossRefGoogle Scholar
  16. 16.
    Trefz FK, Aulela-Scholz C, Blau N. Successful treatment of phenylketonuria with tetrahydrobiopterin. Eur J Pediatr. 2001;160(5):315.CrossRefGoogle Scholar
  17. 17.
    Kuvan™ (Sapropterin Dihydrochloride) prescribing information, BioMarin Pharmaceutical Inc., Novato, CA, 2013. (v5/2015, revised: 07/2015).Google Scholar
  18. 18.
    Trefz FK, Burton BK, Longo N, Casanova MM, Gruskin DJ, Dorenbaum A, Kakkis ED, Crombez EA, Grange DK, Harmatz P, Lipson MH, Milanowski A, Randolph LM, Vockley J, Whitley CB, Wolff JA, Bebchuk J, Christ-Schmidt H, Hennermann JB, Sapropterin Study G. Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. J Pediatr. 2009;154:700–7.CrossRefGoogle Scholar
  19. 19.
    Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U. Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab. 2011;104:S2–9 (PMID: 21937252).CrossRefGoogle Scholar
  20. 20.
    Guldberg P, Levy HL, Hanley WB, Koch R, Matalon R, Rouse BM, Trefz F, de la Cruz F, Henriksen KF, Güttler F. Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study. Am J Hum Genet. 1996;59(1):84–94.Google Scholar
  21. 21.
    Grange DK, Hillman RE, Burton BK, Yano S, Vockley J, Fong CT, Hunt J, Mahoney JJ, Phenylketonuria Demographics Outcomes and Safety (PKUDOS) registry; Maternal Phenylketonuria Observational Program (PKU MOMS) sub-registry. Cohen-Pfeffer JL Sapropterin dihydrochloride use in pregnant women with phenylketonuria: an interim report of the PKU MOMS sub-registry. Mol Genet Metab. 2014;112(1):9–16.  https://doi.org/10.1016/j.ymgme.2014.02.016 (Epub 2014 Mar 12).CrossRefGoogle Scholar
  22. 22.
    Hoskins JA, Jack G, Wade HE, Peiris RJ, Wright EC, Starr DJ, Stern J. Enzymatic control of phenylalanine intake in phenylketonuria. Lancet. 1980;1(8165):392–4.CrossRefGoogle Scholar
  23. 23.
    Sarkissian CN, Shao Z, Blain F, Peevers R, Su H, Heft R, Chang TM, Scriver CR. A different approach to treatment of phenylketonuria: phenylalanine degradation with recombinant phenylalanine ammonia lyase. Proc Natl Acad Sci USA. 1999;96(5):2339–44 (PMID: 10051643).CrossRefGoogle Scholar
  24. 24.
    Sarkissian CN, Gámez A. Phenylalanine ammonia lyase, enzyme substitution therapy for phenylketonuria, where are we now? Mol Genet Metab. 2005;86(Suppl 1):S22-6 (Epub 2005 Sep 13. Review).Google Scholar
  25. 25.
    Zori R, Thomas JA, Shur N, Rizzo WB, Decker C, Rosen O, Li M, Schweighardt B, Larimore K, Longo N. Induction, titration, and maintenance dosing regimen in a phase 2 study of pegvaliase for control of blood phenylalanine in adults with phenylketonuria. Mol Genet Metab. 2018;125:217–27 (PMID: 30146451).CrossRefGoogle Scholar
  26. 26.
    Thomas J, Levy H, Amato S, Vockley J, Zori R, Dimmock D, Harding CO, Bilder DA, Weng HH, Olbertz J, Merilainen M, Jiang J, Larimore K, Gupta S, Gu Z, Northrup H, PRISM investigators. Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM). Mol Genet Metab. 2018;124(1):27–38 (PMID: 29653686).CrossRefGoogle Scholar
  27. 27.
    Longo N, Zori R, Wasserstein MP, Vockley J, Burton BK, Decker C, Li M, Lau K, Jiang J, Larimore K, Thomas JA. Long-term safety and efficacy of pegvaliase for the treatment of phenylketonuria in adults: combined phase 2 outcomes through PAL-003 extension study. Orphanet J Rare Dis. 2018;13:108 (PMID: 29973227).CrossRefGoogle Scholar
  28. 28.
    Sarkissian CN, Gámez A, Wang L, Charbonneau M, Fitzpatrick P, Lemontt JF, Zhao B, Vellard M, Bell SM, Henschell C, Lambert A, Tsuruda L, Stevens RC, Scriver CR. Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria. Proc Natl Acad Sci USA. 2008;105(52):20894–9.  https://doi.org/10.1073/pnas.0808421105.CrossRefGoogle Scholar
  29. 29.
    Palynziq prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761079s000lbl.pdf. Accessed 9 April 2018.
  30. 30.
    Harding CO, Gillingham MB, Hamman K, Clark H, Goebel-Daghighi E, Bird A, Koeberl DD. Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria. Gene Ther. 2006;13:457–62.CrossRefGoogle Scholar

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

Personalised recommendations