Influence of PAH Genotype on Sapropterin Response in PKU: Results of a Single-Center Cohort Study

  • Sarah Leuders
  • Eva Wolfgart
  • Torsten Ott
  • Marcel du Moulin
  • Agnes van Teeffelen-Heithoff
  • Lydia Vogelpohl
  • Ulrike Och
  • Thorsten Marquardt
  • Josef Weglage
  • Reinhold Feldmann
  • Frank Rutsch
Research Report
First Online:
Received:
Revised:
Accepted:
Part of the JIMD Reports book series (JIMD, volume 13)

Abstract

Objective: Identifying phenylalanine hydroxylase (PAH) mutations associated with sapropterin response in phenylketonuria (PKU) would be an advantageous means to determine clinical benefit to sapropterin therapy.

Methods: Sapropterin response, defined as a ≥30 % reduction in phenylalanine (Phe) levels after a dose of 10 mg/kg/day sapropterin for week one and 20 mg/kg/day for week two in 112 PKU patients aged 4–45 years, was assessed in an outpatient setting. PAH was sequenced in all patients. Mutations were correlated with sapropterin response. Dietary Phe intake was increased over a 6-week period in responsive patients.

Results: Forty-six of 112 patients were sapropterin responsive. Genotypes p.[L48S];[L48S] and p.[Y414C];[Y414C] were always associated with response at a low dose. The mutation Y414C (present on 16 alleles) was most frequently associated with response. Patients with presence of the mutation L48S on at least one allele (12 alleles in 7 patients) always showed response to sapropterin. Responsive patients had a mean Phe tolerance increase of 189 % (range 11–742 %). In the 66 nonresponders, mutations R408W (38 alleles) and IVS12+1G>A (18 alleles) were detected most frequently. Genotypes [IVS12+1G>A];[IVS12+1G>A], p.[L348V];[R408W], p.[P281L];[P281L], p.[R158Q];[R408W], and p.[R261Q];[R408W] were always associated with nonresponse.

Conclusion: Data from the study contributes to growing evidence of the relationship between PAH genotype and PKU phenotype. In most cases, response to sapropterin therapy cannot be predicted based on the presence of a single mutation on one allele alone, although the complete PAH genotype may help to predict sapropterin responsiveness in PKU patients.

Keywords

European Union Sapropterin Dihydrochloride Sapropterin Treatment Homozygous R408W 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Notes

Acknowledgements

This study and medical writing support was supported by an unrestricted grant from Merck Serono S.A. Medical writing support was provided by Judy Wiles of Facet Communications Incorporated.

Supplementary material

323239_1_En_263_MOESM1_ESM.docx (50 kb)
Supplementary Table 1 Genotype and responsiveness to sapropterin treatment at high and low doses

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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Sarah Leuders
    • 1
  • Eva Wolfgart
    • 1
  • Torsten Ott
    • 1
  • Marcel du Moulin
    • 2
  • Agnes van Teeffelen-Heithoff
    • 1
  • Lydia Vogelpohl
    • 1
  • Ulrike Och
    • 1
  • Thorsten Marquardt
    • 1
  • Josef Weglage
    • 1
  • Reinhold Feldmann
    • 1
  • Frank Rutsch
    • 1
    • 3
  1. 1.Department of General PediatricsMünster University Children’s HospitalMünsterGermany
  2. 2.Department of PaediatricsUniversity Medical Center Hamburg-EppendorfHamburgGermany
  3. 3.Allgemeine Pädiatrie, Klinik und Poliklinik für Kinder- und JugendmedizinUniversitätsklinikum MünsterMuensterGermany

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