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.
Sarah Leuders and Eva Wolfgart contributed equally to this study
Competing interests: None declared
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Blau N, Bélanger-Quintana A, Demirkol M et al (2009) Optimizing the use of sapropterin (BH4) in the management of phenylketonuria. Mol Genet Metab 96:158–163
Burgard P, Bremer HJ, Bührdel P et al (1999) Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997. Eur J Pediatr 158:46–54
Dobrowolski SF, Borski K, Ellingson CC, Koch R, Levy HL, Naylor EW (2009) A limited spectrum of phenylalanine hydroxylase mutations is observed in phenylketonuria patients in western Poland and implications for treatment with 6R tetrahydrobiopterin. J Hum Genet 54:335–339
Eisensmith RC, Goltsov AA, O’Neill C et al (1995) Recurrence of the R408W mutation in the phenylalanine hydroxylase locus in Europeans. Am J Hum Genet 56:278–286
Enns GM, Koch R, Brumm V et al (2010) Suboptimal outcomes in patients with PKU treated early with diet alone: revisiting the evidence. Mol Genet Metab 101:99–109
Fiege B, Blau N (2007) Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria. J Pediatr 150(6):627–630
Gersting SW, Lagler FB, Eichinger A et al (2010) Pah enu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo. Hum Mol Genet 19:2039–2049
Karacic I, Meili D, Saravka V et al (2009) Genotype-predicted tetrahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) deficiency. Mol Genet Metab 97:165–171
Kure S, Hou DC, Ohura T et al (1999) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr 135:375–378
Kuvan® US Prescribing Information. http://www.kuvan.com/hcp/kuvan-full-prescribing-information.html, Accessed Sep 2013
Lee P, Treacy EP, Crombez E et al (2008) Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria. Am J Med Genet A 146A:2851–2859
Levy H, Milanowski A, Chakrapami A et al (2007) Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase II randomised placebo-controlled study. Lancet 370:504–510
Muntau AC, Röschinger W, Habich M et al (2002) Tetrahydrobiopterin as an alternative treatment for mild phenalketonuria. N Engl J Med 347:2122–2132
National Institutes of Health Consensus Development Panel (2001) National Institutes of Health Consensus Development Conference Statement: Phenylketonuria: screening and management, October 16-18, 2000. Pediatrics 108:972–982
Polak E, Ficek A, Radvanszky J et al (2013) Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genptype-based predictions of BH4-responsiveness. Gene 526(2):347–355
Schweitzer-Krantz S, Burgard P (2000) Survey of national guidelines for the treatment of phenylketonuria. Eur J Pediatr 159(Suppl 2):70–73
Scriver CR, Kaufman S (2001) Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) Metabolic and molecular basis of inherited disease. McGraw-Hill, New York, pp 1667–1724
Scriver CR, Levy H, Donlon J (2008) Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A (eds) The online metabolic and molecular bases of inherited disease. http://www.ommbid.com. chapter 77
Staudigl M, Gersting SW, Danecka MK (2011) The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response. Hum Mol Genet 20:2628–2641
Thöny B, Ding Z, Martinez A (2004) Tetrahydrobioterin protects phenylalanine hydroxylase activity in vivo: implications for tetrahydrobiopterin-responsive hyperphenylalaninemia. FEBS Lett 577:507–511
Trefz FK, Burton BK, Longo N et al (2009a) Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a Phase III, randomized, double-blind, placebo controlled study. Pediatrics 154:700–707
Trefz FK, Scheible D, Götz H, Frauendienst-Egger G (2009b) Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria. J Inherit Metab Dis 32:22–26
Utz JRJ, Lorentz CP, Markowitz D et al (2012) START, a double blind, placebo-controlled pharmacogenetic test of responsiveness to sapropterin dihydrochloride in phenylketonuria patients. Mol Genet Metab 105:193–197
Walter JH, White FJ, Hall SK et al (2002) How practical are recommendations for dietary control in phenylketonuria? Lancet 360:55–57
Wang L, Surendran S, Michals-Matalon K et al (2007) Mutations in the regulatory domain of phenylalanine hydroxylase and response to tetrahydrobiopterin. Genet Test 11:174–178
Weglage J, Ullrich K, Pietsch M et al (1996) Untreated non-phenylketonuric-hyperphenylalaninaemia: intellectual and neurological outcome. Eur J Pediatr 155(Suppl 1):S26–S28
Zschocke J (2003) Phenylketonuria mutations in Europe. Hum Mutat 21:345–356
Zurflüh MR, Zschocke J, Lindner M et al (2008) Molecular genetics of tetrahydrobiopterin responsive phenylalanine hydroxylase deficiency. Hum Mutat 29:167–175
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.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Nenad Blau, PhD
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Rights and permissions
Copyright information
© 2013 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Leuders, S. et al. (2013). Influence of PAH Genotype on Sapropterin Response in PKU: Results of a Single-Center Cohort Study. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports - Case and Research Reports, Volume 13. JIMD Reports, vol 13. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2013_263
Download citation
DOI: https://doi.org/10.1007/8904_2013_263
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-54148-3
Online ISBN: 978-3-642-54149-0
eBook Packages: MedicineMedicine (R0)