Abstract
Adherence to dietary and treatment recommendations is a long-standing concern for adults and adolescents with PKU and treating clinicians. In about 20–30% of PKU patients, Phe levels may be controlled by tetrahydrobiopterin (BH4) therapy. The European PKU 2017 Guidelines recommends treatment with BH4 for cases of proven long-term BH4 responsiveness, with a recommended dosage of Sapropterin 10–20 mg/kg/day.
We report four young Irish patients with mild PKU, known to be BH4 responsive, who were treated with lower doses of Sapropterin for over 7 years.
Case 1: Female, currently age 20. Genotype p. 165T/p/F39L, c.[194T>C]; [117C>G]. Newborn Phe: 851 μmol/L. Pre-Sapropterin Phe tolerance: 600 mg Phe/day to maintain Phe levels <400 μmol/L. Commenced on Sapropterin 400 mg (6.5 mg/kg/day) with increase in Phe tolerance to 800 mg/day.
Case 2: Female, currently age 23. Genotype p. 165T/pF39L; c.[194T>C]; [117C>G]. Newborn Phe: 714 μmol/L. Pre-Sapropterin Phe tolerance: 700 mg Phe/day. Commenced on Sapropterin 400 mg (8 mg/kg/day) with increase in Phe tolerance to 800 mg/day.
Case 3: Male, currently age 22. Genotype p. 165T/p.S349P; c.[194T>C][1045T>C]. Newborn Phe: 1,036 μmol/L. Pre-Sapropterin Phe tolerance: 600 mg Phe/day. Commenced on Sapropterin 400 mg (5.4 mg/kg/day). Increased to 1,600 mg Phe/day.
Case 4: Female, currently age 29. Genotype p.R408W/p/p.Y414C; c.[1222C>T], [1241A>G]. Newborn Phe: 1,600 μmol/L. Pre-Sapropterin tolerance: 450 mg/day. Commenced on Sapropterin 400 mg (5.0 mg/kg/day). Increased to 900 mg Phe/day.
Almost 7 years of surveillance for these four patients has shown that this dose of Sapropterin (range 5–8 mg/kg day) was well tolerated and effective with a significant response to treatment and a marked improvement in quality of life at these lower Sapropterin doses.
This is a preview of subscription content, log in via an institution to check access.
References
Arnold GL, Vladutiu CJ, Orlaski CC et al (2004) Prevalence of stimulant use for attentional dysfunction in children with phenylketonuria. J Inherit Metab Dis 27:137–143
Bosch AM, Burlina A, Cunningham A et al (2015) Assessment of the impact of phenylketonuria and its treatment on quality of life of patients and parents from seven European countries. Orphanet J Rare Dis 10:80. https://doi.org/10.1186/s 13023-015-0294-x
Burton BK, Leviton L, Vespa H et al (2013) A diversified approach for PKU treatment: routine screening yields high incidence of psychiatric distress in phenylketonuria clinics. Mol Genet Metab 108:8–12
Cazzoria C, Cegolon L, Burlina AP et al (2014) Quality of Life (QoL) assessment in a cohort of patients with phenylketonuria. BMC Public Health 14:1243
Demirdas S, Maurice-Stam H, Boelen CC et al (2013) Evaluation of quality of life in PKU before and after introducing tetrahydrobiopterin (BH4); a prospective multi-center cohort study. Mol Genet Metab 110(Suppl):S49–S56
Douglas TD, Ramakrishan U, Kabie JA et al (2013) Longitudinal quality of life analysis in a phenylketonuria cohort provided sapropterin dihydrochloride. Health Qual Life Outcomes 11:218
Feldmann R, Wolfgart E, Weglage J et al (2017) Sapropterin treatment does not enhance the health-related quality of life of patients with phenylketonuria and their parents. Acta Paediatr 106:953–958
Heintz C, Cotton RG, Blau N (2013) Tetrahydrobiopterin, its mode of action on phenylalanine hydroxylase, and importance of genotypes for pharmacological therapy of phenylketonuria. Hum Mutat 34(7):927–936
Hennermann JB, Roloff S, Gebauer C et al (2012) Long-term treatment with tetrahydrobiopterin in phenylketonuria: treatment strategies and prediction of long-term responders. Mol Genet Metab 107:294–301
Jurecki ER, Cederbaum S, Kopesky J et al (2017) Adherance to clinic recommendations among patients with phenylketonuria in the United States. Mol Genet Metab 120(3):190–197
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 146A(22):2851–2859
Levy HL, Milanowski A, Chakrapani A et al (2007) Efficacy of sapropterin dishydrochloride (tetrahydrobioptern, 6R-BH4) for reduction of phenylanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet 370(9586):504–510
Lindegren ML, Krishnaswami S, Reimschisel T et al (2013) A systematic review of BH4 (sapropterin) for the adjuvant treatment of phenylketonuria. JIMD Rep 8:109–119
O’Mahony JF, Coughlan D (2016) The Irish cost-effectiveness threshold: does it support rational rationing or might it lead to unintended harm to Ireland’s health system? PharmacoEconomics 34(1):5–11
Scala I, Concolino D, Della Casa R et al (2015) Long-term follow-up of patients with Phenylketonuria treated with tetrahydrobiopterin: a seven years experience. Orphanet J Rare Dis 10:14. https://doi.org/10.1186/s13023-015-0227-8
Van Spronsen FJ, Van Wegberg AM, Ahring K et al (2017) Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol 5(9):743–756. https://doi.org/10.1016/S2213-8587(16)30320-5. [Epub ahead of print]
Vockley J, Andersson HC, Antshel KM et al (2014) Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med 16:188–200
Walter JH, White FJ, Hall SK et al (2002) How practical are recommendations for dietary control in phenylketonuria? Lancet 360(9326):55–57
Acknowledgement
Ms. Maebh Durkin R. D. is thanked for her assistance with the dietary analysis.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Avihu Boneh, MD, PhD, FRACP
Rights and permissions
Copyright information
© 2017 Society for the Study of Inborn Errors of Metabolism (SSIEM)
About this chapter
Cite this chapter
Doyle, S. et al. (2017). Extended Experience of Lower Dose Sapropterin in Irish Adults with Mild Phenylketonuria. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 40. JIMD Reports, vol 40. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2017_63
Download citation
DOI: https://doi.org/10.1007/8904_2017_63
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-57879-7
Online ISBN: 978-3-662-57880-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)