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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2018

Open Access 01-12-2018 | Position statement

Diagnostic and therapeutic recommendations for the treatment of hyperphenylalaninemia in patients 0–4 years of age

Authors: Ania C. Muntau, Marcel du Moulin, Francois Feillet

Published in: Orphanet Journal of Rare Diseases | Issue 1/2018

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Abstract

Background

Treatment of phenylketonuria (PKU) with sapropterin dihydrochloride in responsive patients from an early age can have many advantages for the patient over dietary restriction alone. Accordingly, approval of sapropterin in the European Union was extended in 2015 to include patients aged 0–4 years, bringing the treatment age range in line with that in the USA and providing an additional treatment option for those patients with PKU who are responsive or partially responsive to treatment with sapropterin. Subsequently, European guidelines have been published on the diagnosis and management of patients with PKU. However, testing for PKU can be demanding and requires particular expertise. We have compiled experience-based, real-world guidance in an algorithmic format to complement the published guidelines, with the overall aim to achieve optimized and individualized care for patients with PKU.

Results

Our guidance covers aspects such as how to perform, monitor and interpret appropriate biochemical measures to achieve effective patient management and desired outcomes, how to perform a tetrahydrobiopterin (BH4) loading test to assess responsiveness in newborns, and how to initiate sapropterin treatment in patients from birth. We also provide our expert opinion on starting pharmacotherapy in patients who were previously managed by diet alone.

Conclusions

Real-world-based guidance is particularly important in managing therapeutic strategies in newborns with PKU to achieve optimal long-term outcomes and will serve as a complement to the other published guidelines.
Appendix
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Literature
1.
Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376(9750):1417–27.CrossRef
2.
Feillet F, van Spronsen FJ, MacDonald A, Trefz FK, Demirkol M, Giovannini M, Belanger-Quintana A, Blau N. Challenges and pitfalls in the management of phenylketonuria. Pediatrics. 2010;126(2):333–41.CrossRef
3.
Ozalp I, Coskun T, Tokatli A, Kalkanoglu HS, Dursun A, Tokol S, Koksal G, Ozguc M, Kose R. Newborn PKU screening in Turkey: at present and organization for future. Turk J Pediatr. 2001;43(2):97–101.PubMed
4.
Guldberg P, Henriksen KF, Sipila I, Guttler F, de la Chapelle A. Phenylketonuria in a low incidence population: molecular characterisation of mutations in Finland. J Med Genet. 1995;32(12):976–8.CrossRef
5.
Aoki K, Ohwada M, Kitagawa T. Long-term follow-up study of patients with phenylketonuria detected by the newborn screening programme in Japan. J Inherit Metab Dis. 2007;30(4):608.CrossRef
6.
Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16(2):188–200.CrossRef
7.
NSP. Management of PKU. UK: National Society for Phenylketonuria Limited; 2004.
8.
Loeber JG. Neonatal screening in Europe; the situation in 2004. J Inherit Metab Dis. 2007;30(4):430–8.CrossRef
9.
Zhou YA, Ma YX, Zhang QB, Gao WH, Liu JP, Yang JP, Zhang GX, Zhang XG, Yu L. Mutations of the phenylalanine hydroxylase gene in patients with phenylketonuria in Shanxi, China. Genet Mol Biol. 2012;35(4):709–13.CrossRef
10.
Mei L, Song P, Xu L. Newborn screening and related policy against phenylketonuria in China. Intractable Rare Dis Res. 2013;2(3):72–6.PubMedPubMedCentral
11.
Targum SD, Lang W. Neurobehavioral problems associated with phenylketonuria. Psychiatry (Edgmont). 2010;7(12):29–32.
12.
Bernegger C, Blau N. High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1,919 patients observed from 1988 to 2002. Mol Genet Metab. 2002;77(4):304–13.CrossRef
13.
Mitchell JJ, Wilcken B, Alexander I, Ellaway C, O'Grady H, Wiley V, Earl J, Christodoulou J. Tetrahydrobiopterin-responsive phenylketonuria: the New South Wales experience. Mol Genet Metab. 2005;86(Suppl 1):S81–5.CrossRef
14.
Muntau AC, Roschinger W, Habich M, Demmelmair H, Hoffmann B, Sommerhoff CP, Roscher AA. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med. 2002;347(26):2122–32.CrossRef
15.
16.
Fiori L, Fiege B, Riva E, Giovannini M. Incidence of BH4-responsiveness in phenylalanine-hydroxylase-deficient Italian patients. Mol Genet Metab. 2005;86(Suppl 1):S67–74.CrossRef
17.
Hennermann JB, Buhrer C, Blau N, Vetter B, Monch E. Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Mol Genet Metab. 2005;86(Suppl 1):S86–90.CrossRef
18.
Keil S, Anjema K, van Spronsen FJ, Lambruschini N, Burlina A, Belanger-Quintana A, Couce ML, Feillet F, Cerone R, Lotz-Havla AS, et al. Long-term follow-up and outcome of phenylketonuria patients on sapropterin: a retrospective study. Pediatrics. 2013;131(6):e1881–8.CrossRef
19.
Zimmermann M, Jacobs P, Fingerhut R, Torresani T, Thony B, Blau N, Baumgartner MR, Rohrbach M. Positive effect of a simplified diet on blood phenylalanine control in different phenylketonuria variants, characterized by newborn BH4 loading test and PAH analysis. Mol Genet Metab. 2012;106(3):264–8.CrossRef
20.
Leuret O, Barth M, Kuster A, Eyer D, de Parscau L, Odent S, Gilbert-Dussardier B, Feillet F, Labarthe F. Efficacy and safety of BH4 before the age of 4 years in patients with mild phenylketonuria. J Inherit Metab Dis. 2012;35(6):975–81.CrossRef
21.
Longo N, Siriwardena K, Feigenbaum A, Dimmock D, Burton BK, Stockler S, Waisbren S, Lang W, Jurecki E, Zhang C, et al. Long-term developmental progression in infants and young children taking sapropterin for phenylketonuria: a two-year analysis of safety and efficacy. Genet Med. 2015;17(5):365–73.CrossRef
22.
Muntau AC, Burlina A, Eyskens F, Freisinger P, De Laet C, Leuzzi V, Rutsch F, Sivri HS, Vijay S, Bal MO, et al. Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial. Orphanet J Rare Dis. 2017;12(1):47.CrossRef
23.
Shintaku H, Ohura T. Sapropterin is safe and effective in patients less than 4-years-old with BH4-responsive phenylalanine hydrolase deficiency. J Pediatr. 2014;165(6):1241–4.CrossRef
24.
Trefz FK, Scheible D, Frauendienst-Egger G. Long-term follow-up of patients with phenylketonuria receiving tetrahydrobiopterin treatment. J Inherit Metab Dis. 2010;33(Suppl 3):S163–9.CrossRef
25.
26.
Blau N, Belanger-Quintana A, Demirkol M, Feillet F, Giovannini M, MacDonald A, Trefz FK, van Spronsen FJ. Optimizing the use of sapropterin (BH(4)) in the management of phenylketonuria. Mol Genet Metab. 2009;96(4):158–63.CrossRef
27.
Singh RH, Rohr F, Frazier D, Cunningham A, Mofidi S, Ogata B, Splett PL, Moseley K, Huntington K, Acosta PB, et al. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genet Med. 2014;16(2):121–31.CrossRef
28.
Danecka MK, Woidy M, Zschocke J, Feillet F, Muntau AC, Gersting SW. Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria. J Med Genet. 2015;52(3):175–85.CrossRef
29.
van Wegberg AMJ, MacDonald A, Ahring K, Belanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Gizewska M, et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12(1):162.CrossRef
30.
Anjema K, Hofstede FC, Bosch AM, Rubio-Gozalbo ME, de Vries MC, Boelen CC, van Rijn M, van Spronsen FJ. The neonatal tetrahydrobiopterin loading test in phenylketonuria: what is the predictive value? Orphanet J Rare Dis. 2016;11:10.CrossRef
31.
Longo N. Disorders of biopterin metabolism. J Inherit Metab Dis. 2009;32(3):333–42.CrossRef
32.
Staudigl M, Gersting SW, Danecka MK, Messing DD, Woidy M, Pinkas D, Kemter KF, Blau N, Muntau AC. The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response. Hum Mol Genet. 2011;20(13):2628–41.CrossRef
33.
Musson DG, Kramer WG, Foehr ED, Bieberdorf FA, Hornfeldt CS, Kim SS, Dorenbaum A. Relative bioavailability of sapropterin from intact and dissolved sapropterin dihydrochloride tablets and the effects of food: a randomized, open-label, crossover study in healthy adults. Clin Ther. 2010;32(2):338–46.CrossRef
34.
Trefz FK, Burton BK, Longo N, Casanova MM, Gruskin DJ, Dorenbaum A, Kakkis ED, Crombez EA, Grange DK, Harmatz P, et al. 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(5):700–7.CrossRef
Metadata
Title
Diagnostic and therapeutic recommendations for the treatment of hyperphenylalaninemia in patients 0–4 years of age
Authors
Ania C. Muntau
Marcel du Moulin
Francois Feillet
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2018
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-018-0911-6

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