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Review
. 2017 Oct 12;12(1):162.
doi: 10.1186/s13023-017-0685-2.

The complete European guidelines on phenylketonuria: diagnosis and treatment

A M J van Wegberg  1 , A MacDonald  2 , K Ahring  3 , A Bélanger-Quintana  4 , N Blau  5   6 , A M Bosch  7 , A Burlina  8 , J Campistol  9 , F Feillet  10 , M Giżewska  11 , S C Huijbregts  12 , S Kearney  13 , V Leuzzi  14 , F Maillot  15 , A C Muntau  16 , M van Rijn  1 , F Trefz  17 , J H Walter  18 , F J van Spronsen  19
Affiliations
Review

The complete European guidelines on phenylketonuria: diagnosis and treatment

A M J van Wegberg et al. Orphanet J Rare Dis. .

Abstract

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.

Keywords: European; Guidelines; Hyperphenylalaninemia; Management; PAH deficiency; PKU; Phenylalanine; Phenylalanine hydroxylase deficiency; Phenylketonuria; Recommendations; Sapropterin; Tetrahydrobiopterin; Treatment.

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Conflict of interest statement

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

K. Ahring was/is a member of the European Nutrition Expert Panel (Merck Serono international, Biomarin).

A. Bélanger-Quintana has received honoraria as a speaker from Nutricia, Vitaflo International, Merck Serono and Recordati, and is a member of the European Nutrition Expert Panel (Merck Serono international, Biomarin), the Sapropterin Advisory Board (Merck Serono international, Biomarin), and KAMPER Advisory Board (Merck Serono international, Biomarin).

N. Blau was/is a member of Merck-Serono and Biomarin Scientific Advisory Board for PKU and has received grants and honorarium from Merck-Serono and BioMarin.

A. Bosch was/is a member of Scientific Advisory Boards for Phenylketonuria that are supported by Merck-Serono SA, Biomarin and by Nutricia, and has received grants and honorarium from Merck-Serono and Nutricia.

A. Burlina was/is a member of Scientific Advisory Boards for Phenylketonuria that are supported by Merck-Serono SA, Biomarin and by Nutricia.

J.Campistol has received honoraria as a consultant and/or speaker from Merck-Serono SA and Nutricia/Danone.

M. Giżewska was/is a member of the Scientific Advisory Board for Phenylketonuria that was supported by Merck-Serono SA, and Biomarin and received honoraria as a consultant and/or speaker for Merck Serono SA and Nutricia.

F. Feillet was/is a member of Scientific Advisory Boards for Phenylketonuria (Merck-Serono SA, Biomarin) and has received honoraria from Merck-Serono, Nutricia/Danone and Excemed.

S.C. J. Huijbregts has participated in strategic advisory boards and received honoraria as a consultant and/or speaker for Merck Serono SA, Biomarin and Nutricia.

S. Kearney received honoraria from Merck Serono and Biomarin.

A. MacDonald has received research funding and honoraria from Nutricia, Vitaflo International, Merck Serono, chaired/chairs the European Nutrition Expert Panel (Merck Serono international and later Biomarin), was/is a member of the Sapropterin Advisory Board (Merck Serono international, Biomarin), and is a member of the Advisory Board Element (Danone-Nutricia).

F. Maillot has received honoraria as a consultant and/or speaker from Merck Serono SA, Nutricia and Arla Foods.

A.C. Muntau was/is a member of Scientific Advisory Boards for Phenylketonuria (Merck Serono SA, Arla Foods, Biomarin); has received research funding from Nutricia, Vitaflo International, Merck Serono and has received honoraria from Merck Serono and Arla Foods.

M. van Rijn was a member of the European Nutritionist Expert Panel in PKU (until 2015), is a member of the ELEMENT (Leading Education in Metabolic Error Nutritional Therapy) Steering Committee for Nutricia International, and has received grants and fees for educational and research activities from Nutricia International and Orphan Europe.

F.J. van Spronsen was/is a member of Scientific Advisory Boards for Phenylketonuria (Merck-Serono SA, Arla Foods, Biomarin) and chairs the Scientific Advisory Board for metabolic diseases of Nutricia, has received grants from Nutricia and Merck-Serono SA), and honoraria from Merck-Serono SA, Vitaflo International, Nutricia/Danone, and Excemed.

F. Trefz received grants from Vitaflo and honoraria as a speaker from Merck-Serono SA.

A. van Wegberg received a grant from the ESPKU.

The other authors declare no competing of interest.

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Figures

Fig. 1
Fig. 1
Phenylalanine hydroxylating system. BH4: tetrahydrobiopterin; DHPR: dihydropteridine reductase; GTP: guanosine triphosphate; GTPCH: GTP cyclohydrolase I; Phe: Phenylalanine; PAH: phenylalanine hydroxylase; PCD: phenylalanine carbinolamie-4a-dehydratase; PTPS: 6-pyruvoyl-tetrahydropterin synthase; SR: sepiapterin reductase
Fig. 2
Fig. 2
Pathophysiology of PKU: Summary of potential mechanisms of neurocognitive impairment by high phenylalanine concentrations. Phe: phenylalanine; BBB, blood–brain barrier; LNAA: Large Neutral Amino Acids; LAT1, L-type amino acid carrier; BH4, tetrahydrobiopterin; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; Tyr, tyrosine; Trp, tryptophan
See this image and copyright information in PMC

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