miércoles, 16 de diciembre de 2015

Orphanet Journal of Rare Diseases | Full text | Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness

Orphanet Journal of Rare Diseases | Full text | Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness



Orphanet Journal of Rare Diseases



Research  

Jeannesson-Thivisol E, Feillet F, Chéry C, Perrin P, Battaglia-Hsu S, Herbeth B, Cano A, Barth M, Fouilhoux A, Mention K, Labarthe F, Arnoux J, Maillot F, Lenaerts C, Dumesnil C, Wagner K, Terral D, Broué P, de Parscau L, Gay C, Kuster A, Bédu A, Besson G, Lamireau D, Odent S, Masurel A, Guéant J, Namour F

Orphanet Journal of Rare Diseases 2015, 10 :158 (15 December 2015)


Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness

Elise Jeannesson-Thivisol12François Feillet12Céline Chéry12Pascal Perrin12Shyue-Fang Battaglia-Hsu12Bernard Herbeth12Aline Cano3Magalie Barth4Alain Fouilhoux5,Karine Mention6François Labarthe7Jean-Baptiste Arnoux8François Maillot9Catherine Lenaerts10Cécile Dumesnil11Kathy Wagner12Daniel Terral13Pierre Broué14Loïc de Parscau15Claire Gay16Alice Kuster17Antoine Bédu18Gérard Besson19Delphine Lamireau20Sylvie Odent21Alice Masurel22Jean-Louis Guéant12 and Fares Namour12*
1Reference Center for Inherited Metabolic Diseases, University Hospital of Nancy, 9 ave Forêt de Haye, BP 184, Vandoeuvre-lès-Nancy, 54511, France
2INSERM U954, Department of Nutrition-Genetics-Environmental Risk Exposure, University of Lorraine, 9 ave Forêt de Haye, BP 184, Vandoeuvre-lès-Nancy, 54511, France
3Reference Center for Inherited Metabolic Diseases, Timone Hospital, Marseille, France
4Department of Biochemistry and Genetics, Angers University Hospital, Angers, France
5Reference Center for Inherited Metabolic Diseases, Hospices Civils de Lyon, Bron, France
6Reference Center for Inherited Metabolic Diseases, Jeanne de Flandres Hospital, Lille, France
7Department of Pediatric Medicine, Clocheville Hospital, Tours, France
8Reference Center for Inherited Metabolic Diseases, Necker-Enfants Malades Hospital, Paris, France
9Department of Internal Medicine, Tours University Hospital, Tours, France
10Department of Pediatrics, Amiens University-Hospital, Amiens, France
11Pediatric Hematology and Oncology, Rouen University-Hospital, Rouen, France
12Department of Pediatrics, Lenval Hospital, Nice, France
13Department of Pediatrics, Hotel-Dieu Hospital, Clermont-Ferrand, France
14Department of Pediatric Hepatology and Metabolic Diseases, Children Hospital, Toulouse, France
15Department of Pediatrics, CHRU Morvan, Brest, France
16Department of Pediatrics, Saint-Etienne University-Hospital, Saint-Etienne, France
17Pediatric Department, Nantes University Hospital, Nantes, France
18Neonatology Department, Mère-Enfant Hospital, Limoges, France
19Department of Neurology, University Hospital of Grenoble, Grenoble, France
20Department of Pediatrics, Pellegrin-Enfants Hospital, Bordeaux, France
21Department of Clinical Genetics, Rennes University Hospital, Rennes, France
22Department of Medical Genetics, Dijon University-Hospital, Dijon, France
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Orphanet Journal of Rare Diseases 2015, 10:158  doi:10.1186/s13023-015-0375-x

François Feillet, Jean-Louis Guéant and Fares Namour contributed equally to this work.
The electronic version of this article is the complete one and can be found online at:http://www.ojrd.com/content/10/1/158

Received:7 August 2015
Accepted:8 December 2015
Published:15 December 2015
© 2015 Jeannesson-Thivisol et al. 
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Abstract

Background

Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria. Sapropterin (BH4), the enzyme cofactor, is an important therapeutical strategy in phenylketonuria. However, PAH is a highly polymorphic gene and it is difficult to identify BH4-responsive genotypes. We seek here to improve prediction of BH4-responsiveness through comparison of genotypes, BH4-loading test, predictions of responsiveness according to the literature and types and locations of mutations.

Methods

A total of 364 French patients among which, 9 % had mild hyperphenylalaninemia, 17.7 % mild phenylketonuria and 73.1 % classical phenylketonuria, benefited from a 24-hour BH4-loading test and had the PAH gene sequenced and analyzed by Multiplex Ligation Probe Amplification.

Results

Overall, 31.6 % of patients were BH4-responsive. The number of different mutations found was 127, including 26 new mutations. The mutations c.434A > T, c.500A > T, c.529G > C, c.1045 T > G and c.1196 T > C were newly classified as being BH4-responsive. We identified 261 genotypes, among which 46 were newly recognized as being BH4-responsive. Even though patients carry 2 responsive alleles, BH4-responsiveness cannot be predicted with certainty unless they present mild hyperphenylalaninemia. BH4-responsiveness cannot be predicted in patients carrying one responsive mutation only. In general, the milder the phenotype is, the stronger the BH4-response is. Almost exclusively missense mutations, particularly in exons 12, 11 and 8, are associated with BH4-responsiveness and any other type of mutation predicts a negative response.

Conclusions

This study is the first of its kind, in a French population, to identify the phenotype associated with several combinations of PAH mutations. As others, it highlights the necessity of performing simultaneously BH4 loading test and molecular analysis in monitoring phenylketonuria patients.
Keywords: 
Phenylketonuria; Tetrahydrobiopterin; BH4-loading test; Genotype; BH4-responsiveness

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