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
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.
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