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

Elise Jeannesson-Thivisol 1 François Feillet 2, 1 Céline Chéry 1 Pascal Perrin 1 Shyue-Fang Battaglia-Hsu 1 Bernard Herbeth 1 Aline Cano 3, 4 Magalie Barth 5 Alain Fouilhoux 6 Karine Mention 7 François Labarthe 8 Jean-Baptiste Arnoux 9 François Maillot 10 Catherine Lenaerts 11 Cécile Dumesnil 12 Kathy Wagner 13 Daniel Terral 14 Pierre Broué 15 Loïc De Parscau 16 Claire Gay 17 Alice Kuster 8 Antoine Bedu 18 Gérard Besson 19 Delphine Lamireau 20 Sylvie Odent 21 Alice Masurel 22 Jean-Louis Guéant 1 Fares Namour 1
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 \textgreater T, c.500A \textgreater T, c.529G \textgreater C, c.1045 T \textgreater G and c.1196 T \textgreater 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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Orphanet Journal of Rare Diseases, BioMed Central, 2015, 10 (1), pp.158. 〈10.1186/s13023-015-0375-x〉
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Elise Jeannesson-Thivisol, François Feillet, Céline Chéry, Pascal Perrin, Shyue-Fang Battaglia-Hsu, et al.. Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness. Orphanet Journal of Rare Diseases, BioMed Central, 2015, 10 (1), pp.158. 〈10.1186/s13023-015-0375-x〉. 〈hal-01255861〉

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