ArticleOrphanet journal of rare diseases2015
Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness.
Article in Orphanet journal of rare diseases, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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13 citing papers in PubMed, 1 synthesis or guideline pooled it, 25 citations in OpenAlex.
- Spectrum of PAH gene mutations in 1547 phenylketonuria patients from Iran: a comprehensive systematic review.Metabolic brain disease · 2021Pooled it
- Genetic diagnosis and molecular characterization of three novel variations in the phenylalanine hydroxylase gene from Chinese patients with phenylketonuria.EXCLI journal · 2026Article
- Spectrum ofBiomedical reports · 2025Article
- Genomic profiling, implications for genotype-based treatment of 131 patients with phenylketonuria and characterization of novel p.Pro416Leu PAH variant.Scientific reports · 2025Article
- Detection of Single-Nucleotide and Copy Number Defects Underlying Hyperphenylalaninemia by Next-Generation Sequencing.Biomedicines · 2023Article
- Follow-up of two newborns with c.158G>A (p.Arg53His) mutation in gene and assessment of the site function.Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2021Article
- Population and evolutionary genetics of the PAH locus to uncover overdominance and adaptive mechanisms in phenylketonuria: Results from a multiethnic study.EBioMedicine · 2020Article
- The study of the full spectrum of variants leading to hyperphenylalaninemia have revealed 10 new variants in the PAH gene.Metabolic brain disease · 2019Article
- Structural and Functional Impact of Seven Missense Variants of Phenylalanine Hydroxylase.Genes · 2019Article
- Genotype-phenotype correlations and BHMolecular genetics & genomic medicine · 2019Article
- Allelic phenotype values: a model for genotype-based phenotype prediction in phenylketonuria.Genetics in medicine : official journal of the American College of Medical Genetics · 2019Article
- Gene mutation and pedigree analysis of tetrahydrobiopterin deficiency in a Uygur family of China.Journal of clinical laboratory analysis · 2019Article
- The Predictive Value of Genetic Analyses in the Diagnosis of Tetrahydrobiopterin (BH4)-Responsiveness in Chinese Phenylalanine Hydroxylase Deficiency Patients.Scientific reports · 2017Article
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28 authors at 20 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundMutations 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.
methodsA 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.
resultsOverall, 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.
conclusionsThis 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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