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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0375-x) contains supplementary material, which is available to authorized users.
Highlights
Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria
Phenylketonuria (PKU, OMIM 261600) is an autosomal recessive disorder caused by a deficient hepatic phenylalanine hydroxylase (PAH) activity [1]
Phenotype distribution Thirty-three patients were identified as mild hyperphenylalaninemia (mHP) (9 %), 65 as mild PKU (mPKU) (17.7 %) and 266 as classic PKU (cPKU) (73.1 %)
Summary
Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria. Phenylketonuria (PKU, OMIM 261600) is an autosomal recessive disorder caused by a deficient hepatic phenylalanine hydroxylase (PAH) activity [1]. Individuals with simultaneous presence of two null alleles exhibit the classic PKU (cPKU) phenotype, whereas individuals with mutations bearing residual enzyme activity display the mild PKU (mPKU) or the mild hyperphenylalaninemia (mHP). PAH is a homotetrameric or homodimeric enzyme, whose activity is regulated by the binding of its substrate, Phenylalanine (Phe), and its cofactor, tetrahydrobiopterin (BH4). Each subunit of this multimeric enzyme is composed of the regulatory, the catalytic and the oligomerization domains [4]
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