Molecular epidemiology and genotype-phenotype correlation in phenylketonuria patients from South Spain

J Hum Genet. 2013 May;58(5):279-84. doi: 10.1038/jhg.2013.16. Epub 2013 Mar 21.


The aim of this study was to identify the most common genotypes in the phenylketonuria (PKU) population of Andalusia, assessing the correlation with the phenotype and the usefulness in predicting the response to treatment with tetrahydrobiopterin. We conducted a retrospective observational study between January 1980 and January 2010 in 147 Andalusian PKU patients assessing phenotype, genotype and response to a 24-h BH4 loading test. Our cohort of patients exhibited 65 different mutations, 69.2% corresponding to the missense type, in a total of 123 different genotypes. IVS10nt-11g>a was the most common mutation (10.9%). Four novel missense mutations were identified: p.L258P; p.E66K, p.R155C and p.P122S. Although generally there is a good genotype-phenotype correlation, for eight of the repeated genotypes a slightly different phenotype was observed. In 96 PKU subjects BH4 challenge was carried out. Patients with previously reported unresponsive mutations on both alleles showed a negative response, while 95.5% (28/29) of the responsive patients carry at least one missense mutation previously associated to the BH4. Our data reveal a great genetic heterogeneity in the Andalusian population. Genotype is quite a good predictor of the phenotype and of the responsiveness to tetrahydrobiopterin, which is relevant for patient management and follow-up.

MeSH terms

  • Adolescent
  • Alleles
  • Child
  • Child, Preschool
  • Female
  • Genetic Association Studies*
  • Genotype
  • Humans
  • Male
  • Molecular Epidemiology
  • Mutation
  • Phenotype
  • Phenylalanine Hydroxylase / genetics
  • Phenylketonurias / epidemiology*
  • Phenylketonurias / genetics*
  • Spain / epidemiology


  • Phenylalanine Hydroxylase