The mutational spectrum analysis showed 47 distinct mutations in 89 families, 37 of them (78.7 % ) corresponding to missense mutations. Six mutations account for 47.2 % of all the investigated alleles, each one with a frequency ¡Ý 5 % (IVS10-11G>A, p.R261Q, p.V388M, p.R176L, p.E280K, p.A300S). The most prevalent HPA mutations in Galicia are the common Mediterranean mutation IVS10-11G>A and p.R261Q, with frequencies of 13.8 % and 10.5 % , respectively. One novel mutation (p.K361Q; c.1081A>C) was also reported. Although a good genotype-phenotype correlation is observed, there is no exact correlation for some genotypes involving mutations p.R261Q, p.I65T or IVS10-11G>A.
Forty seven patients were monitored for post-challenge BH4, establishing genotype-based predictions of BH4-responsiveness in all of them. All phenylketonuric patients with 2 nonresponsive mutations were unresponsive to BH4 and patients with mutations previously associated with BH4 responsiveness in the two alleles had a clear positive response to the test, with the exception of 5 patients with mutations p.R261Q, p.I65T and p.R68S.
Our study supports a similar degree of heterogeneity of the HPA mutation spectrum in Galicia compared to reported data from Southern Europe. Patients carrying null mutations in both alleles showed the highest degree of concordance with the most severe phenotypes. Genotype is a good predictor of BH4 response.