Mutation analysis in hyperphenylalaninemia patients from South Italy.

BACKGROUND: Mutations in the gene encoding phenylalanine hydroxylase (PAH, EC 1.14.16.1) are associated with various degrees of hyperphenylalaninemia (HPA), including classical phenylketonuria (PKU). OBJECTIVE: The aim of the study was to determine the mutations responsible for mild forms of HPA and to relate different clinical phenotypes of HPA patients to their PAH genotypes in order to better predict the clinical phenotype and implement optimal dietary therapy and prognosis in newborns with the disease. METHODS: Phenylalanine hydroxylase (PAH) gene mutations have been analyzed by direct DNA sequencing in 30 HPA patients (Phe levels ranging from 2 to 6mg/dL) from Southern Italy who were identified in a neonatal screening program and a genotype-phenotype correlation was performed. RESULTS: PAH gene mutation was identified in 39 out of 60 alleles with a mutation detection rate of 65%. Eighteen mutations, 2 undescribed, were observed (13 missense mutations, 1 deletion, 4 splice site mutations). Using the "in vitro" predicted residual activity, a good genotype-phenotype correlation was obtained also in a new mild HPA case, a PAH compound heterozygote, previously undetected. CONCLUSION: A marked genetic heterogeneity was found in HPA patients from Southern Italy and a good genotype-phenotype correlation was obtained. Identification of PAH gene mutations responsible for PAH deficiency will therefore be useful in the prediction of biochemical and clinical phenotypes in HPA patients.