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Classical phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are two phenotypes of phenylalanine hydroxylase (PAH) deficiency with different degrees of severity. We have analyzed three families in which classical PKU, MHP and a normal phenotype occurred within each family due to the different combinations of three mutations segregating within the family. Indeed, sequence PAH analysis revealed three different alleles segregating in each family. This report suggests that when discordant phenotypes occur in a family, complete analysis of the PAH gene may be performed in order to support the diagnosis and assist in accurate genetic counseling and patient management. We further support the marked heterogeneity of hyperphenylalaninemia primarily due to allelic heterogeneity at the PAH locus.

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 6 mg/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.