J. Inher. Meìab. Dis. 19 (1996) 15-24 © SSIEM and Kluwer Academic Publishcrs. Printed in thè Nelhcrlaiuis PAH deficiency in Italy: correlation of genotype with phenotype in thè Sicilian population V. ROMANO'*, P. GuLDBERC2, F. GÙTTLER2, C. MELI'. F. MOLLICA', L. PAVONE-, M. GlOVANNINI 4, E. RIVA4, G. BlASUCCI 4, D. LUOTTI4, L. PALILLO5 , F. CALÌ 1 , N. CERATTO', G. ANELLO' and P. Bosco1 ^Laboratorio dì Genetica Molecolare, Istituto per la Ricerca sul Ritardo Mentale e l'Involuzione Cerebrale (I.R.C.C.S.), Traina, ftaly; 2Danisfi Center for Human Genome Research. The John F. Kennedy Instìtute, Glostrup, Deninark: ìdinìca Pediatrica, Università di Catania, Catania: 'Cllnica Pediatrica V, Ospedale S. Paolo, Milano: ^Ospedale dei Bambini, Palermo, Italy *Correspondence: Laboratorio di Genetica Molecolare, OASI Istituto per la Ricerca sul Ritardo Mentale e l'Involuzione Cerebrale (I.R.C.C.S.), Via Conte Ruggero, 73, 94018 Traina (EN), Italy MS received 6.1.95 Accepted 12.9.95 Summary: The results of thè neonatal screening for phenylalanine hydroxylase (PAH) deficiency in Sicily show that its incidence is higher than previously reported for mainland Italians and that non-PKU HPA is in excess of classica! and mild PKU. The latter finding suggests that a high number of non-PKU HPA mutations would occur in thè Sicilian population compared to populations with an inverted PKU/non- PKU HPA ratio. Previous studies have identified 40 mutations accounting for thè majority (98%) of mutant alleles underlying PAH deficiency in Sicily. In order to study thè molecular basis of thè distribution of PAH deficiency phenotypes in thè Sicilian population, we have correlated 31 of those mutations with clinical and metabolic phenotypes in 12 mentally retarded patients, 14 treated patients with classic or mild PKU, and 13 subjects presenting thè non-PKU HPA phenotype. The present study proposes a tentative classification for a large number (26) of PAH gene mutations which may represent an additional tool for establishing a differential diagnosis for PAH deficiency in thè Sicilian population. The recent elucidation of thè molecular basis of phenylalanine hydroxylase (PAH; EC 1.14.16.1) deficiency in Sicily (Guldberg et al 1993; Romano et al 1993) offers a new tool to improve diagnosis, prognosis and treatment of thè disease in this population. The beneficiai impact of molecular studies of thè PAH gene on thè clinical management of phenylketonuria (PKU; McKusick 261600) is documented by thè increasing number of reports on thè analysisof genotype-phenotype relationships (Konecki and Lichter-Konecki 15