Abstract Hyperphenylalaninemia (HPA) is a group of diseases characterized by the persistent elevation of phenylalanine levels in tissues and biological fluids. It is an autosomal recessive disorder affecting 1 in 10,000 in- dividuals in Caucasian populations and about 1 in 6,600 in Catalonia. We report the mutational spectrum of pheny- lalanine hydroxylase deficiency in the population living in Catalonia and the genotype-phenotype correlation. The molecular study was performed in 383 samples correspond- ing to 115 patients from 99 unrelated families and 268 rel- atives. We have characterized 90% of the mutant alleles; there were 57 different mutations, 49 of which have pre- viously been described, 8 being novel mutations and two being large deletions. The 57 mutations detected corre- sponded to: five nonsense, seven frameshift, and eight splice defects, the remainder being missense mutations. These mutations cause 72 different genotypes in the 83 families characterized, confirming the mutational hetero- geneity of phenylketonuria (PKU) in the Mediterranean population. According to our biochemical classification, our HPA population is composed of 40 PKU (35%), 36 variant PKU (31%), and 39 non-PKU HPA (34%). Muta- tions such as IVS10, A403 V, and E390G correlated as ex- pected with the phenotype and the predicted residual ac- tivity in vitro. However, in four cases (I65 T, V388 M, R261Q, and Y414 C), the observed metabolic phenotype was not consistent with the predicted genotypic effect. The identification of the mutations in the PAH gene and the genotype-phenotype correlation should facilitate the evaluation of metabolic phenotypes, diagnosis, imple- mentation of optimal dietary therapy, and determination of prognosis in the patients and genetic counselling for the patient’s relatives. Introduction Hyperphenylalaninemia (HPA) is a group of diseases characterized by the persistent elevation of phenylalanine (Phe) levels in tissues and biological fluids. The most fre- quent form is phenylalanine hydroxylase (PAH; E.C. 1.14.16.1) deficiency, causing phenylketonuria (PKU; McKusick MIM 261600) or non-PKU HPA and corre- sponding to about 98% of all HPA cases. PAH deficiency is an autosomal recessive disorder affecting 1 in 10,000 individuals in Caucasian populations (Scriver et al. 1995) and about 1 in 6,600 in Catalonia. PKU results in mental retardation and other neurological complications that can be avoided by early treatment (Güttler and Lou 1990). It presents a broad phenotype spectrum ranging from classic PKU to moderate HPA depending on the residual enzy- matic activity (Okano et al. 1991; Svensson et al. 1993; Eisensmith et al. 1995). Since the first mutation in the PAH gene was identified in a PKU patient (DiLella et al. 1986), more than 400 mutations have been described (Phenylalanine Hydroxylase Mutation Analysis Consor- Judith Mallolas · M. Antònia Vilaseca · Jaume Campistol · Nilo Lambruschini · Francisco José Cambra · Xavier Estivill · Montserrat Milà Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: genotype-phenotype correlation Hum Genet (1999) 105 : 468–473 © Springer-Verlag 1999 Digital Object Identifier (DOI) 10.1007/s004399900157 Received: 14 July 1999 / Accepted: 3 September 1999 / Published online: 1 October 1999 ORIGINAL INVESTIGATION J. Mallolas · M. Milà (✉) Laboratorio de Genética, Servei Genètica, Esc. 5, 50 piso, Hospital Clínic, c/ Villarroel 170, Barcelona 08036, Spain e-mail: montse@medicina.ub.es, Tel.: +34 93 227 54 00 ext. 2784, Fax: +34 93 451 52 72 M. Milà IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain M. A. Vilaseca Servei Bioquímica, Unitat Integrada Hospital Sant Joan de Déu-Hospital Clínic, Barcelona, Spain J. Campistol Hospital Sant Joan de Déu, Barcelona Servei Neuropediatria, Unitat Integrada Hospital Sant Joan de Déu-Hospital Clínic, Barcelona, Spain N. Lambruschini · F. J. Cambra Hospital Sant Joan de Déu, Barcelona Servei Pediatria, Unitat Integrada Hospital Sant Joan de Déu-Hospital Clínic, Barcelona, Spain Present address: X. Estivill, Medical and Molecular Genetics Center, Hospital Duran i Reynals, L’Hospitalet de Llobregat, Barcelona, Spain