title: The Spectrum of PAH Mutations and Increase of Milder Forms of Phenylketonuria in Sweden During 1965-2014.
abstract: Newborn screening (NBS) for phenylketonuria (PKU) which has a continuum of disease severities has been performed for more than 50 years. The screening method has undergone a continuous development with not only improvements of the positive predictive value but also identification of milder forms of the disease. With the introduction of genetic testing the confirmation of the diagnosis has improved. The Swedish NBS is centralized to one laboratory, which also performs confirmatory testing.Here we present the results of NBS for PKU in Sweden during 1965-2014 describing an increase in diagnosed patients and a shift in the spectrum of phenylalanine hydroxylase (PAH) mutations towards an increasing heterogeneity. Milder mutations common in southern Europe and the Middle East together with lowering of the recall level for phenylalanine (Phe) have led to a shift towards milder phenotypes among the patients identified by the screening program. The inclusion of a Phe and tyrosine (Tyr) ratio as an additional marker has improved the positive predictive value to the present 0.92. Also discussed is what impact earlier sampling has had on the prediction of disease severity, concluding that the shift of age at sampling from 72 to 48 h does not increase the risk of missing patients in need of treatment.
authors.affiliation: Centre for Inherited Metabolic Diseases (CMMS), L7:05, Karolinska University Hospital, Stockholm, SE-171 76, Sweden. annika.ohlsson@ki.se.|Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden. annika.ohlsson@ki.se.
authors.forename: Annika
authors.initials: A
authors.lastname: Ohlsson
authors.affiliation: Centre for Inherited Metabolic Diseases (CMMS), L7:05, Karolinska University Hospital, Stockholm, SE-171 76, Sweden.|Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Helene
authors.initials: H
authors.lastname: Bruhn
authors.affiliation: Centre for Inherited Metabolic Diseases (CMMS), L7:05, Karolinska University Hospital, Stockholm, SE-171 76, Sweden.|Department of Pediatric Endocrinology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.|Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Nordenström
authors.affiliation: Centre for Inherited Metabolic Diseases (CMMS), L7:05, Karolinska University Hospital, Stockholm, SE-171 76, Sweden.|Department of Pediatric Endocrinology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.|Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Zetterström
authors.affiliation: Centre for Inherited Metabolic Diseases (CMMS), L7:05, Karolinska University Hospital, Stockholm, SE-171 76, Sweden.|Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Wedell
authors.affiliation: Centre for Inherited Metabolic Diseases (CMMS), L7:05, Karolinska University Hospital, Stockholm, SE-171 76, Sweden.|Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: von Döbeln
keywords: Mutations; Neonatal screening; Newborn screening; Phenylalanine hydroxylase; Phenylketonuria