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.

Appendices

Concise Sentence

Since the start of NBS for PKU in Sweden due to the use of lower cut offs a major shift towards detecting patients with milder mutations and less severe disease are becoming more common in the Swedish population.

Contribution of Individual Authors

Experimental design and execution: AO and HB

Manuscript preparation: AO and UvD

Data analysis: AO, AW and UvD

Clinical investigation: AN and RZ

All authors have read and revised the final manuscript.

Ulrika von Döbeln serves as guarantor for the article, accepts full responsibility for the work, has access to the data and controls the decision to publish.

Conflict of Interest

The authors have nothing to declare.

Details of funding: Stockholm County Council and the Karolinska Institute Research Foundation.

The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.

Compliance with Ethics Guidelines

Genetic investigation of inborn errors of metabolism, approved by Regional Ethical Committee of Stockholm, 2008/351-31. Informed consent was not required since individual patients cannot be identified in the manuscript.