MinireviewDiagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies
Section snippets
Newborn screening
Phenylketonuria (PKU) is identified through national newborn screening programs [1]. The first efficient test for hyperphenylalaninemia (HPA) was a bacterial inhibition assay developed by Robert Guthrie [2]. The test was based on Bacillus subtilis, which requires phenylalanine (Phe) for growth. The Guthrie test was very useful for mass screening as the dried blood spot (DBS) can be obtained in the hospital or a doctor's office using a standardized filter paper (“Guthrie card”) and mailed to
Phenylalanine loading test
Phenylalanine loading tests were applied since 1956 for the detection of heterozygotes in PKU families [27], until, in the late 1980s, this approach was replaced by molecular analysis of PAH gene haplotypes and mutations [28]. Phenylalanine loading tests gained further interest when Guthrie card mass screening uncovered not only the expected cases of classic PKU but also variants of PKU [29]. Because these variants were initially thought not to require dietary treatment, a reliable
PAH mutations and PKU genotypes (incl. databases)
As already stated, knowing whether a patient has residual PAH enzyme activity can be relevant for the therapeutic approach, the likely Phe tolerance, and the expected response to BH4. Delineation of the mutations of the PAH gene was initiated immediately after the cloning of the gene in 1983 [28]. Initially the most prevalent mutations in the Western European population were identified and characterized with regard to the in vitro residual enzyme activity associated with the respective mutation
Acknowledgments
Authors would like to thank Serono Scientific International Foundation (SSIF) for supporting organization of the workshop on “Diagnosis, classification and genetics of PKU”. This work was supported in part by the Swiss National Science Foundation grant no. 31003A-119982 (to NB). UL is grateful to the German Collaborative Study on PKU for providing the study data whose analysis resulted in Ref. [36] and Fig. 3 of the present communication.
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