Introduction: Newborn screening (NBS) for classical galactosemia (CG) was introduced in the Netherlands in 2007. Multiple screening methods have been used since, and currently a two-tier system is used, with residual enzyme activity of galactose-1-phosphate-uridyltransferase (GALT) and total galactose concentration in dried blood spots as the primary and secondary markers. As it is essential to monitor effectiveness of NBS programs, we assessed the effectiveness of different screening methods used over time (primary aim), and aimed to identify and investigate patients identified through NBS with previously unreported clinical and biochemical phenotypes (secondary aim).
Methods: The effectiveness of different screening methods and their cut-off values (COVs), as used from 2007 through 2015, was determined, and the clinical and biochemical data of all identified patients were retrospectively collected.
Results: All screening methods and COVs resulted in relatively high false-positive rates and low positive predictive values. Total galactose levels in dried blood spots were far above the COV for NBS in all true positive cases. A total of 31 galactosemia patients were identified, and when corrected for a family with three affected siblings, 14% had a previously unreported phenotype and genotype. These individuals did not demonstrate any symptoms at the time of diagnosis while still being exposed to galactose, had galactose-1-phosphate values below detection limit within months after the start of diet, and had previously unreported genotypes.
Conclusion: Optimization of NBS for CG in the Netherlands is warranted because of the high false-positive rate, which may result in significant harm. Furthermore, a surprising 14% of newborns identified with CG by screening had previously unreported clinical and biochemical phenotypes and genotypes. For them, individualized prognostication and treatment are warranted, in order to avoid unnecessary stringent galactose restriction.

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Keywords Classical galactosemia, Galactose oxidation, Incidence, Newborn screening, Prevalence, Variants
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Journal Molecular Genetics and Metabolism
Welling, L, Boelen, A, Derks, T.G.J, Schielen, P.C.J.I, de Vries, M, Williams, M, … Bosch, A.M. (2017). Nine years of newborn screening for classical galactosemia in the Netherlands: Effectiveness of screening methods, and identification of patients with previously unreported phenotypes. Molecular Genetics and Metabolism, 120(3), 223–228. doi:10.1016/j.ymgme.2016.12.012