Welling Lindsey, Boelen Anita, Derks Terry G J, Schielen Peter C J I, de Vries Maaike, Williams Monique, Wijburg Frits A, Bosch Annet M
Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.
Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, The Netherlands.
Mol Genet Metab. 2017 Mar;120(3):223-228. doi: 10.1016/j.ymgme.2016.12.012. Epub 2016 Dec 29.
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).
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.
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.
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.
2007年荷兰开始对经典型半乳糖血症（CG）进行新生儿筛查（NBS）。自那以后使用了多种筛查方法，目前采用的是两级系统，以1-磷酸半乳糖尿苷转移酶（GALT）的残余酶活性和干血斑中的总半乳糖浓度作为主要和次要标志物。由于监测NBS项目的有效性至关重要，我们评估了不同时期使用的筛查方法的有效性（主要目的），并旨在识别和研究通过NBS确诊的具有此前未报告的临床和生化表型的患者（次要目的）。
确定了2007年至2015年期间使用的不同筛查方法及其临界值（COV）的有效性，并回顾性收集了所有确诊患者的临床和生化数据。
所有筛查方法和COV均导致相对较高的假阳性率和较低的阳性预测值。在所有真阳性病例中，干血斑中的总半乳糖水平远高于NBS的COV。共确诊了31例半乳糖血症患者，在排除一个有三名患病兄弟姐妹的家庭后，14%的患者具有此前未报告的表型和基因型。这些个体在诊断时虽仍接触半乳糖但未表现出任何症状，在开始饮食后的数月内1-磷酸半乳糖值低于检测限，且具有此前未报告的基因型。
鉴于荷兰CG的NBS假阳性率高，可能造成重大危害，因此有必要对其进行优化。此外，令人惊讶的是，通过筛查确诊为CG的新生儿中有14%具有此前未报告的临床和生化表型及基因型。对于他们，有必要进行个体化的预后评估和治疗，以避免不必要的严格半乳糖限制。
