Rychlík Ivan, Francová Lidmila, Dostálová Gabriela, Pešková Marie, Pešičková Satu, Ryba Miroslav, Švára František, Nemcová Zuzana, Dusilová Sulková Sylvie, Viklický Ondřej, Reiterová Jana, Ságová Michaela, Geryk Jan, Krátká Karolína, Tesař Vladimír, Linhart Aleš, Macek Milan
Department of Internal Medicine, Third Faculty of Medicine, Charles University, Prague and University Hospital Královské Vinohrady, Prague, Czech Republic.
Second Department of Medicine, Cardiology and Angiology, First Faculty of Medicine, Charles University, Prague, and General University Hospital, Prague, Czech Republic.
Clin Kidney J. 2025 May 28;18(6):sfaf167. doi: 10.1093/ckj/sfaf167. eCollection 2025 Jun.
Fabry disease (FD) is a rare disorder caused by variants in the GLA gene encoding α-galactosidase A (GALA), leading to end-stage kidney disease (ESKD), among other health issues. The 2002 Czech nationwide FD screening in ESKD found undiagnosed cases in dialysis patients by examining GALA activity in dried blood spots (DBS).
The second nationwide FD screening (2016-2018; 21-month study) in ESKD patients on maintenance dialysis therapy (MDT) included 112 Czech dialysis units to assess country-wide FD diagnostic guidelines' efficacy in reducing its underdiagnosis. This involved GALA activity and/or lyso-Gb3 levels with sequencing in positive males, the latter applied first in all females, followed by lyso-Gb3 examination in variant-positive cases. Screening-positive cases were referred to the FD center for follow-up and studies.
The 6352 screened cases represent 93.9% of all MDT patients within the study duration. Eight variants were identified in 39 patients, of which seven were in 35 ESKD cases classified as likely benign (LB), with normal lyso-Gb3 levels in all subjects. Four patients (three males with reduced GALA activity and one sequencing-positive female) bear a "hot variant of uncertain significance" (VUS) c.1181T>C(p.Leu394Pro), significantly enriched compared to the general population, suggesting its association with FD.
This is one of the largest FD screening schemes in a European ESKD cohort. Subsequent studies proved that the hot VUS is linked to alternative FD pathogenesis, thereby substantiating the utility of combining biomarkers and sequencing/bioinformatics in FD screening. The broad application of FD diagnostic guidelines has reduced its underdiagnosis in ESKD.
法布里病（FD）是一种罕见疾病，由编码α-半乳糖苷酶A（GALA）的GLA基因突变引起，可导致终末期肾病（ESKD）及其他健康问题。2002年捷克在全国范围内对终末期肾病患者进行的法布里病筛查通过检测干血斑（DBS）中的GALA活性，在透析患者中发现了未确诊病例。
在2016 - 2018年（为期21个月的研究）对接受维持性透析治疗（MDT）的终末期肾病患者进行的第二次全国性法布里病筛查中，纳入了112个捷克透析单位，以评估全国性法布里病诊断指南在减少漏诊方面的效果。这包括检测GALA活性和/或溶酶体Gb3水平，并对阳性男性进行测序，后者首先应用于所有女性，然后对变异阳性病例进行溶酶体Gb3检测。筛查阳性病例被转诊至法布里病中心进行随访和研究。
在研究期间，共筛查了出6352例病例，占所有接受维持性透析治疗患者的93.9%。在39例患者中鉴定出8种变异，其中7种在35例终末期肾病病例中被分类为可能良性（LB），所有受试者的溶酶体Gb3水平均正常。4例患者（3例GALA活性降低的男性和1例测序阳性的女性）携带“意义未明的热点变异”（VUS）c.1181T>C（p.Leu394Pro），与普通人群相比显著富集，提示其与法布里病有关。
这是欧洲终末期肾病队列中最大规模的法布里病筛查计划之一。后续研究证明，热点意义未明变异与法布里病的另一种发病机制有关，从而证实了在法布里病筛查中结合生物标志物与测序/生物信息学的实用性。法布里病诊断指南的广泛应用减少了其在终末期肾病中的漏诊。
