BACKGROUND: 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). METHODS: 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 GLA 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 in vitro studies. RESULTS: The 6352 screened cases represent 93.9% of all MDT patients within the study duration. Eight GLA 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. CONCLUSIONS: This is one of the largest FD screening schemes in a European ESKD cohort. Subsequent in vitro 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.

• Klíčová slova
• Fabry disease, GLA gene, dialysis, end-stage kidney disease, screening,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Clinical findings in Fabry disease have classically been attributed to loss-of-function variants in the GLA gene that result in α-galactosidase A deficiency, intracellular accumulation of globotriaosylceramides and clinical manifestations. However, over time, increasing number of patients have been identified with GLA variants causing either non-classic Fabry disease or having unclear clinical effects. SUMMARY: Searching for additional etiologic and lysosomal storage-independent factors, investigators have recently identified that certain missense GLA variants not only affect enzymatic activity, but also encode for misfolded α-galactosidase A that itself induces chronic endoplasmic reticulum stress and the unfolded protein response. Thus, Fabry disease pathogenesis may be caused by decreased enzymatic activity as well as cellular toxicity from accumulation of the misfolded α-galactosidase A protein, with the contribution of each factor determined by the type of the genetic variant and host factors. KEY MESSAGES: Defective proteostasis and misfolding of certain missense α-galactosidase A variants induce chronic endoplasmic reticulum stress and the unfolded protein response that may contribute to intra-familial and inter-familial variation in disease penetrance and clinical expressivity. Pharmacologic modulation of defective proteostasis may have therapeutic implications in Fabry disease.

• Klíčová slova
• ER stress activation, Misfolding of α-galactosidase A, Non-classic Fabry disease, Treatment, Unfolding protein response activation,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH