TY  - JOUR
AB  - Background: Fabry disease (FD) is a multisystemic disorder with typical neurological manifestations such as stroke and small fiber neuropathy (SFN), caused by mutations of the alpha-galactosidase A (GLA) gene. We analyzed 15 patients carrying the GLA haplotype -10C>T [rs2071225], IVS2-81_-77delCAGCC [rs5903184], IVS4-16A>G [rs2071397], and IVS6-22C>T [rs2071228] for potential neurological manifestations. Methods and results: Patients were retrospectively analyzed for stroke, transient ischemic attack (TIA), white matter lesions (WML) and SFN with neuropathic pain. Functional impact of the haplotype was determined by molecular genetic methods including real-time PCR, exon trapping, promoter deletion constructs and electrophoretic mobility shift assays. Symptomatic -10T allele carriers suffered from stroke, TIA, WML, and SFN with neuropathic pain. Patients’ mean GLA mRNA expression level was reduced to ~70% (p < 0.0001) and a dose-dependent effect of the -10T allele on GLA mRNA expression was observed in hemi/homozygous compared to heterozygous patients (p < 0.0001). Molecular analyzes revealed that the -10T allele resulted in a reduced promoter activity and an altered transcription factor binding, while a functional relevance of the co-segregated intronic variants was excluded by exon trapping. Conclusions: Based on this complementary approach of clinical observation and functional testing, we conclude that the GLA -10T allele could be causal for the observed neurological manifestations. Future studies are needed to clarify whether affected patients benefit from GLA enzyme replacement therapy for end-organ damage prevention.
AU  - Schelleckes, Michael
AU  - Lenders, Malte
AU  - Guske, Katrin
AU  - Schmitz, Boris
AU  - Tanislav, Christian
AU  - Tanislav, Christian Theodor
AU  - Ständer, Sonja
AU  - Metze, Dieter
AU  - Katona, István
AU  - Weis, Joachim
AU  - Brand, Stefan-Martin
AU  - Duning, Thomas
AU  - Brand, Eva
DA  - 2014-11-26
DO  - doi:10.1186/s13023-014-0178-5
KW  - Neuropathic pain
KW  - Stroke
KW  - Cerebrovascular disease
KW  - Fabry disease
KW  - Gene expression regulation
LA  - eng
N1  - Orphanet Journal of Rare Diseases 9 (2014) 178, 1-13
N1  - Finanziert durch den Open-Access-Publikationsfonds 2014/2015 der Deutschen Forschungsgemeinschaft (DFG) und der Westfälischen Wilhelms-Universität Münster (WWU Münster).
PY  - 2014-11-26
SN  - 1750-1172
TI  - Cryptogenic stroke and small fiber neuropathy of unknown etiology in patients with alpha-galactosidase A -10T genotype
UR  - https://nbn-resolving.org/urn:nbn:de:hbz:6-00399363714
Y2  - 2024-11-22T03:14:02
ER  -