title: Cryptogenic stroke and small fiber neuropathy of unknown etiology in patients with alpha-galactosidase A -10T genotype.
abstract: 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.
  
  
  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.
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany. Michael.Schelleckes@ukmuenster.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Schelleckes
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany. Malte.Lenders@ukmuenster.de.
authors.forename: Malte
authors.initials: M
authors.lastname: Lenders
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany. Katrin.Guske@ukmuenster.de.
authors.forename: Katrin
authors.initials: K
authors.lastname: Guske
authors.affiliation: Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Horstmarer Landweg 39, 48149, Muenster, Germany. Boris.Schmitz@ukmuenster.de.
authors.forename: Boris
authors.initials: B
authors.lastname: Schmitz
authors.affiliation: Department of Neurology, Justus Liebig University Giessen, Klinikstrasse 33, 35385, Giessen, Germany. Christian.Tanislav@neuro.med.uni-giessen.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Tanislav
authors.affiliation: Department of Dermatology, Neurodermatology and Competence Center Pruritus, University of Muenster, Von-Esmarch-Straße 58, 48149, Muenster, Germany. Sonja.Staender@ukmuenster.de.
authors.forename: Sonja
authors.initials: S
authors.lastname: Ständer
authors.affiliation: Department of Dermatology, Neurodermatology and Competence Center Pruritus, University of Muenster, Von-Esmarch-Straße 58, 48149, Muenster, Germany. Dieter.Metze@ukmuenster.de.
authors.forename: Dieter
authors.initials: D
authors.lastname: Metze
authors.affiliation: Institute of Neuropathology, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany. Ikatona@ukaachen.de.
authors.forename: Istvan
authors.initials: I
authors.lastname: Katona
authors.affiliation: Institute of Neuropathology, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany. JWeis@ukaachen.de.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.affiliation: Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Horstmarer Landweg 39, 48149, Muenster, Germany. StefanMartin.Brand@ukmuenster.de.
authors.forename: Stefan-Martin
authors.initials: SM
authors.lastname: Brand
authors.affiliation: Department of Neurology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany. Thomas.Duning@ukmuenster.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Duning
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany. Eva.Brand@ukmuenster.de.
authors.forename: Eva
authors.initials: E
authors.lastname: Brand
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002461:Cell Line, Transformed; D002648:Child; D004916:Erythromelalgia / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D000795:Fabry Disease / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D020521:Stroke / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D055815:Young Adult; D000519:alpha-Galactosidase / Q000235:genetics*
chemical_list: D000519:alpha-Galactosidase