Abstract
BackgroundFabry 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 resultsPatients 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.ConclusionsBased 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0178-5) contains supplementary material, which is available to authorized users.
Highlights
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
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
The non-coding GLA -10T allele, located within the 5′-untranslated region (UTR), has been suggested to be associated with decreased GLA protein expression [4], the -10T allele co-segregates in a haplotype background with three additional intronic variants (IVS281_-77delCAGCC [rs5903184], IVS4-16A>G [rs2071397], and IVS6-22C>T [rs2071228]) [5,6]
Summary
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. The non-coding GLA -10T allele (rs2071225), located within the 5′-untranslated region (UTR), has been suggested to be associated with decreased GLA protein expression [4], the -10T allele co-segregates in a haplotype background with three additional intronic variants (IVS281_-77delCAGCC [rs5903184], IVS4-16A>G [rs2071397], and IVS6-22C>T [rs2071228]) [5,6]. This haplotype has been reported in patients with SFN of unknown etiology as well as in patients with classical FD [5,6]. A weak splice site can be converted, resulting in an increased recognition and the insertion of an intronic sequence into the GLA transcript leading to a cardiac phenotype of FD [7,8]
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