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Cryptogenic stroke and small fiber neuropathy of unknown etiology in patients with alpha-galactosidase A -10T genotype.

Schelleckes M, Lenders M, Guske K, Schmitz B, Tanislav C, Ständer S, Metze D, Katona I, Weis J, Brand SM, Duning T, Brand E - Orphanet J Rare Dis (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany. Michael.Schelleckes@ukmuenster.de.

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.

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.

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Related in: MedlinePlus

Presentation of the retrospective study design. Between 07/2011 and 12/2013 86 new patients presented at the Fabry center of the University Hospital Muenster with Fabry-typical neurological manifestations such as small fiber neuropathy with neuropathic pain, or stroke/TIA of unknown etiology. Out of 86 patients 49 had classical Fabry disease-causing mutations, 12 patients were symptomatic -10T allele carriers and 25 patients had no GLA mutation. Two asymptomatic patients were identified by family screening. We analyzed GLA expression in all detected -10T allele carriers and retrospectively analyzed clinical data.
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Fig1: Presentation of the retrospective study design. Between 07/2011 and 12/2013 86 new patients presented at the Fabry center of the University Hospital Muenster with Fabry-typical neurological manifestations such as small fiber neuropathy with neuropathic pain, or stroke/TIA of unknown etiology. Out of 86 patients 49 had classical Fabry disease-causing mutations, 12 patients were symptomatic -10T allele carriers and 25 patients had no GLA mutation. Two asymptomatic patients were identified by family screening. We analyzed GLA expression in all detected -10T allele carriers and retrospectively analyzed clinical data.

Mentions: The study retrospectively analyzed patients with the GLA -10T haplotype who presented at the Fabry center of the University Hospital of Muenster (IFAZ) between 07/2011 and 12/2013 (Figure 1). All patients had been examined by neurologists, cardiologists and nephrologists at the Fabry center. Neuropathic pain was diagnosed according to the revised criteria of the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG) [10]. All investigations were performed after approval of the Medical Association of Westfalian Lippe and the Ethical Committee of the Medical Faculty of the University of Muenster (project-no.: 2011-347-f, date of report: 07.07.2011). Written informed consent of patients was obtained for molecular analysis and publication.Figure 1


Cryptogenic stroke and small fiber neuropathy of unknown etiology in patients with alpha-galactosidase A -10T genotype.

Schelleckes M, Lenders M, Guske K, Schmitz B, Tanislav C, Ständer S, Metze D, Katona I, Weis J, Brand SM, Duning T, Brand E - Orphanet J Rare Dis (2014)

Presentation of the retrospective study design. Between 07/2011 and 12/2013 86 new patients presented at the Fabry center of the University Hospital Muenster with Fabry-typical neurological manifestations such as small fiber neuropathy with neuropathic pain, or stroke/TIA of unknown etiology. Out of 86 patients 49 had classical Fabry disease-causing mutations, 12 patients were symptomatic -10T allele carriers and 25 patients had no GLA mutation. Two asymptomatic patients were identified by family screening. We analyzed GLA expression in all detected -10T allele carriers and retrospectively analyzed clinical data.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4255940&req=5

Fig1: Presentation of the retrospective study design. Between 07/2011 and 12/2013 86 new patients presented at the Fabry center of the University Hospital Muenster with Fabry-typical neurological manifestations such as small fiber neuropathy with neuropathic pain, or stroke/TIA of unknown etiology. Out of 86 patients 49 had classical Fabry disease-causing mutations, 12 patients were symptomatic -10T allele carriers and 25 patients had no GLA mutation. Two asymptomatic patients were identified by family screening. We analyzed GLA expression in all detected -10T allele carriers and retrospectively analyzed clinical data.
Mentions: The study retrospectively analyzed patients with the GLA -10T haplotype who presented at the Fabry center of the University Hospital of Muenster (IFAZ) between 07/2011 and 12/2013 (Figure 1). All patients had been examined by neurologists, cardiologists and nephrologists at the Fabry center. Neuropathic pain was diagnosed according to the revised criteria of the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG) [10]. All investigations were performed after approval of the Medical Association of Westfalian Lippe and the Ethical Committee of the Medical Faculty of the University of Muenster (project-no.: 2011-347-f, date of report: 07.07.2011). Written informed consent of patients was obtained for molecular analysis and publication.Figure 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany. Michael.Schelleckes@ukmuenster.de.

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.

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.

Show MeSH
Related in: MedlinePlus