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Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant
BACKGROUND: Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma. METHODS: To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855861/ https://www.ncbi.nlm.nih.gov/pubmed/27142856 http://dx.doi.org/10.1186/s13023-016-0441-z |
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author | Lenders, Malte Weidemann, Frank Kurschat, Christine Canaan-Kühl, Sima Duning, Thomas Stypmann, Jörg Schmitz, Boris Reiermann, Stefanie Krämer, Johannes Blaschke, Daniela Wanner, Christoph Brand, Stefan-Martin Brand, Eva |
author_facet | Lenders, Malte Weidemann, Frank Kurschat, Christine Canaan-Kühl, Sima Duning, Thomas Stypmann, Jörg Schmitz, Boris Reiermann, Stefanie Krämer, Johannes Blaschke, Daniela Wanner, Christoph Brand, Stefan-Martin Brand, Eva |
author_sort | Lenders, Malte |
collection | PubMed |
description | BACKGROUND: Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma. METHODS: To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations. RESULTS: p.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 % of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed. CONCLUSIONS: We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-016-0441-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4855861 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-48558612016-05-05 Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant Lenders, Malte Weidemann, Frank Kurschat, Christine Canaan-Kühl, Sima Duning, Thomas Stypmann, Jörg Schmitz, Boris Reiermann, Stefanie Krämer, Johannes Blaschke, Daniela Wanner, Christoph Brand, Stefan-Martin Brand, Eva Orphanet J Rare Dis Research BACKGROUND: Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma. METHODS: To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations. RESULTS: p.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 % of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed. CONCLUSIONS: We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-016-0441-z) contains supplementary material, which is available to authorized users. BioMed Central 2016-05-04 /pmc/articles/PMC4855861/ /pubmed/27142856 http://dx.doi.org/10.1186/s13023-016-0441-z Text en © Lenders et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Lenders, Malte Weidemann, Frank Kurschat, Christine Canaan-Kühl, Sima Duning, Thomas Stypmann, Jörg Schmitz, Boris Reiermann, Stefanie Krämer, Johannes Blaschke, Daniela Wanner, Christoph Brand, Stefan-Martin Brand, Eva Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant |
title | Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant |
title_full | Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant |
title_fullStr | Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant |
title_full_unstemmed | Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant |
title_short | Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant |
title_sort | alpha-galactosidase a p.a143t, a non-fabry disease-causing variant |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855861/ https://www.ncbi.nlm.nih.gov/pubmed/27142856 http://dx.doi.org/10.1186/s13023-016-0441-z |
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