Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant
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RESEARCH
Open Access
Alpha-Galactosidase A p.A143T, a nonFabry disease-causing variant Malte Lenders1, Frank Weidemann2,3, Christine Kurschat4, Sima Canaan-Kühl5, Thomas Duning6, Jörg Stypmann7, Boris Schmitz8, Stefanie Reiermann1, Johannes Krämer2,9, Daniela Blaschke10, Christoph Wanner2, Stefan-Martin Brand8 and Eva Brand1*
Abstract 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. Keywords: Fabry disease, Lyso-Gb3, Variant of unknown significance, Late-onset, GLA mutation, Stroke, Genotype
Background Fabry disease (FD; OMIM #301500) is an X-linked (Xq 22.1) inborn error of glycosphingolipid catabolism due to deficient α-galactosidase A activity (GLA; 300644; [EC 3.2.1.22]). GLA mutations may lead to a classical or nonclassical FD phenotype [1]. A clear link between genotype and phenotype in FD has not yet been established. Classical FD manifestations lead to clinical manifestations such as early stroke, malignant cardiac arrhythmia, myocardial infarction, cardiac failure, left ventricular hypertrophy (LVH) as well as progressive renal impairment, associated with differential systemic cellular accumulation * Correspondence: [email protected] 1 Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Albert-Schweitzer-Campus 1, D-48149 Muenster, Germany Full list of author information is available at the end of the article
of globotriaoslyceramide (Gb3). Several missense and nonsense mutations are accompanied by nearly absent GLA activities and increased lyso-Gb3 levels [2, 3]. Most nonclas
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