Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant.

Malte Lenders,Thomas Duning,Jörg Stypmann,Johannes Krämer,Boris Schmitz,Daniela Blaschke,Christine Kurschat,Stefanie Reiermann,Christoph Wanner,Stefan-Martin Brand,Sima Canaan-Kühl,Eva Brand,Frank Weidemann

doi:10.1186/s13023-016-0441-z

Abstract

BackgroundFabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma.MethodsTo 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.Resultsp.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.ConclusionsWe 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 materialThe online version of this article (doi:10.1186/s13023-016-0441-z) contains supplementary material, which is available to authorized users.

Highlights

Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype
A family screening identified her father, her uncle with his daughter with the p.A143T variant. Both males showed a slightly reduced galactosidase A activity (GLA) activity of ~50 % of the reference level none of the three relatives presented with increased plasma lyso-Gb3 levels, nor other FD-typical organ manifestations
The family history revealed strokes of her paternal grandparents at a higher age, but not in any further relatives of the index patient. Since at this time-point no other stroke-causing diseases could be detected within the index patient, FD was diagnosed and enzyme replacement therapy (ERT) with agalsidase-alfa was initiated, the patient showed no further FD-typical renal or cardiac manifestations

Summary

Introduction

Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. 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]. 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. We retrospectively analyzed the first visit of 25 ERT naïve adult female and male patients, carrying the controversially discussed p.A143T variation in a multicenter study of four German FD centers and compared these data gender-specific to 58 ERT naïve patients (39 females) with other missense GLA mutations to determine a potential clinical impact of p.A143T

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Conclusion