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. 2016 May 4;11(1):54.
doi: 10.1186/s13023-016-0441-z.

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

Malte Lenders  1 , Frank Weidemann  2   3 , Christine Kurschat  4 , Sima Canaan-Kühl  5 , Thomas Duning  6 , Jörg Stypmann  7 , Boris Schmitz  8 , Stefanie Reiermann  1 , Johannes Krämer  2   9 , Daniela Blaschke  10 , Christoph Wanner  2 , Stefan-Martin Brand  8 , Eva Brand  11
Affiliations

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

Malte Lenders et al. Orphanet J Rare Dis. .

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; GLA mutation; Genotype; Late-onset; Lyso-Gb3; Stroke; Variant of unknown significance.

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Figures

Fig. 1
Fig. 1
Magnetic resonance (MR) images of p.A143T patients with cerebrovascular events. a Axial MRI of the index female patient (30 years of age) suffering from an embolic stroke within the vascular territory of the right middle cerebral artery. b Coronal FLAIR-MRI of a male patient (38 years of age) suffering from an embolic stroke within the vascular territory of the left middle cerebral artery. c FLAIR-MR of a female patient (46 years of age) with TIAs and periventricular and subcortical microangiopathic and lacunar ischemic lesions (white arrow). FLAIR: fluid attenuated inversion recovery. TIA: transient ischemic attack
Fig. 2
Fig. 2
a Distribution of residual GLA activities in patients with p.A143T and Fabry disease patients with other missense GLA mutations. b Correlation of residual GLA activities with lyso-Gb3 levels in male Fabry disease patients with other missense GLA mutations and c in male patients with p.A143T. The dotted line represents the upper reference value of measured lyso-Gb3 (0.9 ng/ml). Values are given as medians with 5–95 % confidence intervals
See this image and copyright information in PMC

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