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

作者：Lenders Malte; Weidemann Frank; Kurschat Christine; Canaan Kuehl Sima; Duning Thomas; Stypmann Joerg; Schmitz Boris; Reiermann Stefanie; Kraemer Johannes; Blaschke Daniela; Wanner Christoph; Brand Stefan Martin; Brand Eva^*

来源：Orphanet Journal of Rare Diseases, 2016, 11(1): 54.

DOI：10.1186/s13023-016-0441-z

• Fabry disease
• Lyso-Gb3
• Variant of unknown significance
• Late-onset
• GLA mutation
• Stroke
• Genotype

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 (similar to 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.

• 出版日期2016-5-4