p.E66Q mutation in the GLA gene is associated with a high risk of cerebral small‐vessel occlusion in elderly Japanese males

Abstract

Background and purpose: GLA is the causative gene of Fabry disease, an X-linked lysosomal storage disorder resulting from -galactosidase A (-GAL) deficiency. Stroke is an important manifestation of Fabry disease, and recent epidemiologiccal studies indicated that up to 4.9% of young male cryptogenic stroke patients have GLA mutations. To determine the importance of GLA mutations in the general stroke population, we measured the frequency of GLA mutations in Japanese male ischemic stroke patients with various risk factors and ages.Methods: A total of 475 male ischemic stroke patients (average age 69.7±12.5 years), were enrolled in this study. A blood sample was obtained to produce blood spots for measurement of -GAL activity. Blood samples with decreased enzymatic activity were reassayed and the entire GLA gene was analyzed by direct DNA sequencing if -Gal A activity was consistently low.Results: -Gal A activity was decreased in 10 men, 5 of whom (1.1%) had the GLA gene mutation, p.E66Q. All ischemic stroke patients with p.E66Q mutation had substantial residual -Gal A activity, in contrast to patients with classic-type Fabry disease. Clinically, all patients with p.E66Q mutation were > 50 years old and had multiple small-vessel occlusions (lacunar infarctions). Statistical analysis using Fisher's exact test showed the allele frequency of GLA p.E66Q in patients with small-vessel occlusion to be significantly higher than that in the general Japanese population (odds ratio 3.34, P=0.025).Conclusions: GLA p.E66Q mutation is a genetic risk factor for cerebral small-vessel occlusion in elderly Japanese males.

A Patient with the <i>GLA</i> p.E66Q Mutation Exhibiting Vascular Parkinsonism and Bilateral Pulvinar Lesions

“…Nakamura et al reported that the p.E66Q mutation was associated with a high risk of cerebral small-vessel occlusion in elderly Japanese men (10), and the present case presented with moderate white matter lesions, similar to the report of Nakamura et al Additionally, Takanashi et al reported that all the patients with pulvinar lesions had white matter lesions (2). Therefore, the combination of pulvinar lesions and white matter lesions in Fabry disease may have a common pathophysiology.…”

“…Therefore, the combination of pulvinar lesions and white matter lesions in Fabry disease may have a common pathophysiology. Conversely, Nakamura et al did not observe any pulvinar lesions in their study (10). Therefore, it is difficult to determine a direct relationship between the p.E66Q mutation and the pulvinar lesion.…”

Pathological Renal Findings of Chronic Renal Failure in a Patient with the E66Q Mutation in the &alpha;-galactosidase A Gene

“…Lee et al further demonstrated that white blood cells derived from subjects with the E66Q enzyme display an activity 19.0-30.3% that of normal and concluded that the E66Q mutation is a functional polymorphism. However, the GLA gene E66Q mutation is a genetic risk factor for cerebral small-vessel occlusion in elderly Japanese men, according to Nakamura et al (10). We previously stated that it is questionable whether detecting the E66Q mutation in the GLA gene is adequate for predicting cerebral small-vessel occlusion (20).…”

“…We previously stated that it is questionable whether detecting the E66Q mutation in the GLA gene is adequate for predicting cerebral small-vessel occlusion (20). A study by Nakamura et al (10) used newborns as a control group. However, newborns generally do not exhibit cerebral small-vessel oc- clusion, although they may develop this complication in the future.…”

“…Therefore, the E66Q mutation in the GLA gene may be a functional polymorphism. However, the E66Q mutation in the GLA gene was recently shown to be a genetic risk factor for cerebral small-vessel occlusion in elderly Japanese men by Nakamura et al (10). These two studies thus obtained different outcomes regarding the presence of the E66Q mutation.…”