Mutations of the GLA Gene in Young Patients With Stroke

Abstract

Background and Purpose— Fabry disease is an X-linked monogenic disorder caused by mutations in the GLA gene. Recent data suggest that stroke in young adults may be associated with Fabry disease. We aimed to ascertain the prevalence of this disorder among young adult patients with stroke in Portugal by GLA genotyping. Methods— During 1 year, all patients aged 18 to 55 years with first-ever stroke, who were admitted into any of 12 neurology hospital departments in Portugal, were prospectively enrolled (n=625). Ischemic stroke was classified according to Trial of Org 10172 in Acute Stroke Treatment criteria. Alpha-galactosidase activity was further assayed in all patients with GLA mutations. Results— Four hundred ninety-three patients (mean age, 45.4 years; 61% male) underwent genetic analyses: 364 with ischemic stroke, 89 with intracerebral hemorrhage, 26 with subarachnoid hemorrhage, and 14 with cerebral venous thrombosis. Twelve patients had missense GLA mutations: 9 with ischemic stroke (p.R118C: n=4; p.D313Y: n=5), including 5 patients with an identified cause of stroke (cardiac embolism: n=2; small vessel disease: n=2; other cause: n=1), 2 with intracerebral hemorrhage (p.R118C: n=1; p.D313Y: n=1), and one with cerebral venous thrombosis (p.R118C: n=1). Leukocyte α-galactosidase activity was subnormal in the hemizygous males and subnormal or low-normal in the heterozygous females. Estimated prevalence of missense GLA mutations was 2.4% (95% CI, 1.3% to 4.1%). Conclusions— Despite a low diagnostic yield, screening for GLA mutations should probably be considered in different types of stroke. Restricting investigation to patients with cryptogenic stroke may underestimate the true prevalence of Fabry disease in young patients with stroke.

Prevalence of Fabry Disease and Outcomes in Young Canadian Patients With Cryptogenic Ischemic Cerebrovascular Events

“…26 The third study found 3 of 104 patients with the neutral variant p.D313Y and another with the GVUS p.R118C and reduced leukocyte α-GAL-A activity, suggesting pathogenicity. 27 Conversely, our patient with the same p.R118C mutation had normal lyso-Gb3 blood levels, which does not support pathogenicity.…”

“…The very low prevalence we found is consistent with most previous studies based on various designs (Table 4). [17][18][19][20][21][22][23][24][25][26][27] Two smaller North American studies 17,18 and most European studies [19][20][21][22][23][24] identified Fabry in 0.0% to 1.0% of cryptogenic IS or diverse other cerebrovascular conditions. Only 3 European studies reported a prevalence >1.0% in cryptogenic IS.…”

Clinical Pregenetic Screening for Stroke Monogenic Diseases

“…First, these diseases are really rare in stroke populations. Consistent with this, although Fabry disease was suggested as an important cause of younger onset stroke in 1 study, [33][34][35] further studies have failed to replicate this finding. Second, the diagnostic algorithms may not adequately address these diseases.…”

A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy

“…This makes CE-MS particularly useful as a noninvasive diagnostic screening test in unexplained renal, cardiac or cerebrovascular disease. Several recent studies have shown a high prevalence of Fabry disease in populations with unexplained renal failure [21], [22], [23], [24], stroke [25], [26], [27] or hypertrophic cardiomyopathy [28], [29], [30]. However, screening these populations for Fabry disease is hampered by the low sensitivity of GLA activity measurement in female patients (50% [31]–67% [32]) whereas diagnostic sequencing of the GLA gene is not feasible given the high cost (currently ca.…”