Frequency of Unrecognized Fabry Disease Among Young European-American and African-American Men With First Ischemic Stroke

Abstract

Background and Purpose The cause of initial ischemic stroke in up to 30% of young patients remains unclear. Fabry disease, due to deficient α-galactosidase A (α-Gal A) activity, is a vascular endothelial glycosphingolipid storage disease typically presenting in childhood. With advancing age, patients develop renal, cardiac, and cerebrovascular disease and die prematurely. A European study suggested an increased prevalence of unrecognized Fabry disease in patients with cryptogenic stroke. We hypothesized that α-Gal A deficiency is a rare cause of initial early-onset ischemic stroke in men. Methods The Stroke Prevention in Young Men Study enrolled >550 men (15 to 49 years) with first ischemic stroke in the Baltimore–Washington area in 2004 to 2007. Frozen plasma samples were assayed for α-Gal A activity, and DNA from patients with consistently low plasma α-Gal A activities were sequenced. Results The study sample consisted of 558 men (42% African-American; median age 44 years). Stroke was cryptogenic in 154 men (40% African-American). In 10 patients with low plasma α-Gal A activities, DNA sequencing identified alterations in the α-Gal A gene in 2 patients. The polymorphism, D313Y, which results in low plasma enzyme activity, but near normal levels of cellular activity was seen in one European-American male. The Fabry disease-causing A143T mutation was seen in an African-American male with cryptogenic stroke (0.18% of all strokes: upper 95% CI=0.53%; 0.65% of cryptogenic strokes: upper 95% CI=1.92%). Conclusions In this biracial population, unrecognized Fabry disease is a rare but treatable cause of initial ischemic stroke in young men.

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

“…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.…”

Lyso-Gb3 Indicates that the Alpha-Galactosidase A Mutation D313Y is not Clinically Relevant for Fabry Disease

“…In some of the studies, the alpha-galactosidase A activity in patients with the D313Y mutation was decreased, in others it was not (Froissart et al 2003;Yasuda et al 2003;Baptista et al 2010;Gaspar et al 2010;Wozniak et al 2010). Because of the phenotypic and biochemical partly discrepant results, a large Portuguese stroke study screening for Fabry disease comes to the conclusion, however, that the pathogenicity of the mutation D313Y cannot be conclusively determined without additional information (Baptista et al 2010).…”

Letter Regarding Brouns et al, Baptista et al, and Wozniak et al

“…[1][2][3] Previous studies provided conflicting results with no practical conclusion. 4,5 However, early diagnosis of FD could be crucial because enzyme replacement therapy may prevent severe disease manifestations.…”

“…6 The 3 studies differ according to populations enrolled. [1][2][3] Two studies considered ischemic or hemorrhagic strokes, 1,2 although the relation between FD and hemorrhagic stroke is unclear. Moreover, these 2 studies included patients regardless of stroke etiology, which may have led to underestimation of FD.…”