To date, there have been 2 published studies of the frequency of unrecognized Fabry disease among patients with cryptogenic strokes. Rolfs et al12
reported that 4.9% of 432 males and 2.5% of 289 females with cryptogenic strokes had unrecognized Fabry disease. Subsequently, Brouns et al13
reported that Fabry disease was not identified among 64 Belgian males with cryptogenic strokes. Contrary to the German report, our study indicates that Fabry disease is rare in young adults with first ischemic stroke of undetermined cause.
It is likely that the wide discrepancy in reported prevalence of Fabry disease between our study and the German study is due to differences in study populations (). The German report12
suggested that unrecognized Fabry disease occurred in almost 5% of 18- to 55-year-old men with an otherwise undetermined stroke etiology. In that study, 10% of all cryptogenic stroke cases had multiple cerebrovascular events and 46.7% (10 of 21) of men with a cryptogenic stroke and a Fabry mutation had multiple cerebrovascular events. It is not clear if the German study included only patients with ischemic stroke or included a small percentage of patients with primary intracerebral hemorrhage.
Prevalence of Fabry Disease in Young Men With Cryptogenic Ischemic Stroke
In contrast, our study included only first ischemic stroke cases. When the German study is reanalyzed to include only first ischemic stroke cases, the prevalence of Fabry disease is lower. The German data can be disaggregated into a prevalence of 2.17% patients with Fabry disease among 367 men with first ischemic stroke and a prevalence of 24.3 among 41 men with recurrent ischemic stroke. This lower rate is substantially closer to the rate we report. In addition, the mutations associated with the German cases were not reported, so it is possible that some of the cases may have had the D313Y polymorphism with low plasma enzyme activity, which has an allele frequency of approximately 0.5% among European-Americans but with near normal cellular enzyme activity.20,21
Our study is the first to look at unselected patients with first ischemic stroke. We had hypothesized that the metabolic defect of Fabry disease could be synergistic with other risk factors. In addition, Fabry disease may be associated with cardiomyopathy and the stroke would have been classified as cardioembolic rather than cryptogenic. However, there were no cases of Fabry disease in strokes of known etiology in our study.
The diagnosis of Fabry disease in young patients with stroke is important for several reasons. Although it is not known whether enzyme replacement therapy will prevent ischemic stroke recurrence, it is known to delay or prevent other manifestations of Fabry disease, particularly renal and cardiac complications.23,24
Equally important are the potential benefits for family members. Institution of enzymatic replacement therapy in presymptomatic individuals could potentially eliminate the manifestations of Fabry disease.
The results of our study suggest that the yield for screening is lower for first compared with recurrent cryptogenic ischemic stroke. Although our study did not identify any particular features that would enhance the yield of screening, it remains prudent to consider screening patients with clinical features suggestive of Fabry disease. Because Fabry disease is an X-linked disease, family history should be obtained regarding the (1) mother’s brothers; (2) patient’s brothers; (3) patient’s sons; and (4) patient’s sister’s male children. Female carriers can also manifest disease symptoms.25,26
The occurrence of early or idiopathic end-stage renal disease, proteinuria, cardiac disease, ischemic stroke, hypohidrosis, acroparesthesias, and/or angiokeratomas should suggest the diagnosis of Fabry disease. Genetic testing should be undertaken for the patient and at-risk family members. Affected individuals should be referred for further evaluation and therapeutic intervention.