Elsevier

The Lancet

Volume 366, Issue 9499, 19–25 November 2005, Pages 1794-1796
The Lancet

Articles
Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study

https://doi.org/10.1016/S0140-6736(05)67635-0Get rights and content

Summary

Background

Strokes are an important cause of morbidity and mortality in young adults. However, in most cases the cause of the stroke remains unclear. Anderson-Fabry disease is an X-linked recessive lysosomal storage disease resulting from deficient α-galactosidase and causes an endothelial vasculopathy followed by cerebral ischaemia. To determine the importance of Fabry disease in young people with stroke, we measured the frequency of unrecognised Fabry disease in a cohort of acute stroke patients.

Methods

Between February, 2001, and December, 2004, 721 German adults aged 18 to 55 years suffering from acute cryptogenic stroke were screened for Fabry disease. The plasma α-galactosidase activity in men was measured followed by sequencing of the entire α-GAL gene in those with low enzyme activity. By contrast, the entire α-GAL gene was genetically screened for mutations in women even if enzyme activity was normal.

Findings

21 of 432 (4·9%) male stroke patients and seven of 289 (2·4%) women had a biologically significant mutation within the α-GAL gene. The mean age at onset of symptomatic cerebrovascular disease was 38·4 years (SD 13·0) in the male stroke patients and 40·3 years (13·1) in the female group. The higher frequency of infarctions in the vertebrobasilar area correlated with more pronounced changes in the vertebrobasilar vessels like dolichoectatic pathology (42·9% vs 6·8%).

Interpretation

We have shown a high frequency of Fabry disease in a cohort of patients with cryptogenic stroke, which corresponds to about 1·2% in young stroke patients. Fabry disease must be considered in all cases of unexplained stroke in young patients, especially in those with the combination of infarction in the vertebrobasilar artery system and proteinuria.

Introduction

In Fabry disease, globotriaosylceramide accumulates within the vascular epithelium, kidneys, cornea, heart, and other tissues, causing renal failure, painful acroparaesthesias, typical angiokeratoma, hypohydrosis, and cardiac failure.1 The disease usually causes death in adult life from renal, cardiac, or cerebrovascular complications of vascular disease. The incidence of stroke together with vessel ectasia is about 40% in hemizygous male individuals; young people seem to be most affected. Although stroke is generally regarded as a disease of elderly people, its importance is not negligible in younger adults, and even in children. The worldwide incidence of stroke in young adults (aged 16–55 years) is estimated to be nine to 14 per 100 000 people.2 About 27% of ischaemic strokes are judged to be cryptogenic (ie, no specific cause can be identified), and cryptogenic stroke is more common in young rather than old patients.3 We aimed to measure the frequency of Fabry disease in a cohort of more than 700 young white adults aged 18 to 55 years with acute stroke.

Section snippets

Patients

From February, 2001, to December, 2004, we enrolled 721 consecutive unrelated patients (432 male [60%], 289 female [40%]) from 27 different clinical departments in Germany. All patients were between 18 and 55 years of age and had had an apparently unexplained acute cerebrovascular event, a so-called cryptogenic stroke. Only those patients without typical risk factors for stroke, such as relevant nicotine abuse, significant carotid stenosis, severe obesity, cardiac emboli, patent foramen ovale,

Results

The table shows baseline clinical data for the whole cohort and for those with α-GAL mutations. A total of 32 patients (22 male, ten female) had reduced α-GAL activity and/or in the case of the women had DHPLC-screening abnormalities. DNA from these patients was sequenced for the entire coding region of the α-GAL gene. Biologically significant mutations within the α-GAL gene, which prove the diagnosis of Fabry disease, were identified in 28 patients (21 male, seven female; 4·9% and 2·4% of male

Discussion

The most important result of the study is the high frequency of Fabry disease (4%, 28/721) in this cohort of stroke patients with cryptogenic stroke aged between 18 and 55 years. On the basis that about 27% of all strokes in this age-group are of unknown cause,3 this proportion might correspond to about 1·2% in the general population of stroke patients aged between 18 and 55 years. Fabry disease must be considered in all cases of unexplained stroke in young patients, especially in cases with

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