Articles 1794 www.thelancet.com Vol 366 November 19, 2005 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. Methods 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, and coagulopathies and without a diagnosis being made about the cause of the stroke were enrolled in the study without any further selection criteria. Procedures For determination of the subtype of ischaemic stroke, we used the original TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria. 4 -galactosidase (-GAL) activity was measured in all 721 patients with the artificial fluorogenic substrate, 4-methylumbelliferyl-- D-galactoside (Sigma, St. Louis, MO, USA). We regarded values of leucocyte -GAL activity between 33·2 and 109 nmol MU/h/mg protein (mean 64·8, SD 13·4) as normal. We measured concentrations of Gb3 in plasma by mass spectrometry (LC-MS/MS) using C17-Gb3 as an internal standard as described previously. 5 The reference ranges were: 3·6–7·5 g/mL plasma for normal controls (n=52), 4·3–27·6 g/mL plasma for male hemizygotes (n=34), and 4·4–10·8 g/mL plasma for female heterozygotes (n=44). To identify mutations in Lancet 2005; 366: 1794–96 Published online November 9, 2005 DOI:10.1016/S0140-6736(05) 67635-0 See Comment page 1754 Department of Neurology, University of Rostock, Rostock, Germany (Prof A Rolfs MD, T Böttcher MD, M Zschiesche PhD, P Bauer MD, U Walter MD, E Mix MD PhD, U Strauss MD, R Benecke MD); Institute of Diagnostic and Interventional Radiology, University of Rostock, Rostock, Germany (A Grossmann MD); Department of Medical Genetics, University of Tübingen, Tübingen, Germany (P Bauer); Neurochemical Laboratory, University of Tübingen, Tübingen, Germany (K Harzer MD); Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, University College London, London, UK (P Morris MSc, B Winchester PhD); Department of Gastroenterology, University of Mannheim/Heidelberg, Mannheim, Germany (M Löhr MD); and University Hospital Zurich, Department of Pathology, Institute of Neuropathology, Zürich, Switzerland (J Pahnke MD). Correspondence to: Prof Arndt Rolfs, Department of Neurology, University of Rostock, POB 100 888, 18055 Rostock, Germany arndt.rolfs@med.uni- rostock.de Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study Arndt Rolfs, Tobias Böttcher, Marlies Zschiesche, Peter Morris, Bryan Winchester, Peter Bauer, Uwe Walter, Eilhard Mix, Mathias Löhr, Klaus Harzer, Ulf Strauss, Jens Pahnke, Annette Grossmann, Reiner Benecke 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 -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 -galactosidase activity in men was measured followed by sequencing of the entire -GAL gene in those with low enzyme activity. By contrast, the entire -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 -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.