Fabry Disease: An Underappreciated Cause of Cryptogenic Ischemic Stroke in Young Adults

Abstract & Commentary

By Dara G. Jamieson, MD, Associate Professor, Clinical Neurology, Weill Medical College of Cornell University. Dr. Jamieson is a consultant for Boehringer Ingelheim and Merck, and is on the speaker's bureau for Boehringer Ingelheim, Merck, Ortho-McNeil, and Pfizer.

Synopsis: 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.

Source: Rolfs A, et al. Prevalence of Fabry Disease in Patients with Cryptogenic Stroke: A Prospective Study. Lancet. 2005;366:1794-1796.

Fabry disease is an x-linked recessive lysosomal storage disorder due to deficient activity of β-galactosidase A (β-Gal A) leading to accumulation of globotriaosylceramide in vascular endothelium. The disease predominantly affects males who have very low or undetectable β-Gal A activity. Females may be affected to a variable degree because of random X-chromosome inactivation. The diagnosis in males is made by the determination of very low or absent β-Gal A activity in plasma or peripheral leukocytes. In affected females, the gene mutation must be detected, as β-Gal A levels may vary from normal to low. Clinical onset of the disease may begin in childhood, although without a known family history, the diagnosis may not be made until progression of symptoms into adulthood. Globotriaosylceramide accumulation in the vasculature of the kidney, heart, and brain may lead to renal failure, myocardial infarction, and ischemic stroke at an early age, due to vascular occlusion and a prothrombotic state. The ischemic strokes tend to occur in the posterior circulation, involving both large and small vessels. Characteristic skin (angiokeratomas) and ocular (corneal opacities) lesions, as well as a painful peripheral neuropathy are also found in many affected patients. Early initiation of recombinant human β-galactosidase A replacement therapy can reverse the lysosomal storage and halt disease progression. However, enzyme replacement therapy for Fabry disease is expensive, and its long-term clinical efficacy is uncertain.

Ischemic stroke in young adults may be caused by systemic disorders which are not associated with traditional vascular risk factors. Rolfs and colleagues set out to determine the importance of unrecognized Fabry disease in young patients with acute ischemic stroke. Between February 2001 and December 2004, 721 German adults aged 18-55 years were screened for Fabry disease. All the patients had had a cryptogenic ischemic stroke, without typical vascular risk factors. Activity of plasma β-Gal A was measured in men, followed by sequencing of the entire β-Gal A gene in those men with low enzyme activity. The entire β-Gal A gene was screened for mutations in women, even if enzyme activity was normal. Biologically significant mutations within the β-Gal A gene, establishing the diagnosis of Fabry disease, were found in 21 of 432 (4.9%) of males and 7 of 289 (2.4%) of females. The mean onset of symptomatic cerebrovascular disease associated with Fabry disease was 38.4 years in the male stroke patients and 40.3 years in the females. Stroke in young adults with Fabry disease was significantly more likely to be in the vertebrobasilar distribution, presenting with ataxia, dysarthria, nausea, and dizziness. Based on an estimate of 27% of strokes being cryptogenic, the 4% incidence of Fabry disease corresponds to about 1.2% of the stroke patients aged between 18 and 55 years. The clinical effect of enzyme replacement therapy on cerebrovascular events is unknown, although studies have shown that treatment reverses abnormal cerebral blood flow.

Fabry disease should be added to the multiple etiologies to be considered in young adults with ischemic strokes. The diagnosis is especially important because of the possibility of a specific treatment, which may prevent progressive multi-organ vascular disease. It should be considered in unexplained ischemic stroke in young patients, especially when vertebrobasilar territory infarction is seen in combination with proteinuria.