Cerebrovascular Complications of Fabry’s Disease

Abstract

Fabry's disease (FD) is a rare, sex-linked disorder resulting from a-galactosidase deficiency. Cerebrovascular complications have been reported in the literature but have not been systematically analyzed. We report 2 patients and review 51 previously reported cases (descriptive meta-analysis) to clarify the clinical, radiologic, and pathologic features. The average age at onset of cerebrovascular symptoms was 33.8 years for hemizygous individuals (n = 43) and 40.3 years of heterozygotes (n = 10). The most frequent symptoms and signs were as follows (in descending order of frequency): hemiparesis, vertigo/dizziness, diplopia, dysarthria, nystagmus, nausea/vomiting, head pain, hemiataxia, and ataxia of gait, in the hemizygote group; and memory loss, dizziness, ataxia, hemiparesis, loss of consciousness and hemisensory symptoms, in the heterozygote group. The vertebrobasilar circulation was symptomatic in 67% of the hemizygotes and 60% of the heterozygotes. Intracerebral hemorrhage was found in 4 patients (3 hemizygotes and 1 heterozygote). Elongated, ectatic, tortuous vertebral and basilar arteries were the most common angiographic and pathologic features. For the hemizygotes, the recurrence rate for cerebrovascular disease was 76% and the death rate was 55%; 86% of the heterozygotes had recurrent cerebrovascular event(s) and 40% died. The cerebrovascular manifestations of FD, in both hemizygotes and heterozygotes, are predominantly due to dilative arteriopathy of the vertebrobasilar circulation, frequently recur, and portend a poor prognosis. Mitsias P, Levine SR. Cerebrovascular complications of Fabry's disease. Ann Neurol 1996;40:8-17 Patients and Methods W e reviewed our clinical experience with 2 siblings, 1 male hemizygote and 1 female heterozygote, with cerebrovascular manifestations of FD, and systematically reviewed the literature. Criteria for diagnosis of FD and inclusion into this study included the following: corneal abnormalities, angiokeratoma, positive family history, and decreased a-galactosidase activity on cultured skin fibroblasts or platelets. Literature review cases were identified by using a computerized English language Medline search (key words: Fabry's disease,

Pattern of microstructural brain tissue alterations in Fabry disease

“…Such alterations have been found to be pronounced in cerebral white matter probably because of the arterial supply by long perforating arteries [10]. The posterior cerebral artery territory could also be identified as susceptible for vascular lesions and perfusion disturbances [3,11].…”

“…Numerous mutations have been described that account for deficient activity of the enzyme α-galactosidase A [2] leading to progressive accumulation of neutral glycosphingolipids, mainly globotriaosylceramide (Gb 3 ), in various organ systems. Lipid deposits occur preferentially in vascular endothelium and smooth muscle cells leading to tissue ischemia and vessel occlusion [3]. Clinical hallmarks are neuropathic pain, angiokeratoma, hypohidrosis, renal dysfunction, cardiac and cerebral involvement (especially left ventricular hypertrophy and premature stroke) [4,5].…”

“…Age-dependent cerebral vasculopathy as a result of progressive Gb 3 deposits in the vascular endothelium and vascular smooth muscle could be described at a neuropathological, neuroradiological, and functional level [3,6,7]. The Fabry Outcome Survey (FOS) recorded cerebrovascular events in 12 % of male and 27 % of female patients highlighting the frequent clinical affection of females who had been considered as ■ Abstract Fabry disease (FD) is a lysosomal storage disorder that is associated with marked cerebrovascular disease.…”

Profile of endothelial and leukocyte activation in fabry patients

“…4,5 Cerebrovascular ischemia in Fabry disease has been largely attributed to the progressive deposition of Gb 3 in vascular endothelium, resulting in both luminal compromise and large-vessel ectasia, giving rise to thrombotic and thromboembolic events. 1,6 Although structural compromise to the cerebral arterial vasculature is believed to play a major role in ischemic events, a review of the literature has shown that cerebral ischemia occurs even in the setting of mild to moderate vascular changes. 6 In addition, heterozygote females, who have conventionally been thought to display a less aggressive form of the disease, have more recently been noted to exhibit a very high recurrence rate of recurrent cerebrovascular events.…”

“…1,6 Although structural compromise to the cerebral arterial vasculature is believed to play a major role in ischemic events, a review of the literature has shown that cerebral ischemia occurs even in the setting of mild to moderate vascular changes. 6 In addition, heterozygote females, who have conventionally been thought to display a less aggressive form of the disease, have more recently been noted to exhibit a very high recurrence rate of recurrent cerebrovascular events. It has further been noted that both hemizygous and heterozygous patients have a high recurrence rate of intravascular thrombosis including venous thrombophlebitis.…”