Cryptogenic Stroke and Fabry Disease
Cryptogenic Stroke and Fabry Disease
Although the incidence of ischaemic stroke increases with age, stroke in children and young adults is not uncommon.1 The average population-based annual incidence rate for ischaemic stroke (cases per 100.000 per year) has been reported as about 11.3 among those aged 15 to 49 years.2,3 For at least 20–40% of the stroke cases in young adults no specific causes are found (so-called cryptogenic stroke), even if the patients are examined extensively and very carefully for causes like Moyamoya syndrome, dissection, infection, haemoglobinopathies, coagulopathies, migraine, CADASIL, V. zoster infection, hyperhomo-cysteinemia, oral contraceptives, heart failures etc.4,5 With technical and medical advances this proportion may be as low as 18%.6
The definition of cryptogenic strokes is ambiguous because it can include the mechanism and risk factors. This high percentage of unclarified etiologies of stroke in young adults demands the investigation of even apparently rare diseases, like Fabry disease.
Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from deficiency of the lysosomal hydroxylase, alpha galactosidase A (AGLA).7 In humans, the disease is characterised by the systemic accumulation of the glycosphingolipid substrate, ceramide trihexoside (CTH) and ceramide dihexoside in tissue. Clinical manifestations of Fabry disease include chronic pain, kidney impairment, skin lesions, ocular opacities, vascular deterioration, stroke and cardiac deficiencies leading to premature mortality.8 Recently, enzyme replacement therapy (ERT) has become available.7
Death usually occurs in adult life from renal, cardiac, or cerebrovascular complications of vascular disease. Heterozygote females are either asymptomatic or exhibit fewer signs and symptoms of disease, although there are continually more reports describing females with symptoms similar to the males.9 In the central nervous system (CNS), diffuse storage occurs in the vascular endothelium, with more localised involvement of central neurons together with the dorsal root and autonomic ganglia in the peripheral nervous system. The incidence of stroke together with vessel ectasia is about 40% in hemizygous males;10 mainly younger subjects seem to be affected. The most frequent cerebrovascular symptoms in Fabry patients are hemiparesis, vertigo/dizziness, diplopia, nystagmus and ataxia of gait in the hemizygote group; and memory loss, dizziness, ataxia, hemiparesis, loss of consciousness and hemisensory symptoms in the heterozygote group.11 The cerebrovascular manifestations consist of large-vessel ectasia, large-vessel occlusive disease, and small-vessel disease; the vascular diathesis is reported to have a vertebrobasilar circulation distribution, although the reason for this is unclear. positron emission tomography (PET) investigations suggest a chronic alteration of the nitric oxide (NO) pathway in Fabry disease.12 On the other hand, there exists an increased endothelium-mediated vascular reactivity, where the increased vessel response to acetylcholine with and without NG-monomethyl-Larginine (L-NNMA) suggests altered functionality of non-NO endothelium-dependent vasodilatory pathways. Vessel wall alterations with narrowing of cerebral resistance vessels are likely to comprise cerebral blood flow (CBF) velocity and to contribute to the early and increased incidence of stroke. Hyperintensity in the pulvinar on T1-weighted magnetic resonance imaging (MRI) images seems to be a common finding in Fabry disease, which probably reflects the presence of calcification.13 Increased cerebral blood flow in the posterior circulation, particularly in the thalamus, suggests that the dystrophic calcification is secondary to cerebral hyperperfusion and selective vulnerability of the pulvinar and adjacent thalamic structures.
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