Genetics of Ischaemic Stroke
Genetics of Ischaemic Stroke
Fabry's disease is a congenital metabolic disorder caused by deficient activity of α-galactosidase A (α-gal), resulting in a progressive accumulation of globotriaosylceramide and related glycosphingolipids within vascular endothelial cells, myocardial cells and neurons. The prevalence of Fabry's disease in patients with stroke is variable but has been reported to be as high as 4.9% to 6.9% with a median age of onset of 39 years in men, otherwise the incidence is reported as 1 per 3100 individuals. Although an X linked lysosomal storage disorder, female carriers can develop symptoms suggestive of Fabry's disease with symptoms appearing comparatively later than in men, at a median age of 45.7 years.
Neurological symptoms are wide-ranging with the most common clinical presentation being peripheral neuropathy presenting as burning pain in the extremities and gastrointestinal symptoms. Fabry's disease should be considered in patients with small-fibre neuropathy of unknown cause. Ischaemic stroke and transient ischaemic attack (TIA) are also frequent presentations in Fabry's disease, with abnormalities of the vertebral and basilar arteries particularly common. MRI classically shows high intensity lesions in the pulvinar and torturous and dilated large vessels (dolichoectasia). The well recognised pulvinar sign (hyperintensity in the pulvinar nucleus of the thalami) as well as increased basilar artery diameter are highly characteristic of this disease, although this sign has also been reported in Wernicke's and paraneoplastic encephalopathy, vacuolar leucoencephalopathy in association with coeliac disease as well as sporadic and variant Creutzfeldt-Jakob disease. Fabry's symptoms are not specific and diagnosis through clinical suspicion and imaging is insufficient to confirm diagnosis. Measuring the α-gal activity in leukocytes and plasma and sequencing the α-GAL gene for the over 400 known pathological mutations confirms the presence of Fabry's.
Bi-weekly recombinant α-gal enzyme replacement therapy at a dose of 1 mg/kg body weight has shown benefits for heart, kidney and neuropathic pain, especially if patients are treated early in their disease; however, the risk of stroke remains substantial and management of conventional stroke risk factors is important as well as early augmentation of enzyme replacement therapy.
Fabry's Disease
Fabry's disease is a congenital metabolic disorder caused by deficient activity of α-galactosidase A (α-gal), resulting in a progressive accumulation of globotriaosylceramide and related glycosphingolipids within vascular endothelial cells, myocardial cells and neurons. The prevalence of Fabry's disease in patients with stroke is variable but has been reported to be as high as 4.9% to 6.9% with a median age of onset of 39 years in men, otherwise the incidence is reported as 1 per 3100 individuals. Although an X linked lysosomal storage disorder, female carriers can develop symptoms suggestive of Fabry's disease with symptoms appearing comparatively later than in men, at a median age of 45.7 years.
Neurological symptoms are wide-ranging with the most common clinical presentation being peripheral neuropathy presenting as burning pain in the extremities and gastrointestinal symptoms. Fabry's disease should be considered in patients with small-fibre neuropathy of unknown cause. Ischaemic stroke and transient ischaemic attack (TIA) are also frequent presentations in Fabry's disease, with abnormalities of the vertebral and basilar arteries particularly common. MRI classically shows high intensity lesions in the pulvinar and torturous and dilated large vessels (dolichoectasia). The well recognised pulvinar sign (hyperintensity in the pulvinar nucleus of the thalami) as well as increased basilar artery diameter are highly characteristic of this disease, although this sign has also been reported in Wernicke's and paraneoplastic encephalopathy, vacuolar leucoencephalopathy in association with coeliac disease as well as sporadic and variant Creutzfeldt-Jakob disease. Fabry's symptoms are not specific and diagnosis through clinical suspicion and imaging is insufficient to confirm diagnosis. Measuring the α-gal activity in leukocytes and plasma and sequencing the α-GAL gene for the over 400 known pathological mutations confirms the presence of Fabry's.
Bi-weekly recombinant α-gal enzyme replacement therapy at a dose of 1 mg/kg body weight has shown benefits for heart, kidney and neuropathic pain, especially if patients are treated early in their disease; however, the risk of stroke remains substantial and management of conventional stroke risk factors is important as well as early augmentation of enzyme replacement therapy.
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