CADASIL and genetics of cerebral ischaemia
Recent advances suggest the existence of several autosomal dominantly inherited forms of cerebrovascular disorders. Mutations in diverse genes may induce direct pathological changes in intracranial vessels to cause cerebral ischaemic or haemorrhagic strok
- PDF / 2,352,845 Bytes
- 16 Pages / 612.24 x 793.68 pts Page_size
- 82 Downloads / 188 Views
Summary. Recent advances suggest the existence of several autosomal dominantly inherited forms of cerebrovascular disorders. Mutations in diverse genes may induce direct pathological changes in intracranial vessels to cause cerebral ischaemic or haemorrhagic strokes leading to cognitive impairment and dementia. Similar pathology may also be caused by systemic vascular disease resulting from mutations and polymorphisms in genes that regulate cardiovascular physiology, blood coagulation and metabolic functions. The most common form of familial stroke appears to be CADASIL or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CADASIL is an arterial disease that has been linked to nucleotide substitutions and deletions in the Notch 3 gene. The pathogenesis of the disorder or how the mutations lead to cerebral infarcts and dementia is not known. However, elucidation of the microvascular pathology associated with such genetic disorders not associated with physiological risk factors for cardiovascular disease or stroke can bear much light on primary vascular mechanisms that lead to ischaemic blood flow and neuronal vulnerability. Introduction Cerebrovascular disease is a consequence of impairment of the blood supply to the brain. Ischaemic strokes account for 80% whereas intracerebral or subarachnoid haemorrhages constitute the rest of cerebrovascular disease (Kalimo et aI., 1997). Cerebral infarction provoked by diminished oxygen and glucose availability may result from systemic vascular disease through large vessel emboli and atheromas or intracranial vascular disease. On the other hand hypertension is a frequent cause of cerebral haemorrhages. The extent of ischaemic damage will depend on the type, size and distribution of vessels as well as degree of insult. Oligaemia (hypoperfusion) occurring in the fringes of the ischaemic core (penumbra) or more widely upon impaired autoregulation of cerebral perfusion may lead to further irreversible injury if sustained over a long period. The genetics of cerebrovascular disorders was virtually unknown until recently. They may have evaded genetic association because of widely vari-
W. W. Fleischhacker et al. (eds.), Stroke-Vascular Diseases © Springer-Verlag/Wien 2002
76
R. N. Kalaria et al.
able phenotypes even within single gene disorders. A number of conditions within cerebrovascular disorders are recognized to be inherited in an autosomal dominant fashion. Hereditary forms of cerebrovascular disorders constitute only a small proportion «10%) but they invariably cause extreme morbidity and mortality in both young and old. Causal genes and mutations linked to distinct cerebrovascular pathologies have been identified for several disorders directly affecting vessel structure and function (Kalaria, 2001). These have been variably termed vasculopathies and more precisely designated as angiopathies, arteriopathies and rarely endotheliopathies. Inherited disorders that affect cardiac pathophysiology, thrombosis, haemostasis and mitochondri
Data Loading...
