6 Finally, 117 (49 men) age and sex matched (mean age 60.1 (SD 15.0) years range 35–91) asymptomatic normotensive controls were also recruited. Clinical diagnoses were based on established criteria. All patients with dementia were fully investigated using standard psychometry and neuroimaging techniques. The FTD group (in which the dementia was hypothesised to be aetiologically unrelated to CADASIL) was used as a “positive disease” control group for the AD cohort. In addition, seventy seven patients (36 men) from a specialist young dementia clinic were also recruited (mean age of disease onset 64.4 (SD 9.2) years range 46.7–89.6) comprising 55 with Alzheimer's disease (AD) with or without vascular dementia, and 22 with frontotemporal dementia (FTD). Seventy (40 men) well characterised relatively young patients with radiologically established sporadic ischaemic stroke were recruited (mean age of disease onset 68.8 (SD 13.6) years range 20–90). For these purposes, we designed an array of restriction enzymes and mismatch primers. We sought to establish a simple and reliable genetic test for the Notch3 variants clustering in exons 3 and 4, and to determine the allele frequencies of Notch3 mutations and polymorphisms in patients with stroke and dementia. Indeed, the absence of a readily accessible screening test along with the need to determine the frequency of Notch3 mutations in common related diseases masquerading as CADASIL may slow our ability to understand the pathophysiology of cerebrovascular disease. Whether mutations in such a rare monogenic syndrome account for, or have any effect on, more common phenotypes has not been investigated, partly hampered by the lack of a quick and reliable screening test. 4 5Thus, exons 3 and 4 should be screened as a first stage but, if no mutations are detected and clinical suspicion remains high the remainder of this gene should be sequenced. 3 Mutations clustering in exons 3 and 4 account for about 65% of all patients with CADASIL. 2 The disease is due to mutations in the transmembrane receptor of the Notch3 gene, which either create or destroy a cysteine residue.
1 The clinical picture is accompanied by associated magnetic imaging abnormalities. The test will enable units locally to rapidly screen patients with suspected CADASIL.Ĭerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare inherited adult onset disease characterised most commonly by cerebral ischaemic events (84%) and dementia (31%), but also migraine with aura and mood disturbances. The data suggest that despite the clinical resemblance, CADASIL is not a common masquerading cause of stroke or dementia. In conclusion, a readily usable genetic test for CADASIL has been devised that was used to determine allele frequencies in well characterised cohorts of sporadic stroke and dementia patients. Molecular variant C381T occurred with a higher frequency of 0.13, whereas G684A occurred with a lower frequency (0.09) than previously reported, although there were no statistical differences between selected cohorts.
None of the 14 known mutations and three previously identified polymorphisms (C474A, A587G, and C594A) in exons 3 and 4 were present in 140 stroke, 110 dementia, or 234 control chromosomes. The diagnostic array was found to work well. One hundred and seventeen age and sex matched asymptomatic controls were also identified. Seventy patients with radiologically established sporadic ischaemic stroke and 77 patients from a specialist young dementia clinic were recruited. This array was used to identify the allele frequencies of CADASIL mutations and polymorphisms in selected disease cohorts. Whether these mutations have any influence on common sporadic ischaemic stroke or dementia cases has not been investigated, partly hampered by the lack of a readily usable genetic test.Īn easy to use diagnostic array for CADASIL was designed using various restriction endonucleases for the known mutations in exons 3 and 4 and novel mismatch primers were designed where no such enzymes existed. It is caused by mutations in the Notch3 gene with most clustering in exons 3 and 4. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare inherited adult onset disease characterised most commonly by cerebral ischaemic events and dementia.
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