CLINICAL SPECTRUM OF CADASIL - A STUDY OF 7 FAMILIES

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of the brain recently mapped to chromosome 19. We studied 148 subjects belon ging to seven families by magnetic resonance imaging and genetic linka ge analysis. 45 family members (23 males and 22 females) were clinical ly affected. Frequent signs were recurrent subcortical ischaemic event s (84%), progressive or stepwise subcortical dementia with pseudobulba r palsy (31%), migraine with aura (22%), and mood disorders with sever e depressive episodes (20%). All symptomatic subjects had prominent si gnal abnormalities on MRI with hyperintense lesions on T2-weighted ima ges in the subcortical white-matter and basal ganglia which were also present in 19 asymptomatic subjects. The age at onset of symptoms was mean 45 (SD [10.6]) years, with attacks of migraine with aura occurrin g earlier in life (38.1[8.03] years) than ischaemic events (49.3 [10.7 ] years). The mean age at death was 64.5 (10.6) years. On the basis of MRI data, the penetrance of the disease appears complete between 30 a nd 40 years of age. Genetic analysis showed strong linkage to the CADA SIL locus for all seven families, suggesting genetic homogeneity. CADA SIL is a hereditary cause of stroke, migraine with aura, mood disorder s and dementia. The diagnosis should be considered not only in patient s with recurrent small subcortical infarcts leading to dementia, but a lso in patients with transient ischaemic attacks, migraine with aura o r severe mood disturbances, whenever MRI reveals prominent signal abno rmalities in the subcortical white-matter and basal ganglia. Clinical and MRI investigations of family members are then crucial for the diag nosis which can be confirmed by genetic linkage analysis. The disease is probably largely undiagnosed.