CADASIL is the acronym for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy (the term was coined to designate this disorder in 1993 during an International Workshop). CADASIL is a genetic disease transmitted in an autosomal dominant pattern. The prevalence is not yet established but the disorder is probably underdiagnosed. It is associated with cerebral vascular accidents, mainly ischemic events (lacunar infarcts), and migraine with or without aura. The onset of symptoms occurs around age 40. The disease course is marked by subsequent strokes, mainly as lacunar infarcts, cognitive impairment, psychiatric dysfunction (depressive syndrome, sometimes manic or melancholic episodes). Diagnosis is suspected at clinical examination and confirmed by MRI, which shows leukoaraiosis (white matter lesions) and lacunar infarcts. Some neuroradiological findings support strongly the diagnosis, such as hyperintense lesions on T2-weighted images in the anterior part of the temporal lobes. The causative gene, Notch 3, mapped to chromosome 19p, was identified in 1996. The disorder is genetically homogeneous since all the families affected with CADASIL have been linked to Notch 3. This gene comprises 33 exons. The genetic defects are point mutations, which cluster into specific exons. Notch 3 encodes a membrane protein, which contains cystein-rich EGF (Epidermal growth Factor) like domains, is expressed in smooth muscles cells of small cerebral and extracerebral blood vessels. Pathogenic mutations cause either the loss or gain of a cystein residue and lead to the accumulation of Notch 3 in the membrane. Notch 3 is detected by antibodies in the smooth muscle cells in arterioles. Electron microscopy reveals fragmentation of smooth muscle cells and granular osmiophilic deposits (GOM) within the vascular basal membrane. The significance of GOM is unknown; they are not detected by anti-Notch 3 antibodies. The clinical diagnosisis confirmed by the identification of mutations in Notch 3. Currently, mutation analysis in 12 exons allows to establish the diagnosis in 90% of cases. In absence of mutations in these exons, the full-length gene can be sequenced. Skin biopsy immunostaining remains a mainstay diagnosis test to detect Notch 3 in smooth muscle cells of subcutaneous arterioles. Skin analysis by electron microscopy study is only used in clinical research. To date, there is no efficient drug.
Last update: September 2004