Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: A genetic form of vascular dementia

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a human genetic disease of small vessels characterized by autosomal dominant transmission, presence of small subcortical strokes, and leukoencephalopathy. Lesions affect mainly the brain, but the vasculopathy occurs in other organs and the diagnosis can be made by skin biopsy. Clinical manifestations include strokes, migraine with aura, depression, vascular dementia, and seizures (10%). Onset is at about age 30 with migraine preceded by aura; recurrent ischemic lacunar strokes begin to occur at age 45, usually in patients without traditional vascular risk factors. Brain MRI shows white matter lesions at 20 years of age, and skin biopsies are also positive at this early age. Poststroke vascular depression usually follows, leading to a pseudobulbar syndrome and to severe subcortical vascular dementia; death occurs at a mean age of 65 years. CADASIL maps to the short arm of chromosome 19. Notch3, the mutated gene, was previously unknown in humans and encodes for a large transmembrane receptor belonging to the Notch/LIN-12 family, involved in cell fate during development. Notch3 expression is highly restricted to the vascular smooth muscle cell. Mutations lead to tissular accumulation of the extracellular domain of the protein. Animal models include the Drosophila lethal-Abruptex and transgenic A90C-Tg-mice; pathological changes similar to those observed in CADASIL are seen in the Tg-mice. There is hope that the animal models would eventually provide a successful treatment for CADASIL patients.