Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is the most frequent hereditary cerebral small vessel disease and the first cause of stroke of hereditary origin. The disease is caused by cysteine mutations of the NOTCH3 gene on chromosome 19 and is observed worldwide. The diagnosis can be confirmed by genetic testing or, in difficult cases, by skin biopsy showing the accumulation of extracellular EGFr domains of the NOTCH3 receptor in the vessel wall. This accumulation is observed using immunostaining and leads to large aggregates described as Granular Osmiophilic Material visible (GOM) visible in arterioles and capillaries by electron microscopy. Accumulation of the NOTCH3 protein presumably disrupts protein homeostasis in the vascular wall, aggregates other matrix proteins and finally leads to loss of smooth muscle cells and fibrosis. The clinical spectrum of the disease of usual onset during midadulthood, and which evolves over several decades, includes migraine with aura, transient ischemic attacks or stroke, cognitive and motor decline, neuropsychiatric manifestations, apathy, gait disturbances and at end-stage severe dementia associated with bedridden status. However, the clinical expression of the disease appears largely variable among affected families and individuals. Vascular risk factors and the location of the NOTCH3 mutation along EGFr domains partly modulate the severity of the disease. Additional factors of this variability remain to be identified.