Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: from stroke to vessel wall physiology

Ischaemic stroke, which accounts for 85% of all strokes is characterised by its remarkable aetiopathogenic diversity, with three main varieties: atherothrombotic brain infarction, cardiac emboli, and small artery diseases, and with up to 40% of undetermined cause.1Small artery disease of the brain has long been thought to be restricted to hypertension related lipohyalinosis resulting in lacunar infarcts2 and eventually in Binswanger's encephalopathy, the archetype of subcortical vascular dementia.3

From 1976 onwards we were able to study a large French family, some members of whom were affected by a small artery disease of the brain reminiscent of Binswanger's disease but remarkable by the absence of hypertension and of other vascular risk factors.4-6 This familial cerebral arteriopathy was strikingly similar to eight others reported under various eponyms from 1955 to 1992.7-14 The extensive study of 57 members of this French family led us in 1993 to identify this small artery disease of the brain as a specific entity, to describe its main clinical and MRI features, to propose the acronym CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and, using a positional cloning approach, to locate the responsible gene on chromosome 19.15 Linkage was later confirmed in many families,16-23 which allowed us in 1996 to refine the genetic mapping within a 2 cM interval.24 The next crucial step was the identification of the mutated gene as Notch 3, a gene previously unknown in humans25 which encodes for a large transmembrane receptor belonging to the Notch/lin 12 gene family which is known to be involved in cell fate specification …