Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

History

In 1955, Van Bogaert reported two sisters belonging to a family originating from Belgium having a “subcortical encephalopathy of Binswanger’s type of rapid course” with onset during midadulthood. Their clinical presentation included dementia, gait disturbances, pseudobulbar palsy, seizures, and focal neurologic deficits. Two other sisters died at ages 36 and 43 years after a progressive dementia. The father had a stroke at age 51 and died after a myocardial infarct. The pathologic examination revealed widespread areas of white-matter rarefaction in the brain, associated with multiple small infarcts mainly located in the white matter and basal ganglia.

In 1977, Sourander and Walinder identified hereditary multi-infarct dementia , a familial condition observed in a Swedish pedigree and characterized by dementia associated with pseudobulbar palsy occurring 10–15 years after recurrent stroke-like episodes. Age of onset was between 29 and 38 years; age of death varied from 30 to 53. The authors reported brain lesions identical to those observed by Van Bogaert in three cases, also caused by a small-vessel disease in the brain. The walls of the small arteries were thickened, causing a reduction of their lumen. Atherosclerosis of basal arteries was found in only one family member. In the pedigree, the condition followed an autosomal dominant pattern of transmission. The disease was only recently distinguished from CADASIL.

Prior to 1993, several families having a close presentation were reported, using numerous eponyms: chronic familial vascular encephalopathy , familiäre zerebrale arteriosklerose , familiäre zerebrale Gefäßerkrankung, démence sous-corticale familiale avec leucoencéphalopathie artériopathique , familial disorder with subcortical ischemic strokes, dementia and leukoencephalopathy, and slowly progressive familial dementia with recurrent strokes and white-matter hypodensities on computed tomography (CT) scan.

In 1976, we had a 50-year-old patient with a clinical history of recurrent lacunar infarcts who presented with a large and widespread hypodensity of the white matter on CT scan. He had no vascular risk factors, in particular, no hypertension. Ten years later, his daughter came to see us for a long history of attacks of migraine with aura and transient ischemic attacks and for a recent minor stroke. Her CT scan and MRI showed lesions in the white matter identical to those observed in her father. These two observations were the basis of the extensive clinical, MRI, and genetic study of the whole family, which was a very large one originating from a region in the western part of France (Loire-Atlantique). The data were first presented as “recurrent strokes in a family with diffuse white-matter and muscular lipidosis—a new mitochondrial cytopathy?,” then as “autosomal dominant syndrome with stroke-like episodes and leukoencephalopathy” and later as “autosomal dominant leukoencephalopathy and subcortical ischemic strokes.” Because of the confusion raised by all these different names, we proposed in 1993 the acronym CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) to designate this disease and highlight its main characteristics. After genetic analysis in the large family from Loire-Atlantique, the affected gene was located on chromosome 19 in 1993. In 1996, various mutations of the NOTCH3 gene were found to be responsible for the disease. Since this date, CADASIL has been recognized in hundreds of families in all continents. Thus genetic testing became a means for diagnosis. The gene identification was also crucial to better understanding the pathophysiology of the disease and for the development of transgenic mice models of the disease.

After the gene identification, the evaluation of the prevalence of the disorder became possible. In a population of 994 Caucasian patients with lacunar infarction, aged less than 70 years, the prevalence was found to be 0.5%; this reached 1.5% in individuals having confluent white-matter hyperintensities. In the general population, the prevalence was initially estimated at 1.98/100,000 adults in Scotland based on a national register of the disease. This prevalence was later estimated between 1 and 5/100,00 in other similar studies. ^, Finally, Rutten et al. observed that the prevalence of mutations of the NOTCH3 gene might be much larger in the general population. They observed, in the large database of the Exome Aggregation Consortium (ExAC), from 60.706 unrelated individuals a prevalence of 3.4/1000, but with a vast majority of mutations outside of EGFr domains, 1–6 possibly related to a paucisymptomatic phenotype. ^,