CADASIL: An Autosomal Dominant Genetic Stroke Disorder

Abstract & Commentary

Source: Bousser MG, Tournier-Lasserve EJ. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: From stroke to vessel wall physiology. J Neurol Neurosurg Psychiatry. 2001;70:285-287.

In 1976, Bousser identified a large French family that contained several members who suffered small strokes related to abnormalities of small cerebral arteries at a relatively low age. She identified 8 other families reported in the literature between 1955-1992 and defined their mutual specific qualities as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). In 1993, the gene was identified on chromosome 19 q12 and was specifically identified as Notch 3 in 1995. A molecular diagnostic test is now available for diagnosis. Subsequently, sporadic cases were identified, although the hereditary genes continue to be the cause.

CADASIL produces various symptoms and signs between individual patients, but the principal disturbances consist of ischemic subcortical strokes, dementia, migraine with aura, and emotional-intellectual disturbances. Migraine with aura, if at all, usually appears during the late 20s or early 30 years. Randomly occurring ischemic strokes or apathetic behavior usually strike patients aged 40-50 years. The following 15 years usually represent an ultimate tragedy of severe, mute dementia. Most CADASIL patients die by age 65, although a few "odd ball" persons can remain asymptomatic in their eighth decade.

Diagnosis by the above clinical criteria can be relatively straightforward, particularly when small strokes follow late delayed migraine. MRI consistently identifies hypersignals of T2-weighted images in the periventricular and centrum semiovale. Additional lesions consistently affect the basal ganglia (denying multiple sclerosis) and the pontine tegmentum. Eventually, multifocal, deep leucoencephalopathic infarcts that spare the cerebral cortex appear. Specific diagnosis can be made by skin-muscle biopsies which demonstrate thickening of smooth arteriopathic muscle cells that eventually degenerate. If possibly available, electron microscopy can diagnose the disease by identifying granular, osmophilic materials in smooth arterial muscle.

Commentary

In the last 15 years, Bousser has clinically and genetically identified a new form of inborn vascular disease that selectively, severely damages the brain. Apparently, however, absolute diagnosis can be made by skin-muscle biopsy and the finding of the Notch 3 mutation of chromosome 19. Absolute diagnosis (of CADASIL) also can be suggested by MRI T2 scanning plus pathological diagnoses of skin-muscle biopsy. As she states, "Next important steps will be to determine whether mutations lead to inhibition or activation of the Notch 3 signaling pathway and whether Notch 3 accumulation occurs in a ligand dependent or independent context." —Fred Plum