Article: CADASIL

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of hereditary stroke disorder, and is thought to be caused by mutations of the Notch 3 gene on chromosome 19 (Joutel et al, 1996). The most common clinical manifestations are transient ischemic attacks or strokes, which usually occur between 40 and 50 years of age, although MRI is able to detect signs of the disease years prior to clinical manifestation of disease (Chabriat et al, 1995). The disease leads to death in approximately 20 years (Chabriat et al, 1995).

Pathophysiology

The underlying pathology of CADASIL is progressive degeneration of the smooth muscle cells in blood vessels. Mutations in the Notch 3 gene (on the short arm of chromosome 19) cause an abnormal accumulation of Notch 3 at the cytoplasmic membrane of vascular smooth-muscle cells both in cerebral and extracerebral vessels (Joutel et al, 2000), seen as granular osmiophilic deposits on electron microscopy (Ruchoux et al, 1995).

Interestingly, the Notch 3 gene is in the same locus as the gene for familial hemiplegic migraine.

Clinical Features

CADASIL may start with attacks of migraine with aura or subcortical transient ischemic attacks or strokes, or mood disorders between 35 to 55 years of age. The disease progresses to subcortical dementia associated with pseudobulbar palsy and urinary incontinence, before leading to death approximately 20 years after the onset of symptoms (Chabriat et al, 1995).

Diagnosis

MRI is the diagnostic modality of choice. Hypointensities on T1-weighted images and hyperintensities on T2-weighted images, usually multiple confluent white matter lesions of various sizes, are characteristic. These lesions are concentrated around the basal ganglia, periventricular white matter, and the pons, and are similar to those seen in Binswanger disease (Chabriat et al, 1995; Ropper and Brown, 2005). These white matter lesions are also seen in asymptomatic individuals with the mutated gene (Tournier et al, 1993).

The disease may also be diagnosed by screening for the mutated Notch 3 gene; however, this method is costly and laborious. Since CADASIL is a systemic arteriopathy, evidence of blood vessel damage is seen in small- and medium-sized arteries. It has therefore been suggested that skin biopsies could be used for diagnosis (Joutel et al, 2001); however, the lack of widespread availability of a monoclonal antibody required for diagnosis, limit the utility of this method.

Treatment

No specific treatment is available