CADASIL syndrome

[elias eltoum]

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 theNotch 3 gene on chromosome 19.[1] The disease belongs to a family of disorders called the Leukodystrophies. The most common clinical manifestations are migraine headaches and 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.[2][3]

Signs and symptoms

CADASIL may start with attacks of migrainewith aura or subcortical transient ischemic attacks or strokes, or mood disorders between 35 to 55 years of age. The disease progresses to subcortical dementiaassociated with pseudobulbar palsy andurinary incontinence.Ischemic strokes are the most frequent presentation of CADASIL, with approximately 85% of symptomatic individuals developingtransient ischemic attacks or stroke(s). The mean age of onset of ischemic episodes is approximately 46 years (range 30–70). A classic lacunar syndrome occurs in at least two-thirds of affected patients while hemispheric strokes are much less common. It is worthy to note that ischemic strokes typically occur in the absence of traditional cardiovascular risk factors. Recurrent silent strokes, with or without clinical strokes, often lead to cognitive decline and overt subcortical dementia.

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 cytoplasmicmembrane of vascular smooth-muscle cells both in cerebral and extracerebral vessels,[4]seen as granular osmiophilic deposits onelectron microscopy.[5]

Diagnosis

MRIs show 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.[2][6] These white matter lesions are also seen in asymptomatic individuals with the mutated gene.[7] While MRI is not used to diagnose CADASIL, it can show the progression of white matter changes even decades before onset of symptoms.The definitive test is sequencing the wholeNotch 3 gene, which can be done from a sample of blood. However, as this is quite expensive and CADASIL is a systemicarteriopathy, evidence of the mutation can be found in small and medium-size arteries. Therefore, skin biopsies are often used for the diagnosis