CADASIL

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common inherited stroke disorder. It results from mutations in the NOTCH3 gene on chromosome 19 and is classified as a cerebral small vessel disease, not a leukodystrophy. French researchers Marie-Germaine Bousser and Elisabeth Tournier-Lasserve identified and named the condition in the 1990s, and along with Hugues Chabriat and Anne Joutel, they received the 2019 Brain Prize for their work. Symptoms often begin between ages 35 and 55, with migraine with aura, transient ischemic attacks, strokes, or mood disorders. As the disease progresses, it leads to subcortical dementia, pseudobulbar palsy, and urinary incontinence. Ischemic strokes are the most common symptom, affecting about 85% of symptomatic individuals, with an average onset around age 46 (range 30–70). Most strokes are lacunar syndromes, while hemispheric strokes are rarer. These strokes often occur without traditional cardiovascular risk factors. Silent strokes, which may recur, contribute to cognitive decline and dementia. One reported case involved a schizophreniform organic psychosis. The underlying problem is progressive thickening of smooth muscle cells in blood vessels. Mutations in the NOTCH3 gene cause abnormal buildup of the Notch3 protein on the surface of vascular smooth muscle cells in both brain and other blood vessels, visible as granular osmiophilic deposits under electron microscopy. This leads to leukoencephalopathy. Computer modeling predicts that many mutations cause a significant loss of beta sheet structure in the Notch3 protein. On MRI, CADASIL shows hypointensities on T1-weighted images and hyperintensities on T2-weighted images, with multiple confluent white matter lesions of varying sizes, especially around the basal ganglia, periventricular white matter, and pons—similar to Binswanger disease. These lesions can appear in asymptomatic gene carriers. While MRI can track white matter changes decades before symptoms, it is not used for diagnosis. The definitive test is sequencing the entire NOTCH3 gene from a blood sample, but because CADASIL affects arteries throughout the body, a skin biopsy can also reveal the mutation in small and medium arteries, and is often used as a cheaper alternative. No specific treatment exists for CADASIL.