CADASIL Disease Discovery

Summary

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Description

Small vessel diseases are conditions characterized by the narrowing of small arteries leading to an imbalance of blood supply upon demand. This results in a progressive chronic hypoperfusion with detrimental outcomes for the affected organ system and for the patient. Recent advances in genetic evalu...

Small vessel diseases are conditions characterized by the narrowing of small arteries leading to an imbalance of blood supply upon demand. This results in a progressive chronic hypoperfusion with detrimental outcomes for the affected organ system and for the patient. Recent advances in genetic evaluation have identified several genetic variants causing cerebrovascular small vessel diseases. These diseases have common clinical presentation including recurrent strokes, progressive white matter degeneration, and debilitating dementia. The link between these pathologies is defects in the tunica media of arteries, which is composed mainly of vascular smooth muscle cells (vSMCs). CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy) is caused by mutations in NOTCH3. The disease is of slow onset, with initial clinical manifestations in the third and fourth decade of life, but progressive and fatal. Predominant clinical features include migraine with aura (atypical or isolated), strokes, memory loss, and multiple psychiatric symptoms including dementia. Currently, CADASIL is considered the most common hereditary subcortical vascular dementia, however, treatments are palliative, and there is little prospect of future therapies to directly address causation and block progression. We propose to characterize the etiology and natural history of CADASIL subjects through comprehensive clinical and molecular characterizations. Subjects will be seen at the National Institutes of Health (NIH) once a year for a period of 2 years (total of 3 visits).

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