CADASIL

Abstract

Cerebral small-vessel disease is a prevalent condition that is strongly associated with ischemic stroke and dementia. The most prevalent inherited cause of cerebral small-vessel disease is CADASIL, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a disorder linked to mutations in NOTCH3. The most common symptoms of CADASIL are small ischemic strokes and/or transient ischemic attacks and cognitive impairment, appearing in middle age, that may progress to frank vascular dementia. However, it is increasingly recognized that individual symptom types, onset, and disease severity span a wide spectrum, even among individuals in the same family. Magnetic resonance imaging in CADASIL reveals severe white-matter hyperintensities, evidence of prior subcortical strokes, and, in some cases, microhemorrhages. Several hundred mutations in NOTCH3 have been described worldwide in CADASIL, and virtually all of these mutations alter the cysteine content of the extracellular NOTCH3 gene product. This molecular genetic signature of CADASIL has led to the hypothesis that structural abnormalities in the vascular smooth-muscle protein NOTCH3 trigger arterial degeneration, vascular protein accumulation, and cerebrovascular failure.

Keywords: CADASIL; NOTCH3; cysteine; dementia; neurodegenerative disorder; protein accumulation; small-vessel disease; smooth muscle; stroke.