Role of NOTCH3 Mutations in the Cerebral Small Vessel Disease Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

In this review article, we discuss recent progress in establishing the molecular basis for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; OMIN No. 125310), which is a cerebral small vessel disease (SVD) caused by mutations in the NOTCH3 gene. SVDs are a group of diseases defined by pathological changes affecting small vessels in the brain (small perforating arteries, arterioles, capillaries, and venules). Damage to cerebral white and deep gray matter, enlarged perivascular (VirchowRobin) spaces, cerebral microbleeds, and lacunes are lesions associated with SVDs. SVDs cause ≈20% of all strokes and >40% of dementia cases in elderly and are on the rise in an aging population. SVDs are difficult to diagnose because current imaging modalities only recognize vessels that are ≈10× larger than those primarily affected by SVD. SVDs can be classified into 6 different subtypes: arteriolosclerosis, cerebral amyloid angiopathy, genetic SVD distinct from cerebral amyloid angiopathy, inflammatory and immunologically mediated SVDs, venous collagenosis, and other SVDs (eg, postradiation angiopathy). The third most common category consists of SVD for which there is a genetic basis. This group includes cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, and, the main subject of this review, CADASIL. We provide an overview of recent discoveries in CADASIL and Notch research, with a focus on the molecular underpinnings of the disease. This is a research area with interesting yet sometimes conflicting findings, and we discuss whether CADASIL should be viewed solely as an aggregation disease or whether dysregulated Notch signaling also is central to the vascular pathology in the disease.