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CADASIL: a monogenic condition causing stroke and subcortical vascular dementia
1Department of Neurology, Klinikum Grosshadern, Ludwig Maximilians University, Munich, Germany. mdichgans@nefo.med.uni-muenchen.de
Insights
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by Notch3 mutations, leading to strokes and dementia. This study highlights vascular smooth muscle cell dysfunction and basal lamina deposits in CADASIL.
Area of Science:
- Neurology
- Genetics
- Vascular Biology
Background:
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease.
- It is caused by mutations in the Notch3 gene.
- CADASIL leads to subcortical strokes, vascular dementia, and frequently migraine with aura.
Purpose of the Study:
- To investigate the underlying mechanisms of vessel wall degeneration in CADASIL.
- To understand the role of Notch3 mutations in vascular smooth muscle cell function.
- To characterize the specific angiopathy and lesion patterns in CADASIL.
Main Methods:
- Analysis of Notch3 mutations.
- Magnetic resonance imaging (MRI) to identify lesion patterns.
- Ultrastructural examination of vascular basal lamina.
- Assessment of vascular smooth muscle cell function.
Main Results:
- Notch3 mutations are the primary cause of CADASIL.
- MRI reveals a microangiopathic pattern, notably affecting temporopolar white matter and arcuate fibers.
- Angiopathy features unique basal lamina deposits and vascular smooth muscle cell degeneration.
- Evidence suggests functional impairment of vascular smooth muscle cells.
Conclusions:
- CADASIL pathogenesis involves Notch3-mediated vascular smooth muscle cell dysfunction and basal lamina abnormalities.
- Understanding these mechanisms provides insights into small vessel disease and ischemic damage.
- CADASIL serves as a model for studying vessel wall degeneration.
Abstract:
Mutations in Notch3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an inherited small vessel disease leading to subcortical strokes and vascular dementia. The phenotypic presentation is variable but remarkable for a high frequency of migraine with aura. Magnetic resonance images show a microangiopathic pattern of lesions. Prominent involvement of the temporopolar white matter and involvement of the temporopolar arcuate fibers are conspicuous findings seen in many patients. The underlying angiopathy is characterized by a unique type of ultrastructural basal lamina deposits and by degeneration of vascular smooth muscle cells which are the major source of Notch3 expression. In line with these findings there is evidence for a functional impairment of vascular smooth muscle cells. CADASIL has opened a new perspective in studying basic mechanisms of vessel wall degeneration and ischemic tissue damage related to small vessel disease.