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CADASIL
1Departments of Neurology and Physiology, University of Michigan and VA Ann Arbor Healthcare System, Ann Arbor, MI, United States.
Insights
Cerebral small-vessel disease, often caused by NOTCH3 gene mutations in CADASIL, leads to strokes and dementia. Research links these mutations to vascular degeneration and cerebrovascular failure.
Area of Science:
- Neurology
- Genetics
- Vascular Biology
Background:
- Cerebral small-vessel disease is a major cause of stroke and dementia.
- CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common inherited cause, linked to NOTCH3 mutations.
- CADASIL presents with variable symptoms like strokes and cognitive decline, progressing to vascular dementia.
Purpose of the Study:
- To explore the genetic basis and clinical spectrum of CADASIL.
- To understand the molecular mechanisms underlying NOTCH3-associated cerebrovascular disease.
Main Methods:
- Review of clinical and genetic data from CADASIL patients.
- Analysis of NOTCH3 mutations and their impact on vascular smooth muscle protein.
- Magnetic resonance imaging (MRI) to characterize cerebrovascular changes.
Main Results:
- Hundreds of NOTCH3 mutations identified globally in CADASIL.
- Mutations consistently alter cysteine content in the extracellular NOTCH3 domain.
- MRI shows white-matter hyperintensities, subcortical strokes, and microhemorrhages in affected individuals.
Conclusions:
- NOTCH3 mutations are the primary cause of CADASIL.
- Altered NOTCH3 protein structure is hypothesized to trigger arterial degeneration.
- This leads to vascular protein accumulation and cerebrovascular failure, explaining CADASIL pathology.
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.