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CADASIL.

Michael M Wang¹

¹Departments of Neurology and Physiology, University of Michigan and VA Ann Arbor Healthcare System, Ann Arbor, MI, United States.

Handbook of Clinical Neurology

|February 27, 2018

Summary

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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.

Keywords:

CADASIL NOTCH3 cysteine dementia neurodegenerative disorder protein accumulation small-vessel disease smooth muscle stroke

Related Experiment Videos

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.