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CADASIL: yesterday, today, tomorrow
H Chabriat1,2,3, A Joutel3,4, E Tournier-Lasserve2,3,5
1Department of Neurology and CERVCO, Reference Center for Rare Vascular Diseases of the Eye and Brain, Hôpital Lariboisiére, APHP, Paris, France.
Insights
Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common genetic small vessel disease. Research has identified NOTCH3 gene mutations and outlined the disease
Area of Science:
- Neurology
- Genetics
- Pathophysiology
Background:
- CADASIL, an archetypal small vessel disease of the brain, has been researched for over 40 years.
- Recognized as the most common genetic cerebral small vessel disease.
- The Brain Prize in 2019 highlighted CADASIL research milestones.
Purpose of the Study:
- To review the discovery and research history of CADASIL.
- To highlight key findings in understanding CADASIL pathophysiology and genetics.
- To emphasize the ongoing need for therapeutic development.
Main Methods:
- Discovery through family studies of initial clinical cases.
- Identification of NOTCH3 gene mutations.
- Development of genetic testing and animal models.
Main Results:
- Established CADASIL as the most common genetic cerebral small vessel disease.
- Described the natural history from silent lesions to severe disability and dementia.
- Demonstrated the role of matrix proteins in pathophysiology.
- Facilitated discovery of other monogenic small vessel diseases.
Conclusions:
- CADASIL is widely recognized, but its mechanisms require further elucidation.
- Understanding disease mechanisms is crucial for developing effective therapeutics.
- Ongoing global research will advance CADASIL knowledge and cerebral small vessel disorder research.
Background And Purpose:
In 2019, the Brain Prize crowned the discovery of CADASIL in the 1990s and research efforts on this archetypal small vessel disease of the brain over 40 years.
Methods And Results:
The hereditary origin of this arteriolopathy was discovered from a first clinical case and detailed observation of the patient's family. Thereafter, the role of causative mutations within the NOTCH3 gene were identified, allowing the development of a genetic test and then of an animal model of the disease. These crucial steps led to the discovery progressively that CADASIL is the most common genetic cerebral small vessel disease, to describing for the first time the natural history of a cerebral ischaemic small vessel disease from silent cerebral tissue lesions up to severe motor disability and dementia at the end stage, to demonstrating the central role of matrix proteins in its pathophysiology and to opening the door to the discovery of several other genes involved in monogenic cerebral small vessel diseases.
Discussion:
Today, CADASIL is known to every neurologist, but the disease has not yet revealed all its secrets. A lot of effort is still needed to understand the intimate mechanisms of the disease and the most efficient targets or approaches for the development of efficient therapeutics. The history of CADASIL will be further enriched by multiple ongoing research projects worldwide, at clinical and preclinical level, and will continue to enlighten research in the field of cerebral small vessel disorders.
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