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Disease Severity Staging System for NOTCH3-Associated Small Vessel Disease, Including CADASIL
Gido Gravesteijn1, Julie W Rutten1, Minne N Cerfontaine1
1Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
JAMA Neurology
|November 29, 2024
Summary
A new staging system for NOTCH3-related small vessel disease (SVD) effectively categorizes disease severity from premanifest to end-stage. This validated system aids in clinical and research settings for understanding NOTCH3-SVD progression.
Area of Science:
- Neurology
- Genetics
- Vascular Medicine
Background:
- Cysteine-altering NOTCH3 (NOTCH3cys) variants are common, affecting ~1 in 300 individuals.
- These variants are linked to a wide range of small vessel disease (SVD) severities, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), stroke, dementia, and asymptomatic cases.
- A standardized system to classify NOTCH3-SVD severity is currently lacking.
Purpose of the Study:
- To develop a straightforward staging system for disease severity that encompasses the full clinicoradiological spectrum of NOTCH3-SVD.
- To validate this staging system in independent cohorts.
Main Methods:
- A cohort study was conducted, developing the NOTCH3-SVD staging system in a discovery cohort and validating it in international CADASIL cohorts and the UK Biobank.
- Data from 2,000+ participants with NOTCH3cys variants, including brain MRI and clinical assessments, were analyzed.
- Follow-up data spanning up to 18 years were incorporated.
Main Results:
- The developed NOTCH3-SVD staging system includes 9 stages (0 to 4B), capturing the spectrum from premanifest to end-stage disease.
- Ninety-four percent of participants (1789/1908) followed the defined sequence of disease events.
- The stages correlated significantly with neuroimaging findings, cognitive function, serum neurofilament light chain levels, and 18-year survival.
Conclusions:
- The NOTCH3-SVD staging system effectively captures the complete disease spectrum in individuals with NOTCH3cys variants.
- This system provides a simple, validated tool for consistent disease staging in both clinical practice and research.
- It aids in understanding disease progression and outcomes associated with NOTCH3-SVD.
