Clinical Impact of NOTCH3 Variant Location After First Stroke in CADASIL

Area of Science:

• Neurology
• Genetics
• Vascular Diseases

Background:

• Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a monogenic disorder with variable clinical presentation.
• NOTCH3 gene variants are implicated, but the effect of mutation location on disease progression is not fully understood.

Purpose of the Study:

• To investigate how the location of NOTCH3 gene variants (epidermal growth factor-like repeat domains 1-6 vs. 7-34) affects the long-term clinical trajectory after a first stroke in CADASIL patients.

Main Methods:

• Analysis of clinical data from a large cohort of CADASIL patients categorized by NOTCH3 mutation location.
• Utilized propensity score matching and principal stratification to adjust for covariates and truncation by death.
• Compared stroke recurrence, disability (modified Rankin score ≥3), and mortality using Restricted Mean Survival Time at 2, 5, 10, and 15 years.

Main Results:

• Patients with mutations in domains 1-6 were younger at their first stroke compared to those with mutations in domains 7-34.
• Mortality occurred slightly later in the 7-34 mutation group at 10 and 15 years post-stroke.
• No significant differences were observed in stroke recurrence between the groups; minor differences in time to disability were noted at 5 and 10 years.

Conclusions:

• The location of NOTCH3 variants in CADASIL impacts the age of first stroke onset.
• Mutation location has minimal to no effect on the risk of recurrent stroke, disability progression, or mortality following the initial stroke event.