ArticleAnnals of clinical and translational neurology2026
Clinical Impact of NOTCH3 Variant Location After First Stroke in CADASIL.
Article in Annals of clinical and translational neurology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveDespite its monogenic origin, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy exhibits marked variability in clinical expression and severity. Variants in the NOTCH3 gene, within epidermal growth factor-like repeat domains 1-6 or 7-34, are known to influence disease onset, but their impact on long-term progression remains unclear. This study assesses mutation location effects on post-first stroke clinical trajectories.
methodsClinical data from a large cohort were analyzed (Patients EGFR 1-6 mutation group n = 210 and 7-34 mutation group n = 116) with target emulated trial framework. To study the impact of mutation location on stroke recurrence, disability (modified Rankin score ≥ 3) and mortality, following a first stroke event. Propensity score matching was used to balance covariates between mutation location groups and principal stratification to consider truncation by death. Events occurrence differences were compared using Restricted Mean Survival Time at 2, 5, 10 and 15 years.
resultsAt first stroke, patients with mutation in domains 1-6 were younger than those in the 7-34 mutation group (49.51 ± 7.4 vs. 55.00 ± 7.4 years). Ten years after first stroke event, mortality occurred slightly later in the 7-34 group (9.63 [9.33-9.92] vs. 9.11 [8.71-9.52] years, p = 0.04), also at 15 years (14.0 [13.42-14.63] vs. 12.4 [11.62-13.24] years; p = 0.002). Second stroke occurrence did not differ between groups. Time beyond modified Rankin of 3 slightly differed between groups at 5 and 10 years, with a difference of 0.22 [0.01-0.044] and 0.72 [0.14-1.30] year respectively (p = 0.044 and 0.017).
interpretationAlthough NOTCH3 variants location influences the delay to the first stroke, it has no or little impact on the recurrence of stroke, risk of disability and death after the first stroke manifestation.
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