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Genetic and nongenetic factors associated with CADASIL: A retrospective cohort study

Carolina Ospina¹, Joseph F Arboleda-Velasquez², Daniel Camilo Aguirre-Acevedo¹

¹Neuroscience Group of Antioquia, University of Antioquia, Medellín, Colombia.

Journal of the Neurological Sciences

|October 22, 2020

Insights

Cardiovascular risk factors and NOTCH3 gene mutations influence Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) presentation. Diabetes accelerated stroke onset in carriers, and specific NOTCH3 mutations showed genotype-phenotype links.

Area of Science:

Genetics
Neurology
Cardiology

Background:

Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) exhibits variable clinical presentations.
The role of cardiovascular risk factors and specific NOTCH3 gene mutations in this variability remains incompletely understood.

Purpose of the Study:

To investigate the influence of cardiovascular risk factors and distinct NOTCH3 mutations on the clinical variability of CADASIL.
To explore genotype-phenotype correlations within CADASIL families.

Main Methods:

Retrospective cohort study of 331 individuals, including 90 NOTCH3 mutation carriers.
Cox proportional hazards and competing risk regression models were used to analyze genetic and cardiovascular factors impacting migraine, stroke, and dementia onset.
Analysis considered death as a competing risk.

Main Results:

Cardiovascular risk factor frequencies were similar between NOTCH3 mutation carriers and noncarriers.
Diabetes was significantly associated with an earlier stroke onset in carriers (SHR 2.74).
A genotype-phenotype relationship was observed: C455R mutation carriers had high rates of migraine and earlier onset of migraine and stroke, while R141C carriers showed reduced migraine frequency.

Conclusions:

The study highlights a complex interaction between genetic predisposition (NOTCH3 mutations) and cardiovascular risk factors in shaping CADASIL.
These factors contribute to the observed variability in clinical presentation and disease severity.
Characterizing extended family groups provided valuable genotype-phenotype insights.

Read full analysis

Abstract

Objective:

To explore the role of cardiovascular risk factors and the different NOTCH-3 mutations to explain the variability observed in the clinical presentation of CADASIL.

Methods:

This was a retrospective cohort study of 331 individuals, 90 were carriers of four mutations in the NOTCH3 gene. These four mutations are the ones identified in our region from the genetic evaluation of probands. Cox proportional hazards models were fitted to estimate the effect of genetic and cardiovascular factors on the onset of migraine, first stroke, and dementia. Competing risk regression models considered death as risk.

Results:

Noncarriers (healthy controls from the same families without NOTCH3 mutations) and NOTCH3 mutation carriers had similar frequencies for all cardiovascular risk factors. Diabetes (SHR 2.74, 95% CI 1.52-4.94) was associated with a younger age at onset of strokes among carriers. Additionally, a genotype-phenotype relationship was observed among C455R mutation carriers, with higher frequency of migraines (100%), younger age at onset of migraine (median age 7 years, IQR 8) and strokes (median age 30.5 years, IQR 26). Moreover, fewer carriers of the R141C mutation exhibited migraines (20%), and it was even lower than the frequency observed in the noncarrier group (44.8%).

Conclusions:

This study characterizes extended family groups, allowing us a comparison in the genotype-phenotype. The results suggest a complex interplay of genetic and cardiovascular risk factors that may help explain the variability in the clinical presentation and severity of CADASIL.

Keywords:

CADASIL Diabetes Genotype Migraine Phenotype Stroke

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