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

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Highlights

  • Frequency of cardiovascular risk factors is similar in NOTCH3 mutations carriers.

  • Diabetes may accelerate the onset of stroke in NOTCH3 mutation carriers.

  • C455R NOTCH3 mutation carriers younger age at onset of migraine and strokes.

  • R141C mutation carriers had a lower frequency of migraines than even noncarriers.

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.

Introduction

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary stroke disorder and typically presents with recurrent ischemic strokes involving small brain vessels [1]. It is often associated with migraines, neuropsychiatric disorders, cognitive deterioration and dementia [2].

Although CADASIL is a single-gene disorder with mutations in the NOTCH3 gene, its clinical presentation can vary significantly [[3], [4], [5], [6], [7], [8], [9], [10]], increasing the difficulty to suspect it and recognize a familial pattern, delaying diagnosis in new patients [11]. Previous studies have reported variability in the age at clinical onset of the disease, with some individuals carrying the NOTCH3 mutations suffering their first stroke in their 20s and others in their 60s [3].

The prevalence of CADASIL has been estimated at 0.8 to 5 per 100,000 individuals [[11], [12], [13]].but under-diagnosis and misdiagnosis are suspected to be frequent in this entity [11,14]. Previous literature has reported inconsistent findings on the genotype-phenotype relationship, suggesting a role for other factors as modulators of the disease [9,11,[15], [16], [17], [18]].

There is no specific disease-modifying treatment for CADASIL [19]. Therefore, identification of the factors that can modify the clinical course of the disease will allow the development and implementation of preventive interventions and inform prognosis.

The current study aimed to explore the role of cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, obesity, and smoking) and the different NOTCH-3 mutations to explain the variability observed in the clinical presentation of the disease.

Section snippets

Study design, setting, and participants

This study is an observational retrospective cohort study. It was conducted at the University of Antioquia in Colombia, South America, between January 1980 and December 2017 [10,17,20]. Initial probands had clinical and neuroimaging findings suggestive of CADASIL, final diagnosis was confirmed in all probands by DNA testing of blood samples for characteristic mutations in the NOTCH3 gene. Four NOTCH3 mutations R1031C, C445R, R141C, and R169C were identified. An invitation to genetic testing and

Results

This study included 331 participants who had undergone clinical and genetic evaluation, with a median number of evaluations of 3. The participants were followed up over time, with a maximum duration of 21 years in some individuals (median 4 years). Genetic analysis was extended to relatives of the probands. From proband with R1031C mutation, 58 new carriers (139 noncarriers) were identified. From proband with C455R mutation, 9 additional carriers were identified among family members (43

Discussion

Initial case reports defined CADASIL as a hereditary multi-infarct dementia that occurred in non-hypertensive patients [27], and many of the clinical scales that are still used today to suspect CADASIL and prioritize the patients who should be genotyped, included “the absence of risk factors for cerebrovascular events.” [28,29]. However, the results of the current study showed that a diagnosis of CADASIL frequently coexisted in patients with a history of cardiovascular risk factors, with a

Acknowledgment

We thank Colombian families with CADASIL for making this study possible and for their commitment to research.

Study funding

This work was supported by the Departamento Administrativo de Ciencia, Tecnología e Innovación, COLCIENCIAS, Republic of Colombia (grant numbers 1115-657-41185, 627-2014). The funding source is of governmental nature and was not involved in any stage of this study, as defined by Colombian law.

Statistical Analysis conducted by Dr. Daniel Camilo Aguirre-Acevedo, PhD. Neuroscience Group of Antioquia, University of Antioquia, Medellín, Colombia.

Disclosure

Carolina Ospina reports no disclosures.

Joseph F. Arboleda-Velasquez reports no disclosures.

Daniel Camilo Aguirre-Acevedo reports no disclosures.

Yesica Zuluaga-Castaño reports no disclosures.

Lina Velilla reports no disclosures.

Gloria Patricia Garcia reports no disclosures.

Yakeel T. Quiroz reports no disclosures.

Francisco Lopera reports no disclosures.

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