Genetic and nongenetic factors associated with CADASIL: A retrospective cohort study
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.
References (42)
- et al.
The R110C mutation in Notch3 causes variable clinical features in two Turkish families with CADASIL syndrome
J. Neurol. Sci.
(2006 Jul 15) - et al.
Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
Lancet (London, England).
(1995 Oct 7) - et al.
The CADASIL scale-J, a modified scale to prioritize access to genetic testing for Japanese CADASIL-suspected patients
J. Stroke Cerebrovasc. Dis.
(2019 Jun 1) - et al.
Diabetes and stroke: epidemiology, pathophysiology, pharmaceuticals and outcomes
Am J Med Sci
(2016 Apr 1) - et al.
CADASIL
Lancet Neurol.
(2009 Jul) - et al.
Genotype–phenotype correlations of cysteine replacement in CADASIL
Neurobiol. Aging
(2017 Feb) - et al.
The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1–6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7–34 pathogenic variant
Genet. Med.
(2019 Mar 22) - et al.
Monogenic causes of stroke: now and the future
J. Neurol.
(2015 Dec 3) - et al.
Monitoring cognitive characteristics in a population with hereditary cerebrovascular disease (CADASIL) in Colombia
Rev. Neurol.
(2007) Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients
Brain.
(2004 Aug 19)
Clinical variability of the cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy phenotype in two siblings of a large family showing the same mutation
Int. Med. Case. Rep. J.
R54C mutation of NOTCH3 gene in the First Rungus family with CADASIL, Ginsberg SD, editor
PLoS One.
The phenotypic spectrum of CADASIL: clinical findings in 102 cases
Ann. Neurol.
Clinical Spectrum of CADASIL and the effect of cardiovascular risk factors on phenotype
Stroke.
Clinical characteristics of hereditary cerebrovascular disease in a large family from Colombia
Rev. Neurol.
Changing clinical patterns and increasing prevalence in CADASIL
Acta Neurol. Scand.
The minimum prevalence of CADASIL in Northeast England
Neurology.
The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland
J. Neurol. Neurosurg. Psychiatry
Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL
Ann. Clin. Transl. Neurol.
Intracerebral hemorrhages in CADASIL
Neurology.
The comparisons of phenotype and genotype between CADASIL and CADASIL-like patients and population-specific evaluation of CADASIL scale in China
J. Headache Pain.
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