Carolina Ospina1, Joseph F Arboleda-Velasquez2, Daniel Camilo Aguirre-Acevedo3, Yesica Zuluaga-Castaño4, Lina Velilla4, Gloria P Garcia5, Yakeel T Quiroz6, Francisco Lopera4. 1. Neuroscience Group of Antioquia, University of Antioquia, Medellín, Colombia. Electronic address: carolina.ospinav@udea.edu.co. 2. Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. Electronic address: joseph_arboleda@meei.harvard.edu. 3. Neuroscience Group of Antioquia, University of Antioquia, Medellín, Colombia. Electronic address: daniel.aguirre@udea.edu.co. 4. Neuroscience Group of Antioquia, University of Antioquia, Medellín, Colombia. 5. Neuroscience Group of Antioquia, University of Antioquia, Medellín, Colombia. Electronic address: gpatricia.garcia@udea.edu.co. 6. Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. Electronic address: yquiroz@mgh.harvard.edu.
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.
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.
Authors: Remco J Hack; Minne N Cerfontaine; Gido Gravesteijn; Stephan Tap; Anne Hafkemeijer; Jeroen van der Grond; Marie-Noëlle Witjes-Ané; Frank Baas; Julie W Rutten; Saskia A J Lesnik Oberstein Journal: Stroke Date: 2022-07-13 Impact factor: 10.170