Strokes and stroke risk factors in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) patients

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is pointed out from the group of small vessel diseases and its main feature is considered to be the development of stroke in the absence of well-known cardiovascular stroke risk factors. Nevertheless, such comorbid factors can be present in CADASIL patients. 71 genetically confirmed CADASIL patients were observed, in 31 of whom, a complex investigation including clinical, laboratory, molecular genetic, instrumental and neurovisualization data was performed, and 60 were tested for the presence of variants of polymorphisms in thrombophilic genes to detect their possible significance in development of a cerebral vascular accident. Thrombophilic gene’s testing was also performed in comparison groups including 45 patients with lacunar or small strokes and/or cerebral microangiopathy, and 309 persons who underwent laboratory genetic testing to exclude thrombophilia of a reference group. The results showed presence in CADASIL patients such coexisting stroke risk factors as arterial hypertension in 61.3 %, dyslipidemia in 64.5 %, obesity in 22.6 %, diabetes mellitus in 12.9 %, and smoking in 35.5 %. Other comorbidities included cardiovascular dysfunction presented mainly by cardiac conductive disability in 81.8 %, the signs of connective tissue dysplasia in 50.0 %, migraine in 74.2 %, and autoimmune thyroiditis in 22.6 %. In 78.3% of CADASIL patients, the simultaneous presence of 2-4 pathological alleles was revealed, and the pathological variant 103 G>T in the activated coagulation factor XIII (F13A) (p<0.05) encoding fibrinase was more common compared to the the reference group, which requires further studies as additional non modifiable stroke risk factors in CADASIL patients.

1. Joutel A., Corpechot C., Ducros A. et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia // Nature. 1996;383:707–710. https://doi.org/10.1038/383707a0.

2. Savchenko M. S. CADASIL syndrome. URL: https://www.krasotaimedicina.ru/diseases/genetic/CADASIL (accessed: 20.12.2023). (In Russ.).

3. Yamamoto Y., Liao Y.-C., Lee Y.-C. et al. Update on the Epidemiology, Pathogenesis, and Biomarkers of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy // J Clin Neurol. 2023;19(1):12–27. https://doi.org/10.3988/jcn.2023.19.1.12.

4. Chabriat H., Vahedi K., Iba-Zizen M. T. et al. Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy // Lancet. 1995;346(8980):934–9. https://doi.org/10.1016/s0140-6736(95)91557-5. PMID 7564728. S2CID 44289660.

5. James W. D., Berger T. G. et al. Andrews’ Diseases of the Skin: clinical Dermatology. Saunders Elsevier. 2006. 545 p. ISBN 978-0-7216-2921-6.

6. CADASIL History. URL: www.cadasilfoundation.org (accessed: 03.03.2018).

7. Chabriat H., Joutel A., Vahedi K. et al. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) // Journal des Maladies Vasculaires. 1996;21(5):277–82. PMID 9026542.

8. The Brain Prize 2019: French neuroscientists honoured for outstanding research into small vessel strokes in the brain // FENS.org. URL: https://lundbeckfonden.com/files/media/document/PM_TBP19_EN.pdf (accessed: 15.05.2021).

9. Chabriat H., Joutel A., Dichgans M. et al. CADASIL // Lancet Neurology. 2009;8(7):643–53.

10. Adib-Samii P., Brice G., Martin R. J., Markus H. S. Clinical spectrum of CADASIL and the effect of cardiovascular risk factors on phenotype: study in 200 consecutively recruited individuals // Stroke. 2010;41(4):630–4.

11. Collongues N., Derache N., Blanc F. Inflammatory-like presentation of CADASIL: a diagnostic challenge // BMC Neurol. 2012;12:78. https://doi.org/10.1186/1471-2377-12-78.

12. Singhal S., Bevan S., Barrick T. et al. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype // Brain. 2004;127(9):2031–8.

13. Vyshka G., Kruja J. Clinical variability of the cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencefalopathy phenotype in two siblings of a large family showing the same mutation // Int. Med. Case. Rep. J. 2013;6:59–63.

14. Berkovich R., Sokolov A. Y., Totolyan N. A. et al. Cross-prevalence of multiple sclerosis and stroke evaluated on cohorts of four independent speciality medical centers // Multiple Sclerosis and Related Disorders. 2024;90:105772. https://doi.org/10.1016/j.msard.2024.105772.

15. Simpkins A. N., Janowski M., Oz H. S. et al. BiomarkerApplication for Precision Medicine in Stroke // Transl Stroke Res. 2020;11(4):615–627. https://doi.org/10.1007/s12975-019-00762-3.

16. Davidenkova E. F., Kolosova N. N., Muravyeva Z. M. Hereditary factors in the development of cerebral strokes. L., Medicine, 1976. 152 p. (In Russ.).

17. Kiely D. K., Wolf P. A., Cupples L. A. et al. Familial aggregation of stroke. The Framingham Study // Stroke. 1993;24(9):1366–71. https://doi.org/10.1161/01.str.24.9.1366.

18. Hassan A., Markus H. S. Genetics and ischemic stroke // Brain. 2000;123:1784–1812. https://doi.org/10.1093/brain/123.9.1784.

19. Park J., Song J., Chang J. Y. et al. Genetic and imaging features of CADASIL patients with acute ischemic stroke // Scientific Reports. 2025;15:17113. https://doi.org/10.1038/s41598-025-00220-1.

20. Sirotkina O. V., Ulitina A. S., Pchelina S. N. et al. Leiden mutation of blood coagulation factor V: frequency in various cardiovascular diseases and place in modern clinical guidelines // Genomic medicine in prenatal diagnosis, genetic passport and gene therapy. Collection of Scientific Papers, 2020, pp. 116–121. (In Russ.).

21. Wei L. K., Griffiths L. R., Kooi C. W., Irene L. Meta-Analysis of Factor V, Factor VII, Factor XII, and Factor XIII-A Gene Polymorphisms and Ischemic Stroke // Medicina. 2019;55(4):101. https://doi.org/10.3390/medicina55040101.

22. Maino A., Rosendaal F. R., Algra A. et al. Hypercoagulability Is a Stronger Risk Factor for Ischaemic Stroke than for Myocardial Infarction: A Systematic Review // PLoS One. 2015;10(8):e0133523. https://doi.org/10.1371/journal.pone.0133523.

23. Dulicek P., Ivanova E., Kostal M. et al. Analysis of Risk Factors of Stroke and Venous Thromboembolism in Females with Oral Contraceptives Use// Clin Appl Thromb Hemost. 2018;24(5): 797–802. https://doi.org/10.1177/1076029617727857.

24. Chiasakul T., De Jesus E., Tong J. et al. Inherited Thrombophilia and the Risk of Arterial Ischemic Stroke: A Systematic Review and Meta-Analysis // J Am Heart Assoc. 2019;8(19):e012877. https://doi.org/10.1161/JAHA.119.012877.

25. Poudel S., Zeb M., Kondapaneni V. et al. Association of G20210A Prothrombin Gene Mutation and Cerebral Ischemic Stroke in Young Patients // Cureus. 2020;12(12):e11984. https://doi.org/10.7759/cureus.11984.

26. Berkman S. A., Song S. S. Ischemic Stroke in the Young// Clin Appl Thromb Hemost. 2021;27:10760296211002274. https://doi.org/10.1177/10760296211002274.

27. Tsalta-Mladenov M., Levkova M., Andonova S. Factor V Leiden, Factor II, Protein C, Protein S, and Antithrombin and Ischemic Strokes in Young Adults: A Meta-Analysis // Genes (Basel). 2022;13(11):2081. https://doi.org/10.3390/genes13112081.

28. Bousser M. G., Tournier-Lasserve E., Aylward R. et al. Reccurent strokes in a family with diffuse white-matter abnormalities: a new mitochondrial cytopathy? // J Neurol. 1988;235(suppl 1):S4–5.

29. Tournier-Lasserve E., Iba-Zizen M. T., Romero N. et al. Autosomal dominant syndrome with stroke-like episodes and leukoencephalopathy // Stroke. 1991;22:1297–302.

30. Baudrimont M., Dubas F., Joutel A. et al. Autosomal dominant leukoencephalopathy and subcortical ischemic strokes: a clinico-pathological study // Stroke. 1993; 24:122–5.