Cerebral autosomo-dominant arteriopathy with subcortical infarctions and leukoencephalopathy

The article presents an analysis of the literature and a clinical case of a rare disease from the group of diseases of small vessels — cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL).

It is based on the deposition of osmiophilic granulation material in vessels of small and medium caliber. A mutation in the NOTCH3 gene on chromosome 19p13 leads to significant structural changes in the walls of small arteries due to impaired differentiation and maturation of smooth muscle cells.

CADASIL is characterized by four key symptoms: migraines, recurrent ischemic strokes, mental disorders, and cognitive decline. The clinical case study is presented from the standpoint of a multidisciplinary patient-oriented approach of joint work of neurologists and morphologists. On the basis of clinical and laboratory criteria, a probable diagnosis was made. To confirm it, a muscle biopsy was performed (a musculocutaneous flap from the inner surface of the thighs and forearms), in order to conduct light and electron microscopy. The details of the results of the morphological study, which made it possible to verify the patient’s diagnosis, are presented. Differential diagnostic judgments are presented and recommendations for genetic studies in the family, prognosis and treatment of the patient are given.

1. Insul’t. Rukovodstvo dlja vrachej pod redakciej L.V. Stahovskoj, S.V. Kotova. Moskva: MIA. 2019. 487 p. (In Russ.)

2. Tojima M., Saito S., Yamamoto Y., Mizuno T., Ihara M., Fukuda H. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy with a Novel NOTCH3 Cys323Trp Mutation Presenting Border-Zone Infarcts: A Case Report and Literature Review. J. Stroke Cerebrovasc. Dis. 2016;25(8):28–30. https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.05.013

3. Chabriat H., Bousser M.G. Neuropsychiatric manifestations in CADASIL. Dialogues in Clinical Neuroscience. 2007;9(2):199–208. https://doi.org/10.31887/DCNS.2007.9.2/hchabriat

4. Di Donato I., Bianchi S., De Stefano N., Dichgans M., Dotti M.T., Duering M. et al. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects. BMC Med. 2017;15:41. https://doi.org/10.1186/s12916-017-0778-8

5. Liem M.K., Oberstein S.A., van der Grond J., Ferrari M.D., Haan J. CADASIL and migraine: A narrative review. Cephalalgia. 2010;30(11):1284–9. https://doi.org/10.1177/0333102410370870. PMID: 21038489

6. Chabriat H., Joutel A., Dichgans M., Tournier-Lasserve E., Bousser M.G. Cadasil. Lancet Neurol. 2009;8(7):643–53. https://doi.org/10.1016/S1474-4422(09)70127-9. PMID: 19539236

7. Drazyk A.M., Tan R., Tay J., Traylor M., Das T., Markus H.S. Encephalopathy in a Large Cohort of British Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Patients. Stroke. 2019;50(2):283–290. https://doi.org/10.1161/STROKEAHA.118.023661

8. Buffon F., Porcher R., Hernandez K., Kurtz A., Pointeau S., Bousser M.-G. et al. Cognitive profile in CADASIL. J. Neurol. Neurosurg. Psych. 2006;77:175–80. https://doi.org/10.1136/jnnp.2005.068726

9.

10. Damulin I.V. Cognitive impairment in the defeat of small cerebral vessels. Consilium medicum. 2014;16(9):10–16. (In Russ.)

11. Brookes R.L., Hollocks M.J., Tan R.Y., Morris R.G., Markus H.S. Brief Screening of Vascular Cognitive Impairment in Patients With Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Without Dementia. Stroke. 2016;47(10):2482–2487. https://doi.org/10.1161/STROKEAHA.116.013761

12. Valenti R., Poggesi A., Pescini F., Inzitari D., Pantoni L. Psychiatric disturbances in CADASIL: a brief review. Acta Neurol. Scand. 2008;118(5):291–5. https://doi.org/10.1111/j.16000404.2008.01015.x

13. Velizarova R., Mourand I., Serafini A., Crespel A., Gelisse P. Focal epilepsy as first symptom in CADASIL. Seizure. 2011;20(6):502–4. https://doi.org/10.1016/j.seizure.2011.02.006

14. Oh J.H., Kang B.S., Choi J.C. CADASIL Initially Presented with a Seizure. J. Epilepsy Res. 2016;6(2):104–106. https://doi.org/10.14581/jer.16020

15. Lian L., Li D., Xue Z., Liang Q., Xu F., Kang H. et al. Spontaneous intracerebral hemorrhage in CADASIL. J. Headache Pain. 2013;14(1):98. https://doi.org/10.1186/1129-2377-14-98

16. Ragno M., Berbellini A., Cacchiò G., Manca A., Di Marzio F., Pianese L. et al. Parkinsonism is a late, not rare, feature of CADASIL: a study on Italian patients carrying the R1006C mutation. Stroke. 2013;44(4):1147–9. https://doi.org/10.1161/STROKEAHA.111.000458

17. Pescini F., Nannucci S., Bertaccini B., Salvadori E., Bianchi S., Ragno M. et al. The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale: a screening tool to select patients for NOTCH3 gene analysis. Stroke. 2012;43(11):2871–6. https://doi.org/10.1161/STROKEAHA.112.665927

18. Markus H. Genes for stroke. J. Neurol. Neurosurg. Psych. 2004;75(9):1229–1231. https://doi.org/10.1136/jnnp.2004.036202

19. [Illarioshkin S.N., Abramycheva N.Yu., Kalashnikova L.A., Maksimova M.Yu., Konovalov R.N., Stepanova M.S. et al. Clinical and molecular genetic analysis of cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (TsADASIL) in Russian families. Neurological journal. 2013;18(4):8–16. (In Russ.)

20. Tikka S., Mykkänen K., Ruchoux M.M., Bergholm R., Junna M., Pöyhönen M. et al. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain. 2009;132(Pt 4):933–9. https://doi.org/10.1093/brain/awn364

21. Uchino M. [CADASIL]. Brain Nerve. 2008;60(11):1224–34. (Japanese). PMID: 19069156

22. Ruchoux M.M., Brulin P., Brillault J., Dehouck M.P., Cecchelli R., Bataillard M. Lessons from CADASIL. Ann. NY Acad. Sci. 2002;977:224–31. https://doi.org/10.1111/j.1749-6632.2002.tb04819.x

23. Ueda M., Nakaguma R., Ando Y. [Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)]. Rinsho Byori. 2009;57(3):242–51. (Japanese). PMID: 19363995

24. Navarro E., Díaz F., Muñoz L., Giménez-Roldán S. Arteriopatía cerebral autosómica dominante con infartos subcorticales y leucoencefalopatía (CADASIL). Una revisión [Dominant autosomal cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A review]. Neurologia. 2002;17(8):410–7. (Spanish).

25. Rumbaugh J.A., LaDuca J.R., Shan Y., Miller C.A. CADASIL: the dermatologic diagnosis of a neurologic disease. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J. Am. Acad. Dermatol. 2000;43(6):1128–30. https://doi.org/10.1067/mjd.2000.110399

26. Noh S.M., Chung S.J., Kim K.K., Kang D.W., Lim Y.M., Kwon S.U. et al. Emotional disturbance in CADASIL: its impact on quality of life and caregiver burden. Cerebrovasc. Dis. 2014;37(3):188–94. https://doi.org/10.1159/000357798

27. Tabeeva G.R. Migraine-associated cerebrovascular disorders. Medical Council. 2017;(10):32–35. (In Russ.) https://doi.org/10.21518/2079-701X-2017-10-32-35

28. Devaraddi N., Jayalakshmi G., Mutalik N.R. CARASIL, a rare genetic cause of stroke in the young. Neurol. India. 2018;66(1):232–234. https://doi.org/10.4103/0028-3886.222859

29. Gündüz T., Demirkol Y., Doğan Ö., Demir S., Akçakaya N.H. A Case of Leukoencephalopathy and Small Vessels Disease Caused by a Novel HTRA1 Homozygous Mutation. J. Stroke Cerebrovasc. Dis. 2019;28(11):104354. https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.104354

30. Uemura M., Nozaki H., Kato T., Koyama A., Sakai N., Ando S. et al. HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature. Front Neurol. 2020;11:545. https://doi.org/10.3389/fneur.2020.00545

31. Pia S., Lui F. Melas Syndrome. 2020 Jul 6. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532959/

32. Lorenzoni P.J., Werneck L.C., Kay C.S., Silvado C.E., Scola R.H. When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis? Arq. Neuropsiquiatr. 2015;73(11):959–67. https://doi.org/10.1590/0004-282X20150154

33. Bersano A., Markus H.S., Quaglini S., Arbustini E., Lanfranconi S., Micieli G. et al.; Lombardia GENS Group. Clinical Pregenetic Screening for Stroke Monogenic Diseases: Results From Lombardia GENS Registry. Stroke. 2016;47(7):1702–9. https://doi.org/10.1161/STROKEAHA.115.012281

34. DiFrancesco J.C., Novara F., Zuffardi O., Forlino A., Gioia R., Cossu F. et al. TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy. Neurol. Sci. 2015;36(2):323–30. https://doi.org/10.1007/s10072-014-1944-9

35. Mishra V., Banerjee A., Gandhi A.B., Kaleem I., Alexander J., Hisbulla M. et al. Stroke and Fabry Disease: A Review of Literature. Cureus. 2020;12(12):e12083. https://doi.org/10.7759/cureus.12083

36. Cocozza S., Russo C., Pontillo G., Pisani A., Brunetti A. Neuroimaging in Fabry disease: current knowledge and future directions. Insights Imaging. 2018;9(6):1077–1088. https://doi.org/10.1007/s13244-018-0664-8

37. Sims K., Politei J., Banikazemi M., Lee P. Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry. Stroke. 2009;40(3):788–94. https://doi.org/10.1161/STROKEAHA.108.526293

38. Revesz T., Ghiso J., LashleyT., Plant G., RostagnoA., Frangione B., Holton J.L. Cerebral Amyloid Angiopathies: A Pathologic, Biochemical, and Genetic View. J. Neuropathol. Exp. Neurol. 2003;62(9):885–898. https://doi.org/10.1093/jnen/62.9.885

39. Bugiani O., Giaccone G., Rossi G., Mangieri M., Capobianco R., Morbin M. et al. Hereditary cerebral hemorrhage with amyloidosis associated with the E693K mutation of APP. Arch. Neurol. 2010;67(8):987–95. https://doi.org/10.1001/archneurol.2010.178