CADASIL SYNDROME

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by ischemic strokes occurring in adulthood and a decrease in cognitive abilities which can lead to dementia. Migraine with aura occurs in more than one third of those affected, as well as mood swings and apathy, which may occur independently of depression. Migraine with aura can occur as an early or initial symptom. In cranial MRI, hyperintensities of the white matter are seen mainly temporally and in the area of the internal capsule and are characteristic early changes. Later, the hyperintensities increase, and subcortical infarctions and extended perivascular zones are also seen. The severity of the symptoms can vary greatly within and between families.

The main cause of CADASIL is pathogenic variants in the NOTCH3 gene. This gene codes for the Notch3 transmembrane receptor, which is mainly expressed on the cell surface of vascular smooth muscle cells. More than 95% of the pathogenic variants described so far in CADASIL patients lead to a change in the number of cysteine residues (gain or loss) in the EGF (epidermal growth factor)-like repeat within the extracellular domain of the receptor. This leads to a partial misfolding of the protein and the formation of multimers, which are deposited in the vessel wall. These deposits increase with age and lead to a lack of oxygen and nutrients in the brain. Pathogenic variants in the HTRA1 gene are another cause of CADASIL.

References

Favaretto et al. 2019, J Neurol Sci 396:108 / Wang, 2018, Handb Clin Neurol 148:733 / Di Donato et al. 2017, BMC Med 15(1):41 / Hack et al. 2016, In Adam MP, Ardinger HH, Pagon RA et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020 / Choi et al. 2015, J Stroke 17:7 / Tikka et al. 2014, Brain Pathol 24:525 / André et al. 2010, Arq Neuropsiquiatr 68:287