CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy)

Last reviewed 01/2018

CADASIL stands for cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy. This is a familial dementia syndrome characterised by migraine, adult-onset stroke and dementia (1).

• CADASIL is a hereditary microangiopathy caused by mutations in the NOTCH3 gene on chromosome 19
• microangiopathy is characterised by degeneration and disappearance of vascular smooth muscle cells and depositions of granular osmiophilic material (GOM), which is not amyloid, atherosclerotic, mineral or metallic in nature
• CADASIL patients can be found to have additional (genetic or non-genetic) cardiovascular risk factors. These will interact with the stroke risk associated with CADASIL
  • for example, a report found that smoking in CADASIL patients increased the risk of stroke (2)
• main features of CADASIL are
  • ischaemic episodes, cognitive deficits, migraine with aura, and psychiatric disorders
  • penetrance of the disease is probably around 100%
    • however expression varies in age of onset, severity of clinical symptoms, and progression, between families, as well as within members of the same family
  • median age of onset of stroke in men is 50.7 years and in women 52.5 years of age
  • an ischaemic episode (TIA or stroke) occurs in at least 70–85% of patients. Most patients continue to experience recurrent ischemic episodes
  • cognitive deficits do not seem to be present before 35 years of age and there is marked variation in cognitive impairment in patients over 45 years of age
  • approximately three quarters have dementia at the time of death
  • about one quarter of NOTCH3 mutation carriers in a CADASIL study population were found to have a positive medical history for acute MI and/or current pathological Q-waves on electrocardiogram.

Reference:

1. Joutel A. et al.. Notch 3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996; 387: 288-92.
2. Tonk M, Haan J. A review of genetic causes of ischemic and hemorrhagic stroke. J Neurol Sci. 2007.