The CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, is a hereditary microangiopathy, associated with transient ischemic attacks, recurrent strokes and cognitive impairment.
The prevalence of this disease is not clearly assessed but recent studies demonstrate that the mutation carriers could be estimated 1 in 50000 adults.
There is a correlation between CADASIL and female sex and the first neurological clinical manifestation occurs at the age 30- 40s.
In many cases the first symptoms of CADASIL is migraine,which is associated with aura (sensory,visual,hemiplegia)and comes first other neurological disorders.
Other major symptoms are represented by TIA or stroke type ischemic episodes, which occur mostly as focal, subcortical, with localization in the white matter, basal ganglia and in the brainstem.
There are also psychiatric symptoms as depression and progressive cognitive deterioration and eventually involving into a pseudobulbar syndrome.
In a 6-10% of cases the patients also have epileptic presentations.
The clinical course is characterized by acute worsening periods, chronic progression and stabilization.
Survival is reduced and death occours before 65-68 years of age.
The CADASIL pathogenesis is not clear but we know that there is a correlation with Notch3.
There are about 40 Notch 3 different mutations , and the most part of them are localized on exons 3 and 4.
The mutations are single missense mutations, small deletions in frame and each Notch3 defect determines or loss or addition of a cysteine residue on the N-terminal extracellular domain.
These mutations lead to conformational changes that interfere with Notch3 metabolism and they can stop NICD carboxy-terminal fragment translocation.
We have yet to understand if these mutations result in a harmful gain or loss of function ,but it’s very clear that they induce degeneration and damage vascular cell differentiation and proliferation until the cell death.
Some studies had also been suggested that CADASIL mutations might result in a gain of function with a overexpression of the 21-Kda proteolytic cleavage product
,that corresponds to the ectodomain of the Notch3 receptor and an abnormal accumulation of this protein at the extracellular space, due to impaired clearence, with a toxic effect at expressed tissue.
However this dementia could be associated not only at the vascular system damage but it is also related with cell apoptosis that seems controlled by Notch proteins. It suggests that Notch 3 mutations can damage directly cerebral cells.
The CADASIL is characterized by osmiophilic elettrondense material around vascular smooth muscle cells in many organs.
Cutaneous biopsies in patients affected by CADASIL demonstrate a decrease of endothelial cells, an increased density of cytoplasm, in which there are microfilament bundles. Consequence of this process is represented by arterial wall fybrosis and thickening, with a sensible increase of probability to occlusion and thrombosis.
The disease is caused by mutations in the Notch3 gene located on chromosome 19(human), responsible for the synthesis of Notch 3 protein. It is a member of a group of 4 genes that are responsible for synthesis of surface receptors present on cells, as smooth muscle cells of arteriolar wall in the adult, that are not completely differentiated, allowing them to be able to answer to maturation or proliferation signals.Notch3 is composed by 2321 aminoacids arranged in 34 repeated EGF-like TANDEM sequences, in 3 repeated sequences Notch/LIN12,rich in cysteine and in 6 repeated sequences cdc10/ankyrine.
Only Notch1 e Notch3,of the 4 human Notch genes(Notch1,2,3 and 4)have been implicated in human disease. Mutations in human Notch 1 underlie Alagille syndrome, a dominant congenital disorder associated with abnormalities of the liver, heart, skeleton, eye, and face.
For a diagnosis of CADASIL it should detective a MRI signal abnormalities.
There is an image of widespread leukoencephalopathy predominantly periventricular, which followed the confined areas of alterated signal in the subcortical white matter, basal ganglia, thalamus and brainstem, indicative of lacunar infarcts. In some cases, in the advanced forms, there are also small hemorrhagic lesions or microbleeds.
Cerebral angiography is not useful because it doesn’t explore small diameter vessels,involved by disease.
The osmiophilic elettrondense material(GOM) ,that characterized this syndrome,is found not only in the central nervous system arteries but also in the systemic arterial tree so we can diagnose making skin biopsies and analyzing this material.
Currently there is no specific therapy.
It’s possible to treat migraine with traditional analgesics as paracetamol,Ibuprofen and aspirin. It’s not recommended the use of vasoconstrictors which may further restrict the caliber of cerebral vessels, reducing the brain flow.
Low dose of aspirin(50-100 md/day) can reduce ischemic events but in patients with CADASIl the beneficial effect of this drug is not clear.