CADASIL is an inherited autosomal dominant progressive disorder that affects small arterial vessels. The disease is classified as a non-arteriosclerotic arteriopathy, and results in multiple cerebral subcortical infarcts with migraine, strokes, and white matter injuries with resultant dementia, cognitive impairment and other symptoms.
The prevalence is 1-9 / 100,000. CADASIL is the most frequent monogenic cerebral small vessel disease, and has received a lot of attention in recent years as a model for small vessel diseases, with an increased number of cases. This is approximately 100-fold higher than current estimates of the minimum prevalence of CADASIL, suggesting that CADASIL is much more prevalent than previously suspected.
It is the consequence in most cases of a mutation in the NOTCH3 gene located in the 19 chromosome (gene map locus 19p.13.2-p13.1).
NOTCH3 gene codify for the Notch3 protein, a membrane receptor that intervenes in cell differentiation (embryo), and that is involved in vascular vessel development (and specialization to a vascular cell to be arterial, venous or capillary). The alteration results in Notch3 protein with a default in a cystein residual, changing its conformational aspect and inhibiting its receptor function. In addition these proteins cannot be metabolized and accumulate in the membrane of the smooth muscle cells of the arterial wall. Although it is a generalized arteriopathy involving small and medium sized arteries, it affects preferably the central nervous system (however other vascular systems might be affected, mainly when the disease progresses and worsens).
The disease is most likely to appear in individuals of around 45 years of age or younger. The clinical findings consists of (see table 1 for a summary): migraine attacks, subcortical ischemic strokes, neuropsychiatric symptoms, and dementia with cognitive impairment. Severe deterioration follows in a mean of 25 years. Evidence of cerebral hypoperfusion appears early in the disease process, especially at night (that can worsen white matter lesions) , but the results of studies evaluating cerebrovascular autoregulation are contradictory. Moreover, there is an increased risk of sudden death of cardiac origin: it is associated with significant decrease in heart rate variability, which is consistent with anomalies in cardiac autonomic control; cardiac arrhythmias, QT variability index, and myocardial infarction are more frequent.
Life expectancy is reduced in CADASIL patients. An age at death in men of 64.6 years and in women of 70.7 years has been reported (411 subjects). Pneumonia in patients with disability was the major cause of death (38%), and a high number of sudden unexpected deaths were also observed, up to 26%.
The disease includes cases with a history of hypertension and foci of ischemic destruction in the deep white matter of the cerebral hemispheres. The cerebral cortex is usually preserved and this contrasts with the clinical picture which may closely resemble that of dementia in Alzheimer disease. In fact, the disease can mimic several neurological diseases both central and peripheral (table 2).
There are diagnostic criteria published by Davous et al, updated in Mizuta et al. A review can be found in Hack R, et al.
Apart from genetic test, the diagnostic imaging procedures includes MRI, functional MRI, 3D MRI and 7 tesla MRI.
No specific treatment has been developed. Patients have received symptomatic therapy: acetazolamide, sodium valproate (migraine), acetylcholine inhibitors (cognitive decline), antiplatelet drugs (primary and secondary stroke prevention). The latter one is under discussion due the possible increased haemorrhagic risk.