CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)
- The inherited cerebrovascular illness known as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) first appears in mid-adulthood and is marked by recurrent subcortical ischemic strokes as well as cognitive impairment that eventually leads to dementia.
- About one-third of patients experience mood issues along with aura-accompanied migraines.
How common is CADASIL?
- In Europe, the prevalence of CADASIL is estimated between 1/50,000 and 1/25,000.
Heredity: Autosomal dominant
Age of onset: Adult
What are the symptoms and signs of CADASIL?
- At 45 to 50 years old on average, the disease initially manifests itself, usually as an ischemic stroke or cognitive deterioration. Although the disease’s course and start are unpredictable, dementia or (recurrent) stroke affect more than two thirds of individuals.
- About one-third of patients report having migraines, which typically have an aura.
- The average age of beginning is around thirty years old, and the symptoms frequently appear before dementia signs and stroke. Psychological illnesses are also prevalent and encompass mood swings, indifference, and altered personality traits.
- Acute reversible encephalopathy, which presents with headache, disorientation, and convulsions, epilepsy, and subclinical peripheral neuropathy are less frequent symptoms. Pneumonia is the most common cause of death, followed by asphyxia and sudden unexplained death.
Very Common Symptoms
- Abnormal cerebral white matter morphology
- Lacunar stroke
- Multifocal hyperintensity of cerebral white matter on MRI
- Cerebral ischemia
- Cognitive impairment
- Emotional lability
- Migraine with aura
- Transient ischemic attack
- Arterial stenosis
- Brain atrophy
- Cerebral hemorrhage
- Diabetes mellitus
- Gait disturbance
- Impaired visuospatial constructive cognition
- Intracranial hemorrhage
- Ischemic stroke
- Language impairment
- Loss of consciousness
- Memory impairment
- Motor damage
- Recurrent subcortical infarcts
- Stress urinary incontinence
What causes this condition?
- The NOTCH3 gene, which is found at 19p13.2-p13.1 and codes for the transmembrane receptor NOTCH3, which is primarily expressed by vascular smooth muscle cells, is mutated in more than 95% of cases with CADASIL. Over 90% of the mutations are missense, resulting in a change in the number of cysteines in one of NOTCH3’s exons (exons 2-23) that codes for the epidermal growth factor receptor (EGFR). Instead of the typical six cysteine residues, mutated EGFR has five or seven, which increases the aberrant protein’s ability to multimerize and causes mutation NOTCH3 to accumulate in the vessel wall.
How is this condition diagnosed?
- In situations of stroke or cognitive impairment in younger patients, ischemic abnormalities on magnetic resonance imaging (MRI) (subcortical infarcts, microhemorrhages, symmetrical white matter hypersignals), and a family history of dementia or stroke, the diagnosis of CADASIL should be taken into consideration.
- Molecular analysis can verify the diagnosis by detecting a particular NOTCH3 mutation that modifies cysteine.
- Alternatively, immunohistochemical examination demonstrates positive NOTCH3 staining at the wall, or electron microscopy study of a skin biopsy reveals typical granular deposits in the vascular wall.
Differential diagnoses include
- Binswanger disease
- primary central nervous system vasculitis
- and multiple sclerosis, as well as other genetic diseases such as
- CARASIL, MELAS
- Fabry disease
- small vessel diseases associated with mutations in COL4A1 (e.g. familial porencephaly)
How is this condition treated?
- There is no treatment for CADASIL. Antiplatelet therapy is often used but has not yet demonstrated real effectiveness.
- Symptomatic treatment may be offered to treat migraines and possible concomitant vascular risk factors (hypertension, hypercholesterolemia and diabetes).
- Psychological counseling should be offered to patients and their families as emotional support. Tobacco, angiography, anticoagulants and thrombolytic therapy should be avoided as these increase the risk of cerebrovascular manifestations.
What is the prognosis?
The outlook is not good. Most patients become immobile and develop dementia, needing round-the-clock nursing care. The average death age is 68 years old.
If the disease-causing mutation runs in the family, pre-implantation genetic diagnostics and antenatal diagnosis may be feasible.
Given that the condition is autosomal dominant and typically has a severe history, patients and their families should always benefit from genetic counseling.