CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is the most common hereditary stroke disorder in adults. This inherited condition primarily affects the small blood vessels deep within the brain, causing their walls to thicken. This thickening blocks blood flow, resulting in tissue death (infarcts) and a progressive reduction in circulation. These changes lead to a range of neurological symptoms that typically begin in middle age and cause significant disability over time.
The Genetic Origin of CADASIL
CADASIL is caused by a mutation in the NOTCH3 gene on chromosome 19. This gene provides instructions for the NOTCH3 receptor protein, which is primarily expressed in the smooth muscle cells of small and medium arteries. The specific mutations typically alter the number of cysteine residues within the extracellular portion of the protein.
This genetic change causes the NOTCH3 protein to misfold and accumulate as granular osmiophilic material (GOM) in the walls of the small blood vessels. The accumulation of this material, combined with the degeneration and death of vascular smooth muscle cells, causes the vessel walls to thicken and lose normal function. This arteriopathy narrows the arteries and impairs their ability to regulate blood flow, resulting in reduced circulation and small strokes.
CADASIL follows an autosomal dominant inheritance pattern, meaning only one copy of the mutated NOTCH3 gene is required for a person to develop the disorder. If one parent has CADASIL, there is a 50% chance that they will pass the faulty gene to each of their children. While most cases are inherited, the condition can also rarely result from a spontaneous, non-inherited gene mutation.
Recognizing the Clinical Manifestations
The clinical presentation of CADASIL is highly variable, involving four main symptoms that progress over time. Symptom onset usually occurs between 20 and 50 years old, though severity and progression rate differ significantly, even within the same family.
Migraine headaches are often the first symptom to appear, frequently beginning in young adulthood. These migraines are often accompanied by an aura, which involves temporary sensory disturbances like visual changes or speech difficulties preceding the headache. Approximately 30% to 40% of people with CADASIL experience migraines, with migraine with aura being more common than without.
Recurrent ischemic strokes, often referred to as lacunar strokes, are the most frequent clinical manifestation, affecting 60% to 80% of patients, typically in their 40s and 50s. These strokes occur when the blood supply to small, deep areas of the brain is blocked, leading to sudden neurological deficits. The cumulative effect of these small strokes contributes significantly to the progressive disability associated with the disease.
Progressive cognitive impairment is the second most common manifestation, occurring in most patients. This decline is a form of vascular dementia that begins insidiously, often affecting attention and executive functions (planning, organization, and problem-solving). Impairment can be detected early, sometimes before the first stroke, and usually progresses to overt dementia after age 60.
Psychiatric symptoms are common, observed in 25% to 30% of patients. Depression is the most frequent mood disturbance, often alongside apathy (indifference or lack of motivation). These changes can occur at any stage and are linked to small vessel damage in the frontal white matter and basal ganglia.
Medical Testing and Confirmation
Diagnosis begins with clinical suspicion, usually raised when a patient presents with early-onset stroke, migraines, cognitive impairment, and a family history. Because symptoms mimic other conditions, definitive testing is required for confirmation.
Brain imaging, primarily Magnetic Resonance Imaging (MRI), is a diagnostic step. MRI typically reveals two characteristic findings: subcortical infarcts and leukoencephalopathy (changes in the brain’s white matter). The presence of white matter hyperintensities in the anterior temporal poles and the external capsule is particularly suggestive, helping distinguish CADASIL from other small vessel diseases.
The definitive confirmation of CADASIL requires genetic testing for a mutation in the NOTCH3 gene. The detection rate for a pathogenic NOTCH3 variant is very high, approaching 95% to 100% in individuals with a strong clinical suspicion. Genetic testing is considered the gold standard because of its high specificity.
In rare cases where the genetic test is negative but clinical suspicion remains strong, an alternative method is a skin biopsy. This procedure involves examining a small sample of skin tissue under an electron microscope to look for the characteristic granular osmiophilic material (GOM) deposits in the walls of the skin’s small blood vessels. While once a primary diagnostic tool, it is now primarily used when genetic testing is inconclusive or unavailable.
Current Management Strategies
There is currently no cure or disease-modifying treatment to stop the underlying progression of CADASIL arteriopathy. Management focuses on preventing complications, controlling symptoms, and mitigating vascular risk factors.
A primary focus is on stroke prevention, which involves careful management of vascular risk factors such as high blood pressure, high cholesterol, and diabetes, following standard medical guidelines. Antiplatelet agents like aspirin are often prescribed for secondary stroke prevention, although their use for primary prevention must be weighed against the risk of cerebral microbleeds. Anticoagulants are generally avoided unless a separate condition, like atrial fibrillation, necessitates their use.
For the treatment of migraines, standard acute pain relievers are used. Triptan medications, initially viewed with caution due to their vasoconstrictive properties, are now considered safe for use in CADASIL patients. For prevention, medications like acetazolamide and valproic acid have shown effectiveness in reducing attack frequency. Psychiatric symptoms, such as depression and anxiety, are managed with standard antidepressants and psychological support.
Lifestyle adjustments are emphasized to potentially slow disease progression and prevent vascular events. Avoiding smoking is strongly recommended because it significantly increases the risk of stroke. Regular neurological check-ups monitor the patient’s disability level and cognitive decline, allowing for timely adjustments to supportive care and rehabilitation services.