CADASIL

Overview

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a rare, inherited neurological disorder that affects the small blood vessels in the brain. It is the most common genetic form of stroke and vascular dementia in adults. CADASIL is caused by mutations in the NOTCH3 gene and leads to progressive damage of the brain's white matter. This can result in recurrent strokes, migraines with aura, mood disturbances, cognitive decline, and eventually dementia. Symptoms usually begin in adulthood, typically between the ages of 30 and 50.

Causes

CADASIL is caused by mutations in the NOTCH3 gene, located on chromosome 19. This gene provides instructions for making a receptor protein found in the smooth muscle cells of small blood vessels. The mutation leads to degeneration of these muscle cells and thickening of blood vessel walls, reducing blood flow to the brain. CADASIL is inherited in an autosomal dominant pattern, meaning only one copy of the altered gene is needed to cause the disorder. A person with the mutation has a 50% chance of passing it on to each child.

Symptoms

The symptoms of CADASIL can vary widely in severity and age of onset, but typically include:

• Migraine with aura – often one of the first symptoms, occurring in up to 30% of patients

• Recurrent strokes or transient ischemic attacks (TIAs) – leading to temporary or permanent neurological deficits

• Progressive cognitive impairment – including memory loss, attention deficits, and executive dysfunction

• Dementia – in later stages of the disease

• Mood disturbances – such as depression, apathy, or personality changes

• Seizures – less common but may occur in some patients

• Gait and balance problems – due to brain tissue damage and white matter changes

Symptoms usually progress over decades, gradually leading to increased disability.

Diagnosis

Diagnosis of CADASIL is based on clinical evaluation, neuroimaging, and genetic testing. Key diagnostic steps include:

• Clinical history – noting recurrent strokes, migraines with aura, and family history of similar symptoms

• MRI of the brain – showing characteristic white matter lesions, particularly in the temporal lobes and external capsules

• Genetic testing – confirming a pathogenic mutation in the NOTCH3 gene

• Skin biopsy – may show deposits of granular osmiophilic material (GOM) around small blood vessels under electron microscopy

• Neuropsychological testing – to assess cognitive function and track progression

Treatment

There is currently no cure for CADASIL. Treatment focuses on managing symptoms, preventing stroke complications, and supporting cognitive and emotional health:

• Stroke prevention:

  • Control of risk factors such as hypertension, diabetes, and high cholesterol

  • Avoidance of smoking and excessive alcohol use

  • Aspirin or antiplatelet medications – used cautiously as efficacy in CADASIL is not fully established

• Migraine management:

  • Preventive medications such as beta-blockers, anticonvulsants, or antidepressants

  • Avoidance of migraine triggers

• Cognitive and psychological support:

  • Memory training and cognitive rehabilitation

  • Antidepressants for mood symptoms

  • Psychotherapy and support groups

• Physical and occupational therapy – to manage mobility issues and maintain independence

Prognosis

The prognosis for individuals with CADASIL varies depending on the severity and progression of symptoms. While some individuals may live for many years with mild symptoms, others may experience rapid neurological decline and significant disability by their 50s or 60s. Life expectancy may be reduced, particularly in those with frequent strokes or advanced cognitive impairment. Early diagnosis, risk factor management, and multidisciplinary care can help delay progression and improve quality of life.