From the Guidelines
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a rare genetic disorder affecting blood vessels in the brain, caused by mutations in the NOTCH3 gene, and is inherited in an autosomal dominant pattern. According to the most recent guideline from the American Heart Association/American Stroke Association 1, CADASIL typically causes lacunar strokes, cerebral microhemorrhages, migraines with aura, dementia, and pseudobulbar affect. The classic phenotype of CADASIL is estimated to occur in 1:20,000–1:50,000 individuals, although cysteine-altering NOTCH3 mutations may occur in as many as 1:300–1:450 people worldwide.
Key Characteristics of CADASIL
- Inherited in an autosomal dominant pattern, meaning a person needs only one copy of the mutated gene to develop the condition
- Caused by mutations in the NOTCH3 gene
- Typically causes lacunar strokes, cerebral microhemorrhages, migraines with aura, dementia, and pseudobulbar affect
- Symptoms usually begin between ages 30-50, though they can appear earlier or later
Management and Treatment
There is currently no specific treatment to prevent or cure CADASIL; management focuses on controlling risk factors for stroke, treating symptoms, and providing supportive care. Medications may include aspirin for stroke prevention, drugs for migraine management, and treatments for depression or other psychiatric symptoms. Genetic testing can confirm the diagnosis, and family members of affected individuals should consider genetic counseling since each child of an affected person has a 50% chance of inheriting the mutation. Further research is needed to develop disease-modifying therapies, including gene therapies, for genetic syndromes like CADASIL 1.
From the Research
Definition of CADASIL
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease characterized by recurrent ischemic stroke, cognitive decline progressing to dementia, psychiatric disturbances, and apathy 2.
- It is a hereditary cerebrovascular disease leading to cognitive decline and dementia, usually beginning with migraine in about one-third of the patients 3, 4.
Symptoms and Diagnosis
- Symptoms of CADASIL include migraine with aura, recurrent strokes, cognitive decline, and dementia 2, 3, 4.
- Diagnosis can be made on the basis of characteristic hyperintensities in T2-weighted magnetic resonance images, and presence of pathognomonic granular osmiophilic material in arterial walls, including dermal arteries 3, 4.
Cause and Pathogenesis
- CADASIL is caused by missense point mutations in the Notch3 gene, which encodes a transmembrane receptor protein 3, 4.
- Mutations result in either a gain or loss of one or more cysteine residue(s) in the extracellular amino-terminal region of Notch3, leading to conformational alteration and vascular pathology 3, 4.
Treatment
- There is no specific therapy available for CADASIL, and treatment of migraine in patients with CADASIL poses a theoretical risk due to the vasomodulatory influence of many antimigraine medications 2, 5.
- Alternative preventive migraine treatments in CADASIL may include acetazolamide, sodium valproate, lamotrigine, topiramate, verapamil, or flunarizine 2.