Edited by Joseph Arboleda Velasquez, M.D., Ph.D., Assistant Scientist, Schepens Eye Research Institute, Assistant Professor, Harvard Medical School.

Renee Chan, Research Associate, RareShare

Prevalence of this disease remains unknown and the age at which the signs, symptoms, and severity of CADASIL first begin varies greatly among affected individuals. CADASIL affects both genders equally and has been found worldwide.

CADASIL is a genetic disease and inherited as an autosomal dominant trait, meaning that only a single copy of the abnormal gene is necessary for the disease to appear. Although most individuals with CADASIL have a parent with the disorder, spontaneous (de novo) mutations can also occur in rare instances.

CADASIL is caused by a mutation in the NOTCH3 gene, which contains instructions to create a protein that is found mostly in the smooth muscle cells in the walls of small arteries. This protein, called the Notch3 receptor protein, allows for normal function of the vascular smooth muscle cells. The protein sends signals to the nucleus of the cell when certain molecules bind to the receptor and activate particular genes within the vascular smooth muscle cells. The mutations have been shown to result in deficient Notch 3 function and accumulation of the protein in the smooth muscle cells which leads to damage of these cells in the brain. This results in a reduced blood flow to the brain as well as tissue loss within the white matter and deeper parts of the brain. It can also lead to a self-destruction of these cells.

There are cases in which proteins accumulation and granular osmiophilic material (GOM) deposits (often considered the hallmark of CADASIL) are not present. In strong support of the idea that reduced Notch 3 signaling plays a role in small vessel disease (SVD), recent reports found that bona fide loss-of-function mutations (e.g., premature stop codons, frame shifts) in Notch 3 phenocopy all the hallmarks of CADASIL, including autosomal dominant inheritance, small vessel degeneration, SMC pathology, stroke, leukoencephalopathy, and vascular cognitive impairment (Dotti et al., 2004; Erro et al., 2015; Moccia et al., 2015; Yoon et al., 2015). Humans with loss-of-function mutations in one copy of the Notch3 gene (heterozygotes) develop a disease that is indistinguishable from CADASIL, except for the fact that patients do not develop Notch 3 protein accumulation or GOMs outside of cells (extracellular), which suggests that extracellular Notch 3 accumulation and GOMs are not necessary for damage to the smooth muscle cells and other pathologies seen in CADASIL. In fact, if the loss-of-function Notch3 mutation is in both copies of the gene (homozygous), the phenotype is again similar to CADASIL but with a childhood onset (Pippucci et al., 2015).

CADASIL is characterized by migraines, headaches, cognitive impairment and multiple strokes in adults and young adults, often without cardiovascular risk factors. Other possible symptoms include seizures, cerebellar ataxia, lethargy, spasticity or involuntary muscle contractions, fever, drowsiness or coma, infarcts, and leukoencephalopathy. Specific symptoms can vary greatly even among members of the same family.

Most patients experience recurrent transient ischemic attacks (TIAs or ‘mini-strokes’) or strokes, which can cause weakness in arms and legs as well as the lack of feeling in some parts of the body, speech difficulties and lack of coordination. Repeated strokes can cause progression of symptoms and can also involve cognitive disturbances, loss of bladder control and balance. Strokes are the most common symptoms associated with CADASIL, however, some patients never have strokes at all or have evidence of a stroke on a magnetic resonance imaging (MRI) without any symptoms, known as silent strokes. The onset of strokes is usually around 45-50 years of age, but they can begin earlier or later in life.

Cognitive impairment and decline develops over time in affected patients between ages of 50-60 years although the onset and rate of progression varies. Cognitive issues can begin in the 30s in some people. Progressive impairment can lead to difficulty in concentration, memory deficits, and difficulty in making decisions or solving problems. Some individuals develop a general lack of interest in life (apathy). With increasing age, cognitive decline can eventually result in dementia, a progressive loss of memory, personality changes and impaired reasoning.

Migraines occur in at least half of CADASIL patients. In patients with CADASIL, these headaches are often preceded by “auras”, which is an abnormal or unwell feeling. Auras usually affect vision before migraines for 20-30 minutes but can last longer. Patients with CADASIL can also develop mental health problems ranging from personality and behavioral changes to depression.

Approximately 10% of individuals eventually develop seizures.

There are no universally accepted diagnostic criteria for CADASIL. A diagnosis should be considered in patients with young-onset stroke, cognitive decline, or ischemic changes on MRI positive family history of stroke or dementia may also be indicative of CADASIL.

Microscopic study of a skin sample (biopsy) can reveal characteristic granular deposits in the walls of certain blood vessels. Immunohistochemical analysis can be used to show abnormal accumulation of NOTCH3 protein in the walls of blood vessels.

Distinct changes in brain white matter due to lack of blood flow to the brain (ischemic changes) can be seen on MRI in some individuals.  
Diagnosis can be confirmed by molecular genetic analysis by the identification of a NOTCH3 mutation.

There is currently no treatment for CADASIL. However, drug therapy can be used to treat specific symptoms of the disease. Migraines and headaches can be treated with different drugs such as paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), however drugs that narrow blood vessels (vasoconstrictors) should be avoided, and any risk factors for strokes should be eliminated, like smoking. Any other stroke risk factors such as hypertension, diabetes or blood clotting disorders should be aggressively treated. Drug therapy for depression is sometimes be recommended.  

The disorder is progressive and the earliest forms of CADASIL are the most severe. Around the age of 65, patients with CADASIL often have cognitive problems and dementia and strokes may become common. Affected individuals may eventually experience a loss of independence due to progressive physical and intellectual decline. The disease, however, is highly variable and every person is unique; in some instances, the initial symptoms do not become apparent until very late in life.

Patients living with CADASIL should quit smoking to avoid risk factors for strokes. In addition, psychological support is also important for both the patient and their family as well as genetic counseling.

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