CADASIL (also known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a rare inherited disorder that occurs when the thickening of the walls of small- and medium-sized blood vessels blocks the flow of blood to the brain.

CADASIL is caused by a mutation in the Notch3 gene. This mutation affects the small blood vessels in the white matter of the brain. Often there is a family history of this disease.

Symptoms and disease onset vary greatly but signs typically appear in people between the ages of 20 and 40 years, although some individuals may not show signs until later in life. Symptoms usually progress slowly; by age 65 the majority of individuals with CADASIL will have cognitive problems and dementia.

Symptoms of CADASIL include:

• Migraine headaches
• Multiple strokes progressing to dementia
• Decline in memory and thinking skills (cognitive deterioration)
• Seizures
• Vision problems
• Slow movements and tremors (parkinsonism)
• Psychiatric problems such as mood disturbances (apathy and depression)
• Numbness or weakness
• Rapid onset of vertigo, nausea/vomiting, and abnormal gait in association with head-motion intolerance and abnormal eye movements (acute vestibular syndrome)

Currently there is no cure or effective treatment for CADASIL. Supportive care, including practical help, emotional support, and counseling, is useful for affected people and their families. Migraines should be treated both symptomatically and with preventative methods, depending on the frequency of symptoms. If hypertension, diabetes, high cholesterol, or obstructive sleep apnea are also present, they should be treated. Smoking should be avoided by those with CADASIL as they can increase the risk for strokes.

Mutations in the NOTCH3 gene cause CADASIL. The NOTCH3 gene provides instructions for producing the Notch3 receptor protein, which is important for the normal function and survival of vascular smooth muscle cells. When certain molecules attach (bind) to Notch3 receptors, the receptors send signals to the nucleus of the cell. These signals then turn on (activate) particular genes within vascular smooth muscle cells.

NOTCH3 gene mutations lead to the production of an abnormal Notch3 receptor protein that impairs the function and survival of vascular smooth muscle cells. Disruption of Notch3 functioning can lead to the self-destruction (apoptosis) of these cells. In the brain, the loss of vascular smooth muscle cells results in blood vessel damage that can cause the signs and symptoms of CADASIL.

Normal Function

The NOTCH3 gene provides instructions for making a protein with one end (the intracellular end) that remains inside the cell, a middle (transmembrane) section that spans the cell membrane, and another end (the extracellular end) that projects from the outer surface of the cell. The NOTCH3 protein is called a receptor protein because certain other proteins, called ligands, attach (bind) to the extracellular end of NOTCH3, fitting like a key into a lock. This binding causes detachment of the intracellular end of the NOTCH3 protein, called the NOTCH3 intracellular domain, or NICD. The NICD enters the cell nucleus and helps control the activity (transcription) of other genes.

The NOTCH3 protein plays a key role in the function and survival of vascular smooth muscle cells, which are muscle cells that surround blood vessels. This protein is thought to be essential for the maintenance of blood vessels, including those that supply blood to the brain.

Health Conditions Related to Genetic Changes

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

More than 270 mutations in the NOTCH3 gene have been found to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, commonly known as CADASIL. Almost all of these mutations change a single protein building block (amino acid) in the NOTCH3 protein. The amino acid involved in most mutations is cysteine. The addition or deletion of a cysteine molecule in a certain area of the NOTCH3 protein, known as the EGF-like domain, presumably affects NOTCH3 function in vascular smooth muscle cells. Disruption of NOTCH3 functioning can lead to the self-destruction (apoptosis) of these cells. Damage to vascular smooth muscle cells is thought to cause recurrent strokes and other signs and symptoms of CADASIL.

Lateral meningocele syndrome

At least six NOTCH3 gene mutations have been identified in people with lateral meningocele syndrome. This disorder affects the nervous system, the bones and muscles, and other body systems. The condition is characterized by abnormalities known as lateral meningoceles. Lateral meningoceles are protrusions of the membranes surrounding the spinal cord (known as the meninges) through gaps in the bones of the spine (vertebrae). The protrusions are most common and typically larger in the lower spine. The meningoceles associated with this disorder may damage the nerves that spread from the spine to the rest of the body.

The mutations that cause lateral meningocele syndrome occur at the end of the gene in a region known as exon 33. These gene mutations result in a NOTCH3 protein with an abnormally short (truncated) NICD. The shortened protein is missing the portion that normally causes the breakdown of the NICD after it has performed its function in the cell nucleus and is no longer needed. As a result, the presence of the NICD in the cell is prolonged, and the protein continues to affect the activity of other genes. However, the result of this prolonged NICD activity and its connection to the specific features of lateral meningocele syndrome are not well understood.

Other Names for This Gene

• CADASIL
• CASIL
• Neurogenic locus notch homolog protein 3
• NOTC3_HUMAN
• Notch homolog 3
• Notch homolog 3 (Drosophila)

Genomic Location

The most common signs and symptoms of CADASIL are caused by damage to small blood vessels, especially those within the brain and include: stroke, cognitive impairment, migraine with aura, and psychiatric disturbances. These symptoms are:

• Recurrent ischemic strokes (transient ischemic attack/stroke) in adulthood that may lead to severe disability such as an inability to walk and urinary incontinence. The average age at onset for stroke-like episodes is 46 years. Transient ischemic attacks and stroke are reported in approximately 85% of symptomatic individuals
• Progressive cognitive decline with dementia developing in about 75% of affected people including significant difficulty with reasoning and memory
• Migraine, usually with aura, as the first symptom in the third decade of life
• Psychiatric problems such as mood disturbances (apathy and depression), presenting in about 30% of people with CADASIL
• Seizures with epilepsy is present in 10% of affected people and usually presents at middle age
• Diffuse white matter lesions and subcortical infarcts on neuroimaging.

Less common signs and symptoms may include:

• Other psychiatric issues such as gambling, a seizure lasting 30 minutes or longer, or a cluster of shorter seizures for 30 minutes or more with little or no recovery between episodes (recurrent status epilecticus), psychosis, and bipolar disease
• Slow movements and tremors (parkisionism)
• Memory loss (amnesia)
• Dysfunction of one or more peripheral nerves, typically causing numbness or weakness (neuropathy)
• Muscular weakness due to a muscular disease (myopathy)
• Confusion, fever and coma (CADASIL coma)
• Acute vestibular syndrome ( rapid onset (over seconds to hours) of vertigo, nausea/vomiting, and abnormal gait in association with head-motion intolerance and abnormal eye movements, lasting days to weeks)
• Spinal cord involvement.