CADASIL

Alternate names

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; Dementia, hereditary multi-infarct type; Familial vascular leukoencephalopathy; Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy; CASIL

Definition

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy) is an inherited disease of the blood vessels that occurs when the thickening of blood vessel walls blocks the flow of blood to the brain. The disease primarily affects the small blood vessels in the white matter of the brain.

Epidemiology

CADASIL is likely a rare condition; however, its prevalence is unknown.

Cause

• CADASIL is caused by a variant (mutation) in the NOTCH3 gene.
• The NOTCH3 gene gives the body instructions to make the Notch3 receptor protein, needed for normal function and survival of vascular smooth muscle cells.

Gene mutations

• Mutations in NOTCH3 cause the body to make an abnormal protein, thus impairing the function and survival of vascular smooth muscle cells and causing these cells to self-destruct.
• The loss of vascular smooth muscle cells in the brain causes blood vessel damage that leads to the characteristic features of CADASIL.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

• CADASIL is inherited in an autosomal dominant manner.
• This means that having a mutation in only one copy of the responsible gene in each cell is enough to cause CADASIL.
• In most cases, an affected person inherits the mutated gene from an affected parent.
• In rare cases, CADASIL may result from having a new mutation in the gene, in which case it is not inherited from a parent.
• When a person with an autosomal dominant condition has children, each child has a 50% (1 in 2) chance to inherit the mutated copy of the gene.

Signs and symptoms

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.

Diagnosis

CADASIL should be suspected in individuals with unexplained white matter hyperintensities and a family history of stroke and/or vascular dementia; however, lack of an apparent family history of CADASIL does not preclude the diagnosis . The following clinical signs and neuroimaging findings can be observed in CADASIL.[1].

Clinical signs

• Transient ischemic attacks and ischemic stroke
• Cognitive impairment, manifesting initially with executive dysfunction, with a concurrent stepwise deterioration due to recurrent strokes to vascular dementia
• Migraine with aura, with a mean age of onset of 30 years
• Psychiatric disturbances, most frequently mood disturbances and apathy
• Brain imaging
• Symmetric and progressive white matter hyperintensities, often involving the anterior temporal lobes and external capsules
• Lacunes of presumed vascular origin
• Recent subcortical infarcts
• Dilated perivascular spaces, sometimes referred to as subcortical lacunar lesions
• Brain atrophy
• Cerebral microbleeds

The diagnosis of CADASIL is established in a proband either by identification of a heterozygous pathogenic variant in NOTCH3 by molecular genetic testing.

Treatment

• There is no cure or effective treatment for CADASIL yet.
• While antiplatelet treatment is often used, it is also not proven to be useful and some professionals do not recommend using these because microbleeds in the brain may occur in people with CADASIL, and, for this reason, the safety of antiplatelet drugs in this disease is still unknown.
• Migraine should be treated both symptomatically and prophylactically (with preventative methods), depending on the frequency of symptoms.
• Some medication that have shown some efficacy in some studies, but have not being proven may include acetazolamide, and sodium valproate for the migraine, and acetylcholinesterase inhibitor for cognitive decline.
• When hypertension, diabetes or hypercholesterolemia (high cholesterol) are also present, they should be treated.
• Supportive care, including practical help, emotional support, and counseling, is useful for affected people and their families.
• Yearly follow up by a neurologist with expertise in CADASIL is recommended from the time of diagnosis, as well as other specialists as needed.
• Smoking, angiography, anticoagulants and thrombolytic therapy are all to be avoided by those with CADASIL as they increase the risk of strokes and/or brain bleeding.

NIH genetic and rare disease info

• NIH info on CADASIL

CADASIL is a rare disease.

CADASIL Resources
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