Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, commonly known as CADASIL, is an inherited condition that damages blood vessels in the brain, leading to recurrent strokes and cognitive decline.

Overview

CADASIL is an inherited condition that affects blood flow in blood vessels, particularly cerebral vessels within the brain. The muscle cells surrounding these blood vessels (vascular smooth muscle cells) are abnormal and gradually die. This blood vessel damage (arteriopathy) reduces blood flow and can cause areas of tissue death (infarcts) throughout the body. An infarct in the brain can lead to a stroke. CADASIL is not associated with common stroke risk factors like high blood pressure and high cholesterol, though some affected individuals may also have these health problems.

Symptoms & Clinical Features

The age at which symptoms first begin and their severity vary greatly among affected individuals. Key features include:

• Migraines, often accompanied by visual sensations or auras
• Recurrent seizures (epilepsy)
• Recurrent strokes, which typically begin during mid-adulthood but can occur anytime from teenage years to late adulthood
• Progressive loss of intellectual function (dementia) and changes in mood and personality, caused by recurrent strokes damaging the subcortical region of the brain (the area involved in reasoning and memory)
• Leukoencephalopathy, which is a change in the brain's white matter that can be visualized using magnetic resonance imaging (MRI)

Frequency

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

Causes & Genetic Factors

Mutations in the NOTCH3 gene cause CADASIL. The NOTCH3 gene provides instructions for producing the Notch3 receptor protein, which is vital for the normal function and survival of vascular smooth muscle cells. Normally, when specific molecules bind to Notch3 receptors, signals are sent to the cell nucleus to activate genes necessary for these smooth muscle cells.

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

Associated Gene

• NOTCH3

Inheritance

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered NOTCH3 gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from an affected parent. A few rare cases may result from new mutations in the NOTCH3 gene in people with no family history of the disorder.

Other Names for This Condition

• CADASIL
• Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy
• Familial vascular leukoencephalopathy
• Hereditary dementia, multi-infarct type