Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare, inherited genetic disorder affecting the small blood vessels in the brain. This condition is the most common form of hereditary stroke disorder that primarily impacts adults. The disease follows a progressive course, leading to neurological symptoms and a reduced life expectancy. Understanding the biological cause and progression of CADASIL is important for patients and their families.
Understanding the Underlying Cause of CADASIL
CADASIL is caused by a mutation in the NOTCH3 gene, which is located on chromosome 19. This gene provides instructions for making the Notch3 receptor protein, which is expressed mainly in the vascular smooth muscle cells (VSMCs) that surround small arteries. The normal function of this protein is important for the survival and proper signaling within these muscle cells.
The mutations involved in CADASIL typically result in a change that adds or removes a cysteine amino acid in one of the protein’s Epidermal Growth Factor-like (EGF-like) repeats. This alteration causes the Notch3 protein to misfold and aggregate. The damaged protein fragment then accumulates outside the smooth muscle cells within the vessel wall.
This accumulation forms characteristic deposits known as granular osmiophilic material (GOM), which is a pathological hallmark of the disease. The buildup of GOM leads to the degeneration and loss of the VSMCs, causing the small arteries to thicken and become damaged (arteriopathy). This damage restricts blood flow, predisposing the brain to recurrent ischemic events and chronic tissue damage.
Typical Life Expectancy and Mortality Factors
CADASIL is associated with a reduced life expectancy compared to the general population, with death typically occurring in the sixth or seventh decade of life. Studies report the mean age at death for individuals with CADASIL to be approximately 61 years, though this can vary widely. There is a noticeable difference between sexes, with the median age at death often reported around 64 to 65 years for men and 70 to 71 years for women.
The primary causes of death are directly related to the progressive destruction of brain tissue caused by the damaged small vessels. Severe ischemic stroke and complications from advanced vascular dementia are the main terminal events. In the final stages, patients often become completely dependent and bedridden, leading to secondary causes of death like pneumonia.
Several factors influence the prognosis and the rate of decline. A younger age at the first appearance of stroke symptoms is linked to a more rapid disease progression and a shorter survival time. Furthermore, the specific location of the NOTCH3 gene mutation can affect the severity of the disease, with some mutations being associated with a lower age at death.
Conventional vascular risk factors, such as uncontrolled hypertension, also play an important role in accelerating the disease trajectory. Men tend to have a shorter survival time and experience a lower age of onset for severe disability compared to women, indicating a faster disease progression. The presence of these factors contributes to the variability in survival time.
Stages of Functional Decline and Symptom Progression
The clinical course of CADASIL is characterized by a gradual, chronic progression of neurological and psychiatric symptoms that often begin in early to mid-adulthood. The earliest symptoms frequently involve migraine headaches, particularly those accompanied by an aura, appearing between the ages of 20 and 40 years. These migraines do not usually cause permanent damage.
The accumulation of small, silent strokes (subcortical infarcts) and diffuse white matter lesions, visible on brain imaging, forms the substrate for the later, more severe symptoms. Around the mid-40s to mid-50s, recurrent transient ischemic attacks (TIAs) or completed ischemic strokes typically begin to occur. These events lead to focal neurological deficits, although these can sometimes regress in the early stages of the disease.
Progressive cognitive impairment is a defining feature, starting with subtle deficits in executive functions and processing speed, and gradually worsening over decades. This decline leads to vascular dementia in most individuals by the age of 65. The cumulative impact of the brain lesions also causes severe mood disturbances, with depression and apathy being common.
As the disease advances, mobility becomes impaired due to the accumulation of subcortical damage. Gait disturbance, balance difficulties, and motor deficits develop, leading to increasing physical disability and dependency. This functional decline often culminates in a state of severe disability and the need for complete care.
Current Management Strategies and Quality of Life
Since there is currently no cure or specific treatment to halt the underlying vascular degeneration in CADASIL, management focuses on alleviating symptoms and reducing the risk of further ischemic events. Strict control of conventional vascular risk factors is a primary strategy, including aggressive treatment of hypertension and counseling for smoking cessation. This preventative approach aims to minimize the additional burden on the already compromised small cerebral vessels.
To prevent ischemic stroke, antiplatelet agents like aspirin may be prescribed. However, the efficacy is not definitively established and must be weighed against the potential risk of intracerebral hemorrhage. Vasoconstrictive medications, such as triptans often used for typical migraines, are generally avoided in CADASIL patients due to concerns about restricting blood flow.
Symptomatic treatment is used to improve quality of life. Mood disorders, particularly depression, can be managed with standard antidepressant medications. Physical therapy and occupational therapy are important to help patients manage gait disturbances and maintain mobility. Although evidence is limited, some medications used for Alzheimer’s disease, such as acetylcholinesterase inhibitors, may be considered for cognitive symptoms.