cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (commonly called CADASIL) is a hereditary disorder that mainly affects the small blood vessels of the brain. Pathogenic changes in the NOTCH3 gene alter a protein critical for vascular integrity, leading to recurrent strokes, migraine episodes, and progressive neurological changes. Symptoms usually begin in early to middle adulthood, although age of onset and severity vary widely among affected individuals. The condition is considered uncommon, affecting roughly 1 to 9 people in every 100,000. Both males and females can be affected when they inherit one altered copy of the gene from an affected parent.

CADASIL primarily presents with neurological and cognitive features. Early signs often include migraine headaches, frequently but not always accompanied by aura, or brief episodes called transient ischemic attacks that resemble mild strokes. As the disorder progresses, individuals may experience lacunar strokes and develop difficulties with movement such as hemiparesis. Cognitive changes are common, ranging from slowed thinking and impaired visuospatial skills to more pronounced cognitive impairment and personality changes. Psychiatric manifestations such as emotional lability, apathy, psychosis, and perseverative or abnormally rigid thought patterns can also appear. Magnetic resonance imaging typically shows multifocal white-matter hyperintensities and other abnormalities that precede or parallel clinical symptoms. Urinary incontinence may develop later as additional brain regions are affected. Less common findings include visual loss, brief loss of consciousness, or arterial stenosis in larger vessels. Not all individuals experience all features, and severity varies considerably between—even within—families.

CADASIL results from heterozygous pathogenic variants in the NOTCH3 gene on chromosome 19. The NOTCH3 protein helps regulate the function and survival of smooth-muscle cells that line small arteries. When the protein is altered, these cells accumulate abnormal material, causing vessel wall thickening and reduced blood flow that underlies strokes and white-matter damage. The condition follows an autosomal dominant inheritance pattern, meaning one altered copy of NOTCH3 is sufficient to increase the risk of disease. Each child of an affected individual has a 50 percent chance of inheriting the variant. Even within the same family, symptom type and severity can vary considerably, a phenomenon known as variable expressivity. Genetic counseling is strongly recommended for affected individuals and at-risk relatives.

Currently, management focuses on supportive care, risk reduction, and multidisciplinary monitoring, as no disease-specific therapies have been approved. Controlling vascular risk factors—especially hypertension, diabetes, and smoking—is central to reducing stroke frequency. Standard migraine treatments can help alleviate headache episodes. After a stroke, rehabilitation with physical, occupational, and speech therapy supports recovery of function. Because cognitive and psychiatric symptoms may evolve, regular neuropsychological evaluation and, when appropriate, treatment with cognitive or behavioral interventions are often beneficial. Long-term management includes regular surveillance to detect complications early. Neurological follow-up visits, periodic brain MRI to track white-matter changes, and monitoring for mood or cognitive decline assist in timely intervention. As urinary incontinence can arise, urology consultation may be indicated. Care is best coordinated through a multidisciplinary team that may include neurologists, psychiatrists or psychologists, rehabilitation specialists, and genetic counselors. Patients should discuss individual treatment strategies and clinical trial opportunities with their healthcare team.

The long-term outlook for CADASIL varies widely. Some individuals experience infrequent strokes and maintain functional independence for many years, while others develop progressive cognitive impairment and disability at a younger age. Outcomes described in medical literature continue to evolve as standards of care improve, particularly with aggressive management of vascular risk factors and access to comprehensive rehabilitation services. Families often find it helpful to connect with neurologists experienced in hereditary stroke disorders and with genetic counselors for ongoing guidance and support.

CADASIL is an active research area with numerous ongoing clinical trials investigating ways to protect the brain’s small vessels, reduce stroke risk, or slow white-matter damage. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.