What is CADASIL?

A clear definition

CADASIL is an acronym for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. Each piece of the name describes the disease:

• Cerebral — affects the brain.
• Autosomal Dominant — inherited from one affected parent; each child has a 50% risk.
• Arteriopathy — a disease of the arteries, specifically the small ones.
• Subcortical Infarcts — small strokes deep beneath the cortex.
• Leukoencephalopathy — damage to the white matter visible on MRI.

Clinically, CADASIL is the most common monogenic (single-gene) cause of stroke and vascular dementia. It is classified as a hereditary cerebral small vessel disease (CSVD), with the small arteries supplying the deep brain tissue progressively failing over decades.

The genetics: NOTCH3 and chromosome 19

CADASIL is caused by changes (variants) in the NOTCH3 gene, located on chromosome 19. NOTCH3 gives the body instructions for making a protein that supports the muscle cells wrapping the small arteries — including the small arteries deep in the brain. When those instructions are altered, the protein doesn't fold the right way, misshapen protein slowly builds up in and around the artery walls, and over years those arteries stop working the way they should.

Two things are worth knowing:

• Where in the gene the change happens can matter. Some locations are associated with more severe disease that starts earlier; others are associated with milder, later-onset disease. This is one of the big reasons CADASIL can look so different from one family to another — and even from one person to another in the same family.
• Having the variant does not predict a specific life course. Individual expression varies enormously, even in people who share the exact same variant. Genetics can tell you the diagnosis; it can't hand you a timeline.

The scientific details (for clinicians and researchers)

Most CADASIL-causing variants are missense changes that add or remove a cysteine residue in one of the 34 epidermal growth factor-like repeat (EGFr) domains in the extracellular portion of NOTCH3. Cysteines in these domains normally pair to form disulfide bonds critical for correct folding; a pathogenic variant leaves an unpaired cysteine, driving misfolding, extracellular aggregation of the NOTCH3 ectodomain, and toxicity to vascular smooth muscle cells.

Variants in EGFr domains 1–6 are typically associated with classical, severe CADASIL, while variants in domains 7–34 tend to associate with later-onset, milder phenotypes. This correlation is important but not absolute — expressivity remains highly variable even for identical variants. More than 270 distinct pathogenic NOTCH3 variants have been reported worldwide; some (R169C, R544C) recur in specific populations and have been studied in detail for their genotype–phenotype correlations.

How CADASIL is inherited

CADASIL is autosomal dominant, meaning a single copy of a pathogenic NOTCH3 variant is sufficient to cause disease. Practically, this means:

• Each child of a parent with CADASIL has a 50% chance of inheriting the variant.
• Both males and females are affected equally.
• Inheriting the variant is not the same as having a predictable disease course. In genetics this is called expressivity — how the variant is expressed in each person. Two siblings who inherit the exact same NOTCH3 variant can have very different courses: one might be significantly affected at 45 while another remains nearly asymptomatic at 70. Expressivity depends on the specific variant, likely on other genes and environmental factors, and on some things we don't yet fully understand.
• The disease is typically traceable across multiple generations, although milder variants can appear to "skip" generations because of that variable expressivity, late onset, or earlier deaths from unrelated causes.
• De novo (new) NOTCH3 variants are rare but documented, so absence of a clear family history does not rule out CADASIL.

What's happening in the vessels

CADASIL is a disease of the small blood vessels — mainly the tiny arteries deep in the brain. Over years, the protein made by the NOTCH3 gene builds up in and around the walls of those arteries. The build-up thickens the artery walls, damages the muscle cells that help the arteries work, and gradually reduces how well blood flows to the deep parts of the brain.

That reduced blood flow is what can lead to the kinds of change CADASIL is known for: small deep strokes, tiny bleeds, and gradual changes in the brain's white matter. The same protein build-up has been found in blood vessels in other tissues (like skin and muscle), but the brain feels it most because it depends so heavily on those small vessels for its blood supply.

The scientific details (for clinicians and researchers)

The cellular and molecular consequence of NOTCH3 misfolding is the accumulation of granular osmiophilic material (GOM) — pathognomonic deposits in the basement membrane around vascular smooth muscle cells. GOM, together with extracellular accumulation of the NOTCH3 ectodomain (NOTCH3^ECD), drives:

• Loss of vascular smooth muscle cells
• Thickening and fibrosis of the small artery walls
• Impaired vasoreactivity and cerebral autoregulation
• Chronic hypoperfusion of deep white matter
• Recurrent lacunar (small, deep) infarcts
• Microbleeds and progressive white-matter injury

CADASIL is a systemic small-vessel disease — GOM has been demonstrated in skin, muscle, and other tissues. The brain dominates the clinical picture because of its extreme dependence on the perfusion supplied by these small, end-arterial vessels.

How common is CADASIL?

The clinical prevalence of CADASIL has been estimated at roughly 2–5 per 100,000 adults, but this almost certainly understates how common NOTCH3 variants actually are. Population genomic data — for example from the UK Biobank — suggest that pathogenic NOTCH3 variants may be present in approximately 1 in 300 to 1 in 400 individuals.

The gap between those two numbers is important — and, we think, a reason for hope. Most of the people who carry a NOTCH3 variant but have not been clinically diagnosed have very few symptoms, or none at all. Many will never develop severe disease. The heavy stories that dominate online forums and social groups are, statistically, a self-selected minority — they aren't representative of what happens to most people who carry a variant. Severe cases exist and are real; they are also a smaller share of the whole than an online search would suggest.

The practical implication: earlier identification, informed genetic counselling, and standard management of modifiable vascular risk factors are widely regarded as the most helpful current steps for someone with a NOTCH3 variant.

Commonly reported patterns across the lifespan

• 20s–30s

  Migraine with aura may appear

  Migraine with aura is one of the earlier manifestations reported in CADASIL, sometimes more prolonged or atypical than common migraine. About 30–40% of people with CADASIL experience migraine with aura; many do not.

• 30s–50s

  Mood or cognitive changes may begin

  Some people report apathy, depression, or subtle executive-function difficulties that emerge without obvious explanation. These changes are sometimes first attributed to life stress.

• 40s–70s

  Stroke and TIA are more commonly reported

  Recurrent small, deep strokes and TIAs (mini-strokes) are a common part of the picture in this age range, and often occur without classical vascular risk factors. Not everyone with CADASIL has strokes.

• 50s–70s

  Vascular cognitive impairment can occur

  Some people develop stepwise change in attention, processing speed, and executive function. A smaller share develop frank dementia, gait disturbance, or pseudobulbar features. Others remain functionally independent into much later life.

• Throughout

  Wide variability between individuals

  Modifiers — vascular risk factors, lifestyle, likely other genetic and environmental factors — matter. Individual expression can vary considerably even within a single family.

Conditions CADASIL can look like

CADASIL is sometimes mistaken for other conditions — some genetic, some not — that can look similar on brain scans or cause overlapping symptoms. Knowing what else might be on the list can help make sense of why the path to a CADASIL diagnosis is sometimes long or roundabout.

• Multiple sclerosis (MS) — an autoimmune condition of the nervous system that can also cause white-matter changes on brain MRI. CADASIL has often been misdiagnosed as MS in the past because the scans can look similar, but the two conditions are quite different and are diagnosed in different ways.
• Age-related small vessel disease — changes in the brain's small blood vessels that usually show up later in life alongside high blood pressure, diabetes, or a history of smoking. It shares imaging features with CADASIL but doesn't run in families and isn't caused by a NOTCH3 change.
• CARASIL — a rarer cousin of CADASIL, caused by changes in a different gene (HTRA1). It's inherited a different way (both parents must carry a copy), tends to start earlier, and can also cause early hair loss and back stiffness.
• HTRA1-related small vessel disease (sometimes called CADASIL2) — another HTRA1-linked condition that looks a lot like CADASIL clinically and on MRI, but is genetically distinct.
• Fabry disease — a rare inherited condition that can cause strokes along with problems in the kidneys, heart, and skin. It's diagnosed with different genetic and enzyme tests.
• MELAS — a condition that affects the mitochondria (the "power plants" of cells) and can cause stroke-like episodes. It's passed down through the mother's side of the family.
• Migraine with prolonged aura — most migraine has nothing to do with CADASIL. But when unusual migraines run in a family alongside strokes at younger ages, it's worth looking more closely.

The scientific details (for clinicians and researchers)

Condition	Key contrast with CADASIL
Multiple sclerosis (MS)	MS lesions are typically periventricular, juxtacortical, or in the corpus callosum, with active enhancement and CSF oligoclonal bands. CADASIL spares the corpus callosum and U-fibers, characteristically involves anterior temporal poles and external capsules, and is genetically defined.
Sporadic small vessel disease	Sporadic CSVD shares MRI features but typically presents later, with strong hypertensive/diabetic risk-factor profiles, no autosomal-dominant family history, and no NOTCH3 variant.
CARASIL	Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. Caused by HTRA1 mutations. Recessive; often associated with alopecia and spondylosis. Typically more severe and earlier-onset than CADASIL.
HTRA1-related dominant CSVD (sometimes called CADASIL2)	Heterozygous HTRA1 variants cause a dominantly inherited small-vessel disease that overlaps with CADASIL clinically and on MRI but is genetically distinct. Because it resembles CADASIL so closely, the HTRA1 dominant form is sometimes referred to as CADASIL2.
Fabry disease	X-linked lysosomal storage disease — strokes plus systemic features (renal, cardiac, dermatological). Diagnosed by enzyme assay and GLA gene testing.
MELAS	Mitochondrial encephalomyopathy with stroke-like episodes. Maternal inheritance, lactic acidosis, characteristic occipital lesions.
Migraine with prolonged aura	Without other features, isolated migraine is far more common than CADASIL — but a strong family history of stroke or atypical aura should prompt deeper evaluation.

Prognosis and long-term outlook

Long-term outcome in CADASIL varies considerably from person to person. Many individuals live independently for decades after diagnosis with good function; others have a more challenging course. Individual outcome cannot be reliably predicted from genetic testing alone.

General principles of care that may support long-term function include:

• Managing modifiable vascular risk factors (blood pressure, smoking, diabetes, lipids) as clinicians would for anyone at elevated stroke risk
• Discussing individual medication considerations with a CADASIL-aware clinician — including any specific cautions relevant to a particular person's history
• Migraine care in consultation with a headache specialist where symptoms warrant
• Engagement with multidisciplinary care as needed: neurology, genetics, mental health, rehabilitation

CADASIL-specific interventions proven to reverse or stop disease progression are not yet available. Research to identify such treatments is ongoing.

Myths and misconceptions

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Learn more

Continue exploring CADASIL with our deep-dive pages on symptoms, diagnosis, treatment, and current research.