👪

Inheritance

1

Autosomal Dominant

CADASIL follows autosomal dominant inheritance with high penetrance. De novo mutations are rare but reported.

Show evidence (1 reference)

DOI:10.3389/fneur.2025.1662012 SUPPORT Human Clinical

"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant disorder characterized by midlife-onset cerebrovascular disease and dementia."

This review confirms the autosomal dominant inheritance pattern of CADASIL.

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Pathophysiology

8

NOTCH3 Mutation and ECD Aggregation

Mutations in NOTCH3, primarily missense mutations affecting cysteine residues in the extracellular EGF-like repeat domains, lead to abnormal NOTCH3 extracellular domain (ECD) multimerization and accumulation in small vessel walls. Wild-type and mutant NOTCH3 ECD co-aggregate, and this co-aggregation is a major driver of arterial pathology and vascular smooth muscle cell loss.

vascular associated smooth muscle cell link pericyte link

Notch signaling pathway link

brain link

Downstream

Granular Osmiophilic Material (GOM) Accumulation Misfolded NOTCH3 ECD accumulates in the basement membrane of small arteries and assembles into the granular osmiophilic material that is the pathological hallmark of CADASIL.

Matrisome Sequestration and HTRA1 Loss-of-Function Excess vessel-wall NOTCH3 ECD abnormally recruits matrisome proteins (TIMP3, vitronectin, LTBP1, clusterin) and produces an HTRA1 loss-of- function profile, propagating dysregulation of vascular ECM proteostasis.

ER Stress and Complement-Mediated Vessel Wall Injury NOTCH3 ECD misfolding triggers endoplasmic reticulum (ER) stress in mural cells, driving pro-inflammatory cytokine and adhesion molecule expression and complement deposition at the vessel wall.

Show evidence (2 references)

PMID:38386425 SUPPORT Model Organism

"wild-type Notch3ECD coaggregated with mutant Notch3ECD and that elimination of 1 copy of wild-type Notch3 in TgNotch3R169C was sufficient to attenuate Notch3ECD accumulation and arterial pathology. These findings suggest that Notch3ECD accumulation, involving mutant and wild-type NOTCH3, is a..."

This study demonstrates that wild-type and mutant NOTCH3 ECD co-aggregate, and that reducing wild-type NOTCH3 attenuates both ECD accumulation and arterial pathology in a mouse model, supporting aggregation-driven toxicity as a major disease mechanism.

DOI:10.3390/biom14010127 SUPPORT Human Clinical

"In contrast, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 is adult-onset and considered to be caused by accumulation of the mutant NOTCH3 extracellular domain (N3ECD) and, possibly, by an impairment in Notch signaling."

This review confirms the dual-mechanism framework for CADASIL: N3ECD accumulation combined with possible Notch signaling impairment.

Granular Osmiophilic Material (GOM) Accumulation

Characteristic pathological deposits of granular osmiophilic material accumulate in the basement membrane of small arteries. GOM contains NOTCH3 extracellular domain fragments along with co-deposited extracellular matrix proteins including TIMP3 and vitronectin. GOM deposition is pathognomonic for CADASIL and correlates with vascular smooth muscle cell degeneration.

vascular associated smooth muscle cell link

extracellular matrix organization link

Downstream

Small Vessel Arteriopathy and Hypoperfusion Progressive GOM-laden vessels lose smooth muscle cells, develop medial fibrosis and luminal narrowing, and fail to autoregulate cerebral blood flow.

Show evidence (2 references)

PMID:30855338 SUPPORT Human Clinical

"Granular osmiophilic material deposits around blood vessels are also a unique CADASIL feature and appear to have a role in sequestering proteins that are essential for blood vessel homeostasis."

This review confirms GOM deposits as a unique pathological feature of CADASIL that sequesters proteins important for vascular homeostasis.

DOI:10.3389/fnmol.2024.1391040 SUPPORT Model Organism

"The NOTCH3 R75Q mouse model showed pathological characteristics of CADASIL, with age-dependent NOTCH3ECD, granular osmiophilic material, and degenerated smooth muscle cells detected in the brain."

The NOTCH3 R75Q knock-in mouse model recapitulates GOM deposition and smooth muscle cell degeneration in an age-dependent manner, confirming the link between GOM accumulation and VSMC loss.

Matrisome Sequestration and HTRA1 Loss-of-Function

Aggregating NOTCH3 ECD in CADASIL vessels abnormally recruits and sequesters matrisome proteins (TIMP3, vitronectin, LTBP1, clusterin), producing an HTRA1 loss-of-function profile in cerebral arterioles. Impaired ECM proteostasis amplifies vessel wall remodeling and biases the small artery phenotype toward fibrotic thickening with reduced matrix turnover.

vascular associated smooth muscle cell link

extracellular matrix organization link ⚠ ABNORMAL proteolysis link ↓ DECREASED

Downstream

Small Vessel Arteriopathy and Hypoperfusion Matrisome co-aggregation and HTRA1 inactivation accelerate vessel wall fibrosis, mural cell dysfunction, and luminal narrowing.

Show evidence (2 references)

PMID:23649698 SUPPORT Human Clinical

"Further proteomic and immunohistochemical analyses identified two functionally important extracellular matrix proteins, tissue inhibitor of metalloproteinases 3 (TIMP3) and vitronectin (VTN) that are sequestered into Notch3(ECD)-containing aggregates."

Direct biochemical and immunohistochemical evidence that TIMP3 and vitronectin are sequestered into NOTCH3 ECD aggregates in CADASIL brain and artery samples, anchoring the matrisome co-aggregation mechanism.

PMID:23649698 SUPPORT Human Clinical

"Specifically, our results suggest a dysregulation of TIMP3 activity, which could contribute to mutant Notch3(ECD) toxicity by impairing extracellular matrix homeostasis in small vessels."

TIMP3 dysregulation, downstream of NOTCH3 ECD sequestration, impairs ECM homeostasis in cerebral small vessels, supporting the matrisome/proteostasis arm of CADASIL pathophysiology.

ER Stress and Complement-Mediated Vessel Wall Injury

Mutant NOTCH3 ECD misfolding triggers endoplasmic reticulum (ER) stress in arterial smooth muscle cells with heat-shock protein induction, pro-inflammatory cytokine (IL-6) and adhesion molecule (ICAM-1) upregulation, and robust activation of the alternative complement pathway (Factor B, C3d, and C5b-9 deposition) on cerebral microvessels. This vessel-wall immunopathology amplifies VSMC injury and engages perivascular microglia/macrophages.

vascular associated smooth muscle cell link endothelial cell link microglial cell link

response to endoplasmic reticulum stress link complement activation, alternative pathway link inflammatory response link

Downstream

Small Vessel Arteriopathy and Hypoperfusion ER stress and complement-mediated injury accelerate VSMC loss and mural cell dysfunction, contributing to small-vessel arteriopathy.

Show evidence (2 references)

PMID:37158955 SUPPORT Human Clinical

"We further found evidence for activation of the alternative pathway of complement. Immunolocalisation of complement Factor B, C3d and C5-9 terminal complex but not C1q was apparent in ~ 70% of cerebral vessels."

Vessel-wall alternative complement activation is documented across ~70% of CADASIL cerebral microvessels, supporting a complement- mediated injury mechanism downstream of ER stress.

PMID:37158955 SUPPORT In Vitro

"Functional VSMC cultures bearing the NOTCH3 Arg133Cys mutation showed increased gene expression of the pro-inflammatory cytokine interleukin 6 and ICAM-1 by 16- and 50-fold, respectively."

In vitro mutant-VSMC induction of IL-6 and ICAM-1 establishes a cell-autonomous inflammatory axis that complements the in situ complement findings.

Small Vessel Arteriopathy and Hypoperfusion

Progressive thickening of arterial walls with loss of vascular smooth muscle cells leads to luminal narrowing, reduced cerebral blood flow, and chronic hypoperfusion of subcortical white matter. This results in white matter injury, lacunar infarcts, and progressive neurodegeneration.

vascular associated smooth muscle cell link endothelial cell link

vascular associated smooth muscle cell apoptotic process link

cerebral hemisphere white matter link

Downstream

White Matter Ischemic Injury Chronic hypoperfusion and impaired cerebral autoregulation cause progressive ischemic injury and demyelination of deep subcortical white matter.

Microvascular Fragility and Iron Deposition Diseased small vessels become fragile, leaking blood products and seeding hemosiderin and parenchymal iron deposits in cortical and subcortical brain regions.

Recurrent Ischemic Stroke Small vessel occlusion or critical luminal narrowing produces deep lacunar infarcts, the clinical correlate of subcortical ischemic stroke in CADASIL.

Show evidence (1 reference)

PMID:38386425 SUPPORT Model Organism

"Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation of the extracellular domain of the NOTCH3 receptor (Notch3ECD) are the 2 core features of CADASIL, a common cerebral small vessel disease caused by highly stereotyped dominant mutations in NOTCH3."

This paper identifies arterial smooth muscle cell loss and NOTCH3 ECD accumulation as the two core pathological features of CADASIL.

Microvascular Fragility and Iron Deposition

Beyond ischemic injury, CADASIL small vessels become fragile and permeable, producing perivascular hemosiderin leakage, capillary hemosiderin deposits, and parenchymal iron accumulation across cortex, white matter, basal ganglia, and cerebellum. These vessel-wall fragility lesions are the substrate for cerebral microbleeds detected on MRI.

vascular associated smooth muscle cell link endothelial cell link

regulation of blood-brain barrier permeability link ⚠ ABNORMAL

brain white matter link basal ganglion link

Downstream

Cerebral Microbleeds Perivascular and parenchymal hemosiderin/iron deposition produces the microbleeds characteristic of CADASIL on susceptibility-weighted MRI.

Show evidence (2 references)

PMID:36715085 SUPPORT Human Clinical

"Cerebral microbleeds (CMBs) detected on magnetic resonance imaging are common in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)."

Establishes microbleeds as a common CADASIL imaging feature whose neuropathological substrate is investigated in the same study.

PMID:36715085 SUPPORT Human Clinical

"PVH was most pronounced in the frontal white matter and basal ganglia around small to medium sized arterioles, with no predilection for the vicinity of vessels with severe vascular changes or infarcts."

Distribution of perivascular hemosiderin around small to medium arterioles in frontal white matter and basal ganglia underpins the microvascular fragility mechanism.

White Matter Ischemic Injury

Chronic hypoperfusion and recurrent micro-ischemic events drive progressive injury to subcortical and periventricular white matter, with myelin loss, oligodendrocyte vulnerability, and axonal injury. This produces the diffuse leukoencephalopathy and characteristic MRI white matter hyperintensity pattern (anterior temporal poles, external capsule, periventricular and frontoparietal white matter) and is the substrate for cumulative cognitive and motor disability.

oligodendrocyte link pericyte link

myelination link ↓ DECREASED response to ischemia link

cerebral hemisphere white matter link temporal lobe link external capsule link

Downstream

White Matter Hyperintensities Demyelination and gliosis appear as confluent T2/FLAIR hyperintensities, typically involving anterior temporal poles and external capsule.

Leukoencephalopathy Cumulative white matter injury manifests pathologically as diffuse leukoencephalopathy.

Cognitive Impairment Disconnection from white matter tract injury produces executive, processing speed, and memory deficits.

Dementia Cumulative subcortical ischemic injury, lacunes, and white matter damage culminate in vascular dementia.

Gait Disturbance Fronto-subcortical circuit injury causes vascular gait apraxia and progressive gait disturbance.

Apathy Disruption of fronto-striatal circuits underlies prominent apathy.

Show evidence (1 reference)

DOI:10.3389/fneur.2025.1573052 SUPPORT Human Clinical

"The most prevalent and earliest imaging alterations in CADASIL are white matter hyperintensities in the periventricular white matter, temporal pole, external capsule, frontoparietal white matter, and other areas on magnetic resonance imaging."

Topography of white matter injury maps to the imaging-defined leukoencephalopathy of CADASIL.

Immune Activation and ECM Remodeling

Proteomic profiling in CADASIL patients reveals an immune- and matrisome-oriented plasma signature with elevated RSPO1, FGF19, MMP-10 and reduced PPY, alongside enrichment of complement/inflammatory pathways, leukocyte adhesion, and ECM organization, supporting roles for vascular remodeling and immune activation in disease progression.

proteolysis link extracellular matrix organization link

Show evidence (1 reference)

DOI:10.3390/jcm13113138 SUPPORT Human Clinical

"Significant differences in protein expression were observed between CADASIL patients and controls. RSPO1 and FGF-19 exhibited elevated levels (p < 0.05), while PPY showed downregulation (p < 0.05) in CADASIL patients, suggesting their involvement in disease pathogenesis."

Proteomic analysis identifies differentially expressed proteins in CADASIL plasma with enrichment of complement/inflammatory and ECM organization pathways.

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Pathograph

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Phenotypes

11

Cardiovascular 2

Recurrent Ischemic Stroke VERY_FREQUENT Lacunar stroke (HP:0032325)

Show evidence (1 reference)

DOI:10.3389/fneur.2025.1573052 SUPPORT Human Clinical

"The clinical manifestations of CADASIL include migraines, recurrent ischemic stroke, progressive cognitive deterioration, and psychiatric symptoms."

This review confirms recurrent ischemic stroke as a core clinical manifestation of CADASIL.

Subcortical Lacunar Infarcts VERY_FREQUENT Lacunar stroke (HP:0032325)

Show evidence (1 reference)

PMID:36535904 SUPPORT Human Clinical

"In the CADASIL genotype-phenotype data set, HR-EGFr domains 8, 11 and 26 patients had a significantly higher risk of stroke (P = 0.002), disability (P = 0.041), nWMHv (P = 1.8 × 10-8), PSMD (P = 2.6 × 10-8) and lacune volume (P = 0.006) than MR-EGFr patients."

Lacune volume is treated as a distinct quantitative MRI biomarker of CADASIL severity, separate from clinical stroke events, validating the chronic-structural-lesion phenotype.

Nervous System 8

Migraine with Aura FREQUENT Migraine with aura (HP:0002077)

Show evidence (1 reference)

DOI:10.3389/fneur.2025.1573052 PARTIAL Human Clinical

"The clinical manifestations of CADASIL include migraines, recurrent ischemic stroke, progressive cognitive deterioration, and psychiatric symptoms."

This review lists migraines as a core clinical manifestation of CADASIL.

Cognitive Impairment VERY_FREQUENT Cognitive impairment (HP:0100543)

Show evidence (2 references)

DOI:10.3389/fneur.2025.1573052 SUPPORT Human Clinical

"The clinical manifestations of CADASIL include migraines, recurrent ischemic stroke, progressive cognitive deterioration, and psychiatric symptoms."

This review confirms progressive cognitive deterioration as a core CADASIL phenotype.

DOI:10.3389/fneur.2025.1662012 SUPPORT Human Clinical

"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant disorder characterized by midlife-onset cerebrovascular disease and dementia."

This review describes dementia as a defining feature of CADASIL.

Mood Disturbances FREQUENT Depression (HP:0000716)

Show evidence (1 reference)

DOI:10.3389/fneur.2025.1573052 PARTIAL Human Clinical

"The clinical manifestations of CADASIL include migraines, recurrent ischemic stroke, progressive cognitive deterioration, and psychiatric symptoms."

Psychiatric symptoms, including mood disturbances, are listed as a core clinical manifestation of CADASIL.

White Matter Hyperintensities VERY_FREQUENT Hyperintensity of cerebral white matter on MRI (HP:0030890)

Show evidence (2 references)

DOI:10.3389/fneur.2025.1573052 SUPPORT Human Clinical

"The most prevalent and earliest imaging alterations in CADASIL are white matter hyperintensities in the periventricular white matter, temporal pole, external capsule, frontoparietal white matter, and other areas on magnetic resonance imaging."

This review confirms white matter hyperintensities in characteristic locations as the most prevalent and earliest imaging finding in CADASIL.

PMID:30855338 SUPPORT Human Clinical

"Cerebral white matter changes observed by MRI are a key CADASIL characteristic in young adult patients often before severe symptoms and trigger NOTCH3 genetic testing."

This review confirms cerebral white matter MRI changes as a key early CADASIL characteristic that often prompts genetic testing.

Leukoencephalopathy VERY_FREQUENT Leukoencephalopathy (HP:0002352)

Retained as a core neuroimaging phenotype reflected in the disease name; no separate frequency-specific evidence block is asserted here.

Dementia FREQUENT Dementia (HP:0000726)

Show evidence (1 reference)

DOI:10.3389/fneur.2025.1662012 SUPPORT Human Clinical

"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant disorder characterized by midlife-onset cerebrovascular disease and dementia."

Dementia is identified as a defining characteristic of CADASIL.

Apathy FREQUENT Apathy (HP:0000741)

Show evidence (1 reference)

DOI:10.3389/fneur.2025.1573052 PARTIAL Human Clinical

"The clinical manifestations of CADASIL include migraines, recurrent ischemic stroke, progressive cognitive deterioration, and psychiatric symptoms."

Apathy is a common psychiatric symptom in CADASIL, grouped under the broader psychiatric manifestations.

Gait Disturbance FREQUENT Gait disturbance (HP:0001288)

Retained as a downstream clinical consequence of cumulative subcortical ischemic injury and white matter disease; no separate evidence block is asserted here.

Other 1

Cerebral Microbleeds FREQUENT Cerebral hemorrhage (HP:0001342)

Show evidence (2 references)

PMID:36715085 SUPPORT Human Clinical

"Cerebral microbleeds (CMBs) detected on magnetic resonance imaging are common in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)."

Establishes cerebral microbleeds as a common neuroimaging finding in CADASIL, with neuropathological correlates of perivascular hemosiderin and parenchymal iron deposition.

PMID:36715085 SUPPORT Human Clinical

"CADASIL subjects had a significant increase in hemosiderin/iron deposits compared with controls. This increase was principally seen with PID."

Quantitative neuropathology confirms increased brain hemosiderin and parenchymal iron deposits in CADASIL, the substrate for MRI-visible microbleeds.

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Genetic Associations

1

NOTCH3 (Causative)

Show evidence (6 references)

DOI:10.3389/fneur.2025.1662012 SUPPORT Human Clinical

"It is caused by mutations in the NOTCH3 gene, which affects the amount of cysteine in the extracellular domain (ECD) of the receptor, leading to protein misfolding and receptor aggregation. Emerging evidence indicates that beyond classical missense mutations, other variants including..."

This review confirms NOTCH3 mutations as causative and describes the expanding spectrum of pathogenic variants beyond classical cysteine-altering mutations.

PMID:30855338 SUPPORT Human Clinical

"NOTCH3 mutation locations are highly variable, correlate to disease severity and consistently affect the cysteine balance within extracellular Notch3."

This review confirms that NOTCH3 mutations consistently affect cysteine balance and that mutation location correlates with disease severity.

PMID:36535904 SUPPORT Human Clinical

"Nine EGFr domains were classified as an HR-EGFr, which included EGFr domains 1-6, but additionally also EGFr domains 8, 11 and 26."

Defines the high-risk EGFr domain set used for NOTCH3 variant risk stratification in CADASIL.

+ 3 more references

💊

Treatments

4

Antiplatelet Therapy

Action: Pharmacotherapy NCIT:C15986

Secondary stroke prevention with antiplatelet agents, though evidence specific to CADASIL is limited.

Migraine Prophylaxis

Action: Pharmacotherapy NCIT:C15986

Management of migraine with aura, avoiding vasoconstrictors like triptans due to theoretical stroke risk.

Supportive Care

Action: supportive care MAXO:0000950

Management of vascular risk factors, cognitive rehabilitation, and treatment of psychiatric symptoms.

Genetic Counseling

Action: genetic counseling MAXO:0000079

Genetic counseling is recommended for affected individuals and at-risk family members given the autosomal dominant inheritance pattern and high penetrance.

{ }

Source YAML

click to show

name: CADASIL Type 1
creation_date: '2026-02-14T02:39:04Z'
updated_date: '2026-05-08T18:54:20Z'
description: >-
  Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and
  Leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by
  mutations in the NOTCH3 gene. It is the most common monogenic cause of stroke
  and vascular dementia in adults. The disease is characterized by recurrent
  ischemic strokes, progressive cognitive decline, migraine with aura, and
  psychiatric disturbances. Pathologically, it involves progressive degeneration
  of vascular smooth muscle cells in small arteries, abnormal accumulation of the
  NOTCH3 extracellular domain (ECD) as granular osmiophilic material (GOM), and
  co-deposition of extracellular matrix proteins, leading to thickening of
  vessel walls and luminal narrowing.
category: Mendelian
disease_term:
  preferred_term: CADASIL
  term:
    id: MONDO:0007432
    label: cerebral arteriopathy with subcortical infarcts and leukoencephalopathy
parents:
- Hereditary Stroke Disorder
- Small Vessel Disease
review_notes: >-
  2026-04-25 audit fix (issue  # 1737): replaced fabricated cache content for
  PMID:36606642 (Yamamoto et al. 2023, J Clin Neurol) with the real PubMed
  abstract via `just fetch-reference --force`, then re-anchored the prevalence
  evidence snippet to an exact quote from that abstract. The prior snippet
  ("3.4 and 3.8 per 100,000" for cysteine-altering NOTCH3 variants) does not
  appear in the actual abstract; the paper reports a clinical CADASIL
  prevalence of 1.3-4.1 per 100,000 adults. Prevalence percentage and notes
  updated to match the paper. The prior 3.4-3.8 per 100,000 figure for
  cysteine-altering variants likely came from a different source (e.g., Rutten
  et al. gnomAD-derived NOTCH3 variant frequencies) and should be re-cited if
  retained in a future curation pass.
prevalence:
- population: General population
  percentage: 1.3-4.1 per 100,000 adults
  notes: >-
    CADASIL was classically considered a very rare disease with a clinical
    prevalence of 1.3-4.1 per 100,000 adults, but recent large-scale genomic
    studies have revealed a substantially higher prevalence of pathogenic
    NOTCH3 variants in the general population, with the highest carrier
    frequency among Asians. Sequencing-based NOTCH3 carrier frequencies are
    therefore far higher than clinically recognized CADASIL because of
    variable penetrance and variant context.
  evidence:
  - reference: PMID:36606642
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CADASIL was once considered a very rare disease with an estimated prevalence of 1.3-4.1 per 100,000 adults."
    explanation: >-
      This 2023 review summarizes the classical clinical CADASIL prevalence
      estimate while noting that recent large-scale genomic studies show
      pathogenic NOTCH3 variants are far more common in the general
      population, particularly among Asians.
pathophysiology:
- name: NOTCH3 Mutation and ECD Aggregation
  description: >-
    Mutations in NOTCH3, primarily missense mutations affecting cysteine
    residues in the extracellular EGF-like repeat domains, lead to abnormal
    NOTCH3 extracellular domain (ECD) multimerization and accumulation in
    small vessel walls. Wild-type and mutant NOTCH3 ECD co-aggregate, and
    this co-aggregation is a major driver of arterial pathology and vascular
    smooth muscle cell loss.
  gene:
    preferred_term: NOTCH3
    description: >-
      Receptor whose extracellular domain aggregates into granular osmiophilic
      material (GOM) deposits, driving vascular smooth muscle cell loss and
      arteriopathy.
    term:
      id: hgnc:7883
      label: NOTCH3
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  - preferred_term: pericyte
    term:
      id: CL:0000669
      label: pericyte
  biological_processes:
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  downstream:
  - target: Granular Osmiophilic Material (GOM) Accumulation
    description: >-
      Misfolded NOTCH3 ECD accumulates in the basement membrane of small
      arteries and assembles into the granular osmiophilic material that is
      the pathological hallmark of CADASIL.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38386425
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        wild-type Notch3ECD coaggregated with mutant Notch3ECD and that
        elimination of 1 copy of wild-type Notch3 in TgNotch3R169C was
        sufficient to attenuate Notch3ECD accumulation and arterial pathology.
      explanation: >-
        Aggregating NOTCH3 ECD in vessel walls is the proximal step that
        seeds GOM deposition.
  - target: Matrisome Sequestration and HTRA1 Loss-of-Function
    description: >-
      Excess vessel-wall NOTCH3 ECD abnormally recruits matrisome proteins
      (TIMP3, vitronectin, LTBP1, clusterin) and produces an HTRA1 loss-of-
      function profile, propagating dysregulation of vascular ECM proteostasis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - NOTCH3 ECD multimer surfaces sequester matrisome proteins
    - HTRA1 protease activity reduced by sequestration
    evidence:
    - reference: PMID:23649698
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Further proteomic and immunohistochemical analyses identified two
        functionally important extracellular matrix proteins, tissue
        inhibitor of metalloproteinases 3 (TIMP3) and vitronectin (VTN)
        that are sequestered into Notch3(ECD)-containing aggregates.
      explanation: >-
        Direct evidence that NOTCH3 ECD aggregation is the upstream event
        that sequesters TIMP3 and vitronectin into the matrisome co-
        aggregates in CADASIL.
  - target: ER Stress and Complement-Mediated Vessel Wall Injury
    description: >-
      NOTCH3 ECD misfolding triggers endoplasmic reticulum (ER) stress in
      mural cells, driving pro-inflammatory cytokine and adhesion molecule
      expression and complement deposition at the vessel wall.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - mutant NOTCH3 ECD misfolding activates the unfolded protein response
    - ICAM-1/IL-6 upregulation in NOTCH3-mutant VSMCs
    evidence:
    - reference: PMID:37158955
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Proteomics of isolated cerebral microvessels showed alterations in
        several proteins, many associated with endoplasmic reticulum (ER)
        stress including heat shock proteins.
      explanation: >-
        Mutant NOTCH3 ECD misfolding establishes ER stress in cerebral
        microvessels, linking the proximal aggregation lesion to immune
        activation.
  evidence:
  - reference: PMID:38386425
    reference_title: "Protein aggregates containing wild-type and mutant NOTCH3 are major drivers of arterial pathology in CADASIL."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      wild-type Notch3ECD coaggregated with mutant Notch3ECD and that
      elimination of 1 copy of wild-type Notch3 in TgNotch3R169C was
      sufficient to attenuate Notch3ECD accumulation and arterial pathology.
      These findings suggest that Notch3ECD accumulation, involving mutant
      and wild-type NOTCH3, is a major driver of arterial SMC loss in
      CADASIL, paving the way for NOTCH3-lowering therapeutic strategies.
    explanation: >-
      This study demonstrates that wild-type and mutant NOTCH3 ECD
      co-aggregate, and that reducing wild-type NOTCH3 attenuates both
      ECD accumulation and arterial pathology in a mouse model, supporting
      aggregation-driven toxicity as a major disease mechanism.
  - reference: DOI:10.3390/biom14010127
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, cerebral autosomal dominant arteriopathy with subcortical
      infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 is
      adult-onset and considered to be caused by accumulation of the mutant
      NOTCH3 extracellular domain (N3ECD)
      and, possibly, by an impairment in Notch signaling.
    explanation: >-
      This review confirms the dual-mechanism framework for CADASIL:
      N3ECD accumulation combined with possible Notch signaling impairment.
- name: Granular Osmiophilic Material (GOM) Accumulation
  description: >-
    Characteristic pathological deposits of granular osmiophilic material
    accumulate in the basement membrane of small arteries. GOM contains
    NOTCH3 extracellular domain fragments along with co-deposited
    extracellular matrix proteins including TIMP3 and vitronectin. GOM
    deposition is pathognomonic for CADASIL and correlates with vascular
    smooth muscle cell degeneration.
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  downstream:
  - target: Small Vessel Arteriopathy and Hypoperfusion
    description: >-
      Progressive GOM-laden vessels lose smooth muscle cells, develop medial
      fibrosis and luminal narrowing, and fail to autoregulate cerebral blood
      flow.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - vascular smooth muscle cell apoptosis
    - medial fibrosis and arterial wall thickening
    evidence:
    - reference: DOI:10.3389/fnmol.2024.1391040
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The NOTCH3 R75Q mouse model showed pathological characteristics of
        CADASIL, with age-dependent NOTCH3ECD, granular osmiophilic material,
        and degenerated smooth muscle cells detected in the brain.
      explanation: >-
        Age-dependent GOM accumulation co-occurs with VSMC degeneration,
        supporting a direct path from deposit burden to small-vessel
        arteriopathy.
  evidence:
  - reference: PMID:30855338
    reference_title: "CADASIL: new advances in basic science and clinical perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Granular osmiophilic material deposits around blood vessels are also
      a unique CADASIL feature and appear to have a role in sequestering
      proteins that are essential for blood vessel homeostasis.
    explanation: >-
      This review confirms GOM deposits as a unique pathological feature of
      CADASIL that sequesters proteins important for vascular homeostasis.
  - reference: DOI:10.3389/fnmol.2024.1391040
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The NOTCH3 R75Q mouse model showed pathological characteristics of
      CADASIL, with age-dependent NOTCH3ECD, granular osmiophilic material,
      and degenerated smooth muscle cells detected in the brain.
    explanation: >-
      The NOTCH3 R75Q knock-in mouse model recapitulates GOM deposition
      and smooth muscle cell degeneration in an age-dependent manner,
      confirming the link between GOM accumulation and VSMC loss.
- name: Matrisome Sequestration and HTRA1 Loss-of-Function
  description: >-
    Aggregating NOTCH3 ECD in CADASIL vessels abnormally recruits and
    sequesters matrisome proteins (TIMP3, vitronectin, LTBP1, clusterin),
    producing an HTRA1 loss-of-function profile in cerebral arterioles.
    Impaired ECM proteostasis amplifies vessel wall remodeling and biases
    the small artery phenotype toward fibrotic thickening with reduced
    matrix turnover.
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  - preferred_term: proteolysis
    term:
      id: GO:0006508
      label: proteolysis
    modifier: DECREASED
  downstream:
  - target: Small Vessel Arteriopathy and Hypoperfusion
    description: >-
      Matrisome co-aggregation and HTRA1 inactivation accelerate vessel
      wall fibrosis, mural cell dysfunction, and luminal narrowing.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - sequestered TIMP3 and vitronectin disrupt arterial ECM homeostasis
    - reduced HTRA1 protease activity impairs clearance of misfolded ECM
  evidence:
  - reference: PMID:23649698
    reference_title: "Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further proteomic and immunohistochemical analyses identified two
      functionally important extracellular matrix proteins, tissue
      inhibitor of metalloproteinases 3 (TIMP3) and vitronectin (VTN)
      that are sequestered into Notch3(ECD)-containing aggregates.
    explanation: >-
      Direct biochemical and immunohistochemical evidence that TIMP3 and
      vitronectin are sequestered into NOTCH3 ECD aggregates in CADASIL
      brain and artery samples, anchoring the matrisome co-aggregation
      mechanism.
  - reference: PMID:23649698
    reference_title: "Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specifically, our results suggest a dysregulation of TIMP3 activity,
      which could contribute to mutant Notch3(ECD) toxicity by impairing
      extracellular matrix homeostasis in small vessels.
    explanation: >-
      TIMP3 dysregulation, downstream of NOTCH3 ECD sequestration,
      impairs ECM homeostasis in cerebral small vessels, supporting the
      matrisome/proteostasis arm of CADASIL pathophysiology.
- name: ER Stress and Complement-Mediated Vessel Wall Injury
  description: >-
    Mutant NOTCH3 ECD misfolding triggers endoplasmic reticulum (ER) stress
    in arterial smooth muscle cells with heat-shock protein induction,
    pro-inflammatory cytokine (IL-6) and adhesion molecule (ICAM-1)
    upregulation, and robust activation of the alternative complement
    pathway (Factor B, C3d, and C5b-9 deposition) on cerebral microvessels.
    This vessel-wall immunopathology amplifies VSMC injury and engages
    perivascular microglia/macrophages.
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  - preferred_term: complement activation, alternative pathway
    term:
      id: GO:0006957
      label: complement activation, alternative pathway
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Small Vessel Arteriopathy and Hypoperfusion
    description: >-
      ER stress and complement-mediated injury accelerate VSMC loss and
      mural cell dysfunction, contributing to small-vessel arteriopathy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - alternative-pathway complement activation injures medial VSMCs
    - ICAM-1/IL-6 induction recruits perivascular macrophages
    evidence:
    - reference: PMID:37158955
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Functional VSMC cultures bearing the NOTCH3 Arg133Cys mutation
        showed increased gene expression of the pro-inflammatory cytokine
        interleukin 6 and ICAM-1 by 16- and 50-fold, respectively.
      explanation: >-
        Mutant-VSMC inflammatory induction (IL-6, ICAM-1) provides a
        cell-autonomous link from ER stress to vessel-wall pathology.
  evidence:
  - reference: PMID:37158955
    reference_title: "ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We further found evidence for activation of the alternative pathway
      of complement. Immunolocalisation of complement Factor B, C3d and
      C5-9 terminal complex but not C1q was apparent in ~ 70% of cerebral
      vessels.
    explanation: >-
      Vessel-wall alternative complement activation is documented across
      ~70% of CADASIL cerebral microvessels, supporting a complement-
      mediated injury mechanism downstream of ER stress.
  - reference: PMID:37158955
    reference_title: "ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional VSMC cultures bearing the NOTCH3 Arg133Cys mutation
      showed increased gene expression of the pro-inflammatory cytokine
      interleukin 6 and ICAM-1 by 16- and 50-fold, respectively.
    explanation: >-
      In vitro mutant-VSMC induction of IL-6 and ICAM-1 establishes a
      cell-autonomous inflammatory axis that complements the in situ
      complement findings.
- name: Small Vessel Arteriopathy and Hypoperfusion
  description: >-
    Progressive thickening of arterial walls with loss of vascular smooth
    muscle cells leads to luminal narrowing, reduced cerebral blood flow,
    and chronic hypoperfusion of subcortical white matter. This results in
    white matter injury, lacunar infarcts, and progressive neurodegeneration.
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: vascular associated smooth muscle cell apoptotic process
    term:
      id: GO:1905288
      label: vascular associated smooth muscle cell apoptotic process
  locations:
  - preferred_term: cerebral hemisphere white matter
    term:
      id: UBERON:0002437
      label: cerebral hemisphere white matter
  downstream:
  - target: White Matter Ischemic Injury
    description: >-
      Chronic hypoperfusion and impaired cerebral autoregulation cause
      progressive ischemic injury and demyelination of deep subcortical
      white matter.
    causal_link_type: DIRECT
  - target: Microvascular Fragility and Iron Deposition
    description: >-
      Diseased small vessels become fragile, leaking blood products and
      seeding hemosiderin and parenchymal iron deposits in cortical and
      subcortical brain regions.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36715085
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CADASIL subjects had a significant increase in hemosiderin/iron
        deposits compared with controls.
      explanation: >-
        Autopsy data link CADASIL arteriopathy to elevated brain
        hemosiderin/iron deposition.
  - target: Recurrent Ischemic Stroke
    description: >-
      Small vessel occlusion or critical luminal narrowing produces deep
      lacunar infarcts, the clinical correlate of subcortical ischemic
      stroke in CADASIL.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:38386425
    reference_title: "Protein aggregates containing wild-type and mutant NOTCH3 are major drivers of arterial pathology in CADASIL."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation
      of the extracellular domain of the NOTCH3 receptor (Notch3ECD) are
      the 2 core features of CADASIL, a common cerebral small vessel
      disease caused by highly stereotyped dominant mutations in NOTCH3.
    explanation: >-
      This paper identifies arterial smooth muscle cell loss and NOTCH3 ECD
      accumulation as the two core pathological features of CADASIL.
- name: Microvascular Fragility and Iron Deposition
  description: >-
    Beyond ischemic injury, CADASIL small vessels become fragile and
    permeable, producing perivascular hemosiderin leakage, capillary
    hemosiderin deposits, and parenchymal iron accumulation across cortex,
    white matter, basal ganglia, and cerebellum. These vessel-wall fragility
    lesions are the substrate for cerebral microbleeds detected on MRI.
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: regulation of blood-brain barrier permeability
    term:
      id: GO:1905603
      label: regulation of blood-brain barrier permeability
    modifier: ABNORMAL
  locations:
  - preferred_term: brain white matter
    term:
      id: UBERON:0002316
      label: white matter
  - preferred_term: basal ganglion
    term:
      id: UBERON:0002420
      label: basal ganglion
  downstream:
  - target: Cerebral Microbleeds
    description: >-
      Perivascular and parenchymal hemosiderin/iron deposition produces the
      microbleeds characteristic of CADASIL on susceptibility-weighted MRI.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36715085
    reference_title: "Neuropathology of microbleeds in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebral microbleeds (CMBs) detected on magnetic resonance imaging
      are common in patients with cerebral autosomal dominant arteriopathy
      with subcortical infarcts and leukoencephalopathy (CADASIL).
    explanation: >-
      Establishes microbleeds as a common CADASIL imaging feature whose
      neuropathological substrate is investigated in the same study.
  - reference: PMID:36715085
    reference_title: "Neuropathology of microbleeds in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PVH was most pronounced in the frontal white matter and basal
      ganglia around small to medium sized arterioles, with no
      predilection for the vicinity of vessels with severe vascular
      changes or infarcts.
    explanation: >-
      Distribution of perivascular hemosiderin around small to medium
      arterioles in frontal white matter and basal ganglia underpins the
      microvascular fragility mechanism.
- name: White Matter Ischemic Injury
  description: >-
    Chronic hypoperfusion and recurrent micro-ischemic events drive
    progressive injury to subcortical and periventricular white matter,
    with myelin loss, oligodendrocyte vulnerability, and axonal injury.
    This produces the diffuse leukoencephalopathy and characteristic MRI
    white matter hyperintensity pattern (anterior temporal poles, external
    capsule, periventricular and frontoparietal white matter) and is the
    substrate for cumulative cognitive and motor disability.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  - preferred_term: pericyte
    term:
      id: CL:0000669
      label: pericyte
  biological_processes:
  - preferred_term: myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: DECREASED
  - preferred_term: response to ischemia
    term:
      id: GO:0002931
      label: response to ischemia
  locations:
  - preferred_term: cerebral hemisphere white matter
    term:
      id: UBERON:0002437
      label: cerebral hemisphere white matter
  - preferred_term: temporal lobe
    term:
      id: UBERON:0001871
      label: temporal lobe
  - preferred_term: external capsule
    term:
      id: UBERON:0004545
      label: external capsule of telencephalon
  downstream:
  - target: White Matter Hyperintensities
    description: >-
      Demyelination and gliosis appear as confluent T2/FLAIR
      hyperintensities, typically involving anterior temporal poles and
      external capsule.
    causal_link_type: DIRECT
  - target: Leukoencephalopathy
    description: >-
      Cumulative white matter injury manifests pathologically as diffuse
      leukoencephalopathy.
    causal_link_type: DIRECT
  - target: Cognitive Impairment
    description: >-
      Disconnection from white matter tract injury produces executive,
      processing speed, and memory deficits.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - subcortical disconnection of fronto-subcortical circuits
  - target: Dementia
    description: >-
      Cumulative subcortical ischemic injury, lacunes, and white matter
      damage culminate in vascular dementia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cumulative ischemic burden
    - lacunar infarcts
  - target: Gait Disturbance
    description: >-
      Fronto-subcortical circuit injury causes vascular gait apraxia and
      progressive gait disturbance.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Apathy
    description: >-
      Disruption of fronto-striatal circuits underlies prominent apathy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: DOI:10.3389/fneur.2025.1573052
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prevalent and earliest imaging alterations in CADASIL are
      white matter hyperintensities in the periventricular white matter,
      temporal pole, external capsule, frontoparietal white matter, and
      other areas on magnetic resonance imaging.
    explanation: >-
      Topography of white matter injury maps to the imaging-defined
      leukoencephalopathy of CADASIL.
- name: Immune Activation and ECM Remodeling
  description: >-
    Proteomic profiling in CADASIL patients reveals an immune- and
    matrisome-oriented plasma signature with elevated RSPO1, FGF19, MMP-10
    and reduced PPY, alongside enrichment of complement/inflammatory pathways,
    leukocyte adhesion, and ECM organization, supporting roles for vascular
    remodeling and immune activation in disease progression.
  biological_processes:
  - preferred_term: proteolysis
    term:
      id: GO:0006508
      label: proteolysis
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: DOI:10.3390/jcm13113138
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significant differences in protein expression were observed between
      CADASIL patients and controls. RSPO1 and FGF-19 exhibited elevated
      levels (p < 0.05), while PPY showed downregulation (p < 0.05) in
      CADASIL patients, suggesting their involvement in disease pathogenesis.
    explanation: >-
      Proteomic analysis identifies differentially expressed proteins in
      CADASIL plasma with enrichment of complement/inflammatory and ECM
      organization pathways.
phenotypes:
- name: Recurrent Ischemic Stroke
  category: Neurological
  frequency: VERY_FREQUENT
  description: >-
    Subcortical lacunar infarcts are the hallmark feature, typically
    beginning in the 4th-5th decade. Most patients experience multiple
    strokes leading to cumulative disability.
  phenotype_term:
    preferred_term: Lacunar stroke
    term:
      id: HP:0032325
      label: Lacunar stroke
  evidence:
  - reference: DOI:10.3389/fneur.2025.1573052
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical manifestations of CADASIL include migraines, recurrent
      ischemic stroke, progressive cognitive deterioration, and psychiatric
      symptoms.
    explanation: >-
      This review confirms recurrent ischemic stroke as a core clinical
      manifestation of CADASIL.
- name: Migraine with Aura
  category: Neurological
  frequency: FREQUENT
  description: >-
    Migraine with aura, often with prolonged or atypical aura, is frequently
    the earliest manifestation, appearing in the 2nd-3rd decade.
  phenotype_term:
    preferred_term: Migraine with aura
    term:
      id: HP:0002077
      label: Migraine with aura
  evidence:
  - reference: DOI:10.3389/fneur.2025.1573052
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical manifestations of CADASIL include migraines, recurrent
      ischemic stroke, progressive cognitive deterioration, and psychiatric
      symptoms.
    explanation: >-
      This review lists migraines as a core clinical manifestation of
      CADASIL.
- name: Cognitive Impairment
  category: Neurological
  frequency: VERY_FREQUENT
  description: >-
    Progressive cognitive decline affecting executive function, processing
    speed, and memory. Vascular dementia develops in most patients by age 65.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: DOI:10.3389/fneur.2025.1573052
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical manifestations of CADASIL include migraines, recurrent
      ischemic stroke, progressive cognitive deterioration, and psychiatric
      symptoms.
    explanation: >-
      This review confirms progressive cognitive deterioration as a core
      CADASIL phenotype.
  - reference: DOI:10.3389/fneur.2025.1662012
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebral autosomal dominant arteriopathy with subcortical infarcts and
      leukoencephalopathy (CADASIL) is an autosomal dominant disorder
      characterized by midlife-onset cerebrovascular disease and dementia.
    explanation: >-
      This review describes dementia as a defining feature of CADASIL.
- name: Mood Disturbances
  category: Psychiatric
  frequency: FREQUENT
  description: >-
    Depression and apathy are common, often preceding or accompanying
    cognitive decline. Some patients develop more severe psychiatric symptoms.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: DOI:10.3389/fneur.2025.1573052
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical manifestations of CADASIL include migraines, recurrent
      ischemic stroke, progressive cognitive deterioration, and psychiatric
      symptoms.
    explanation: >-
      Psychiatric symptoms, including mood disturbances, are listed as a
      core clinical manifestation of CADASIL.
- name: White Matter Hyperintensities
  category: Neuroimaging
  frequency: VERY_FREQUENT
  description: >-
    Extensive white matter hyperintensities on T2/FLAIR MRI, characteristically
    involving the anterior temporal lobes and external capsules - a pattern
    relatively specific for CADASIL.
  phenotype_term:
    preferred_term: Hyperintensity of cerebral white matter on MRI
    term:
      id: HP:0030890
      label: Hyperintensity of cerebral white matter on MRI
  evidence:
  - reference: DOI:10.3389/fneur.2025.1573052
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prevalent and earliest imaging alterations in CADASIL are
      white matter hyperintensities in the periventricular white matter,
      temporal pole, external capsule, frontoparietal white matter, and
      other areas on magnetic resonance imaging.
    explanation: >-
      This review confirms white matter hyperintensities in characteristic
      locations as the most prevalent and earliest imaging finding in
      CADASIL.
  - reference: PMID:30855338
    reference_title: "CADASIL: new advances in basic science and clinical perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebral white matter changes observed by MRI are a key CADASIL
      characteristic in young adult patients often before severe symptoms
      and trigger NOTCH3 genetic testing.
    explanation: >-
      This review confirms cerebral white matter MRI changes as a key early
      CADASIL characteristic that often prompts genetic testing.
- name: Leukoencephalopathy
  category: Neurological
  frequency: VERY_FREQUENT
  description: >-
    Progressive damage to the white matter of the cerebrum resulting from
    chronic small vessel disease and hypoperfusion. This is the defining
    neuropathological feature reflected in the disease name.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  notes: >-
    Retained as a core neuroimaging phenotype reflected in the disease name;
    no separate frequency-specific evidence block is asserted here.
- name: Dementia
  category: Neurological
  frequency: FREQUENT
  description: >-
    Progressive vascular dementia developing from cumulative ischemic
    injury and white matter disease. Most patients develop dementia by
    their 6th-7th decade.
  phenotype_term:
    preferred_term: Dementia
    term:
      id: HP:0000726
      label: Dementia
  evidence:
  - reference: DOI:10.3389/fneur.2025.1662012
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebral autosomal dominant arteriopathy with subcortical infarcts and
      leukoencephalopathy (CADASIL) is an autosomal dominant disorder
      characterized by midlife-onset cerebrovascular disease and dementia.
    explanation: >-
      Dementia is identified as a defining characteristic of CADASIL.
- name: Apathy
  category: Psychiatric
  frequency: FREQUENT
  description: >-
    Reduced motivation and initiative, often accompanying cognitive decline
    and contributing to functional disability.
  phenotype_term:
    preferred_term: Apathy
    term:
      id: HP:0000741
      label: Apathy
  evidence:
  - reference: DOI:10.3389/fneur.2025.1573052
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical manifestations of CADASIL include migraines, recurrent
      ischemic stroke, progressive cognitive deterioration, and psychiatric
      symptoms.
    explanation: >-
      Apathy is a common psychiatric symptom in CADASIL, grouped under
      the broader psychiatric manifestations.
- name: Gait Disturbance
  category: Neurological
  frequency: FREQUENT
  description: >-
    Progressive gait difficulties resulting from subcortical ischemic
    injury and white matter disease.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  notes: >-
    Retained as a downstream clinical consequence of cumulative subcortical
    ischemic injury and white matter disease; no separate evidence block is
    asserted here.
- name: Cerebral Microbleeds
  category: Neuroimaging
  frequency: FREQUENT
  description: >-
    Small foci of chronic blood product (hemosiderin) deposition detected
    on susceptibility-weighted or T2*-gradient echo MRI. Reflect
    microvascular fragility from CADASIL arteriopathy with perivascular
    leakage. Microbleed burden, particularly in basal ganglia and
    thalamus, correlates with disease severity and increased risk of
    incident ischemic stroke. Mapped to the most specific available HPO
    term (HP:0001342, Cerebral hemorrhage) - HPO does not yet provide a
    dedicated "cerebral microbleed" term.
  phenotype_term:
    preferred_term: Cerebral microbleed
    term:
      id: HP:0001342
      label: Cerebral hemorrhage
  evidence:
  - reference: PMID:36715085
    reference_title: "Neuropathology of microbleeds in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebral microbleeds (CMBs) detected on magnetic resonance imaging
      are common in patients with cerebral autosomal dominant arteriopathy
      with subcortical infarcts and leukoencephalopathy (CADASIL).
    explanation: >-
      Establishes cerebral microbleeds as a common neuroimaging finding
      in CADASIL, with neuropathological correlates of perivascular
      hemosiderin and parenchymal iron deposition.
  - reference: PMID:36715085
    reference_title: "Neuropathology of microbleeds in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CADASIL subjects had a significant increase in hemosiderin/iron
      deposits compared with controls.
      This increase was principally seen with PID.
    explanation: >-
      Quantitative neuropathology confirms increased brain hemosiderin
      and parenchymal iron deposits in CADASIL, the substrate for
      MRI-visible microbleeds.
- name: Subcortical Lacunar Infarcts
  category: Neuroimaging
  frequency: VERY_FREQUENT
  description: >-
    Chronic, structural lacunar infarcts visible as small fluid-filled
    cavities on T2/FLAIR MRI - distinct from the acute lacunar stroke
    event captured under "Recurrent Ischemic Stroke". Lacune burden
    (lacune volume) is a quantitative MRI biomarker of CADASIL severity
    and tracks with EGFr domain risk and clinical disability. Subcortical
    infarcts are part of the disease's defining name. Mapped to HP:0032325
    (Lacunar stroke) - the most specific HPO term available, with
    Neuroimaging category indicating the chronic structural lesion rather
    than the acute event.
  phenotype_term:
    preferred_term: Subcortical lacunar infarcts (chronic MRI)
    term:
      id: HP:0032325
      label: Lacunar stroke
  evidence:
  - reference: PMID:36535904
    reference_title: "Three-tiered EGFr domain risk stratification for individualized NOTCH3-small vessel disease prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the CADASIL genotype-phenotype data set, HR-EGFr domains 8, 11
      and 26 patients had a significantly higher risk of stroke
      (P = 0.002), disability (P = 0.041), nWMHv
      (P = 1.8 × 10-8), PSMD (P = 2.6 × 10-8) and lacune volume
      (P = 0.006) than MR-EGFr patients.
    explanation: >-
      Lacune volume is treated as a distinct quantitative MRI biomarker
      of CADASIL severity, separate from clinical stroke events,
      validating the chronic-structural-lesion phenotype.
genetic:
- name: NOTCH3
  association: Causative
  gene_term:
    preferred_term: NOTCH3
    term:
      id: hgnc:7883
      label: NOTCH3
  notes: >-
    Autosomal dominant mutations in NOTCH3 cause CADASIL. Over 95% are
    missense mutations affecting cysteine residues in the 34 EGF-like
    repeat domains, leading to an odd number of cysteines and abnormal
    protein folding. Cysteine-sparing variants can also cause CADASIL-like
    pathology. Variant location within EGFr (EGF-like repeat) domains
    stratifies into three risk tiers: high-risk (HR-EGFr) domains include
    1-6 plus 8, 11, and 26; medium-risk (MR-EGFr) and low-risk (LR-EGFr)
    cover the remaining domains. HR-EGFr carriers have an ~10-fold higher
    odds of stroke than LR-EGFr carriers and a higher vascular NOTCH3
    aggregation load, supporting an aggregation-driven genotype-phenotype
    severity gradient.
  evidence:
  - reference: DOI:10.3389/fneur.2025.1662012
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is caused by mutations in the NOTCH3 gene, which affects the
      amount of cysteine in the extracellular domain (ECD) of the receptor,
      leading to protein misfolding and receptor aggregation. Emerging
      evidence indicates that beyond classical missense mutations, other
      variants including cysteine-sparing missense mutations, homozygous
      mutations, small deletions, duplications, splice site mutations,
      a deletion/insertion and loss-of-function mutations may lead to
      distinct phenotypes with variable severity and disease penetrance.
    explanation: >-
      This review confirms NOTCH3 mutations as causative and describes
      the expanding spectrum of pathogenic variants beyond classical
      cysteine-altering mutations.
  - reference: PMID:30855338
    reference_title: "CADASIL: new advances in basic science and clinical perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NOTCH3 mutation locations are highly variable, correlate to disease
      severity and consistently affect the cysteine balance within
      extracellular Notch3.
    explanation: >-
      This review confirms that NOTCH3 mutations consistently affect
      cysteine balance and that mutation location correlates with disease
      severity.
  - reference: PMID:36535904
    reference_title: "Three-tiered EGFr domain risk stratification for individualized NOTCH3-small vessel disease prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nine EGFr domains were classified as an HR-EGFr, which included EGFr
      domains 1-6, but additionally also EGFr domains 8, 11 and 26.
    explanation: >-
      Defines the high-risk EGFr domain set used for NOTCH3 variant risk
      stratification in CADASIL.
  - reference: PMID:36535904
    reference_title: "Three-tiered EGFr domain risk stratification for individualized NOTCH3-small vessel disease prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NOTCH3cys variants located in EGFr domains 1-6 are associated with a
      more severe phenotype than NOTCH3cys variants located in EGFr domains
      7-34.
    explanation: >-
      Establishes the canonical EGFr domain location effect on phenotype
      severity that underlies the three-tiered risk classification.
  - reference: PMID:36535904
    reference_title: "Three-tiered EGFr domain risk stratification for individualized NOTCH3-small vessel disease prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NVFOR was significantly associated with vascular NOTCH3 aggregation
      load (P = 0.006), but not with NOTCH3 signalling activity (P = 0.88).
    explanation: >-
      Genotype-based EGFr risk classification correlates with vascular
      NOTCH3 aggregation rather than canonical signaling, supporting
      aggregation-driven toxicity as the dominant CADASIL mechanism.
  - reference: DOI:10.3389/fnmol.2024.1391040
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We demonstrate that NOTCH3ECD induced by NOTCH3 R75Q mutation has
      toxic effects on cells and reveal the deposition characteristics of
      NOTCH3ECD in the brain. This provides a feasible model and lays the
      foundation for further studies on the pathogenesis and therapeutic
      strategies of NOTCH3 cysteine-sparing mutations.
    explanation: >-
      This study provides in vitro and in vivo evidence that the
      cysteine-sparing NOTCH3 R75Q mutation is pathogenic, expanding
      the spectrum of causative NOTCH3 variants.
inheritance:
- name: Autosomal Dominant
  description: >-
    CADASIL follows autosomal dominant inheritance with high penetrance.
    De novo mutations are rare but reported.
  evidence:
  - reference: DOI:10.3389/fneur.2025.1662012
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebral autosomal dominant arteriopathy with subcortical infarcts and
      leukoencephalopathy (CADASIL) is an autosomal dominant disorder
      characterized by midlife-onset cerebrovascular disease and dementia.
    explanation: >-
      This review confirms the autosomal dominant inheritance pattern
      of CADASIL.
diagnosis:
- name: MRI white matter lesion recognition
  description: >-
    Brain MRI findings, especially characteristic cerebral white matter
    abnormalities in the correct clinical context, are used to raise suspicion
    for CADASIL and guide confirmatory NOTCH3 testing.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: MAXO:0000424
      label: magnetic resonance imaging procedure
  results: White matter hyperintensities, lacunes, and microbleeds in a CADASIL-compatible distribution.
  evidence:
  - reference: PMID:30855338
    reference_title: "CADASIL: new advances in basic science and clinical perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebral white matter changes observed by MRI are a key CADASIL
      characteristic in young adult patients often before severe symptoms
      and trigger NOTCH3 genetic testing.
    explanation: The review supports MRI white matter changes as a diagnostic clue that prompts genetic testing.
- name: NOTCH3 molecular confirmation
  description: >-
    Molecular diagnosis identifies pathogenic NOTCH3 variants, classically
    cysteine-altering extracellular-domain variants, while recognizing the
    broader pathogenic variant spectrum now reported.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  results: Pathogenic NOTCH3 variant consistent with CADASIL.
  evidence:
  - reference: DOI:10.3389/fneur.2025.1662012
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is caused by mutations in the NOTCH3 gene, which affects the
      amount of cysteine in the extracellular domain (ECD) of the receptor,
      leading to protein misfolding and receptor aggregation.
    explanation: This review supports NOTCH3 variant detection as confirmatory for CADASIL.
treatments:
- name: Antiplatelet Therapy
  description: >-
    Secondary stroke prevention with antiplatelet agents, though evidence
    specific to CADASIL is limited.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Migraine Prophylaxis
  description: >-
    Management of migraine with aura, avoiding vasoconstrictors like
    triptans due to theoretical stroke risk.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Supportive Care
  description: >-
    Management of vascular risk factors, cognitive rehabilitation, and
    treatment of psychiatric symptoms.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Genetic Counseling
  description: >-
    Genetic counseling is recommended for affected individuals and
    at-risk family members given the autosomal dominant inheritance
    pattern and high penetrance.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
datasets:
references:
- reference: DOI:10.1007/s00415-023-12177-0
  title: 'Prevalence, clinical characteristics, and risk factors of intracerebral haemorrhage in CADASIL: a case series and systematic review'
  found_in:
  - CADASIL_Type_1-deep-research-falcon.md
  findings:
  - statement: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and is characterised by early onset stroke and dementia.
    supporting_text: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and is characterised by early onset stroke and dementia.
    evidence:
    - reference: DOI:10.1007/s00415-023-12177-0
      reference_title: 'Prevalence, clinical characteristics, and risk factors of intracerebral haemorrhage in CADASIL: a case series and systematic review'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and is characterised by early onset stroke and dementia.
      explanation: Deep research cited this publication as relevant literature for CADASIL Type 1.
- reference: DOI:10.1055/s-0042-1758756
  title: Clinical and epidemiological profiles from a case series of 26 Brazilian CADASIL patients
  found_in:
  - CADASIL_Type_1-deep-research-falcon.md
  findings:
  - statement: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cause of ischemic stroke and the most common form of non-atherosclerotic stroke.
    supporting_text: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cause of ischemic stroke and the most common form of non-atherosclerotic stroke.
    evidence:
    - reference: DOI:10.1055/s-0042-1758756
      reference_title: Clinical and epidemiological profiles from a case series of 26 Brazilian CADASIL patients
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cause of ischemic stroke and the most common form of non-atherosclerotic stroke.
      explanation: Deep research cited this publication as relevant literature for CADASIL Type 1.
- reference: DOI:10.1177/0271678x221126280
  title: 'Phenotypic variability in 446 CADASIL patients: Impact of NOTCH3 gene mutation location in addition to the effects of age, sex and vascular risk factors'
  found_in:
  - CADASIL_Type_1-deep-research-falcon.md
  findings:
  - statement: 'Phenotypic variability in 446 CADASIL patients: Impact of NOTCH3 gene mutation location in addition to the effects of age, sex and vascular risk factors'
    supporting_text: The recent discovery that the prevalence of cysteine mutations in the NOTCH3 gene responsible for CADASIL was more than 100 times higher in the general population than that estimated in patients highlighted that the mutation location in EGFr-like-domains of the NOTCH3 receptor could have a major effect on the phenotype of the disease.
    evidence:
    - reference: DOI:10.1177/0271678x221126280
      reference_title: 'Phenotypic variability in 446 CADASIL patients: Impact of NOTCH3 gene mutation location in addition to the effects of age, sex and vascular risk factors'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The recent discovery that the prevalence of cysteine mutations in the NOTCH3 gene responsible for CADASIL was more than 100 times higher in the general population than that estimated in patients highlighted that the mutation location in EGFr-like-domains of the NOTCH3 receptor could have a major effect on the phenotype of the disease.
      explanation: Deep research cited this publication as relevant literature for CADASIL Type 1.
- reference: DOI:10.1186/s40246-019-0255-x
  title: Investigating diagnostic sequencing techniques for CADASIL diagnosis
  found_in:
  - CADASIL_Type_1-deep-research-falcon.md
  findings:
  - statement: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene.
    supporting_text: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene.
    evidence:
    - reference: DOI:10.1186/s40246-019-0255-x
      reference_title: Investigating diagnostic sequencing techniques for CADASIL diagnosis
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene.
      explanation: Deep research cited this publication as relevant literature for CADASIL Type 1.
- reference: DOI:10.14806/ej.24.0.921
  title: 'NOTCH3 and CADASIL syndrome: a genetic and structural overview'
  found_in:
  - CADASIL_Type_1-deep-research-falcon.md
  findings:
  - statement: CADASIL syndrome is a rare disease that belongs to a group of disorders called leukodystrophies.
    supporting_text: CADASIL syndrome is a rare disease that belongs to a group of disorders called leukodystrophies.
    evidence:
    - reference: DOI:10.14806/ej.24.0.921
      reference_title: 'NOTCH3 and CADASIL syndrome: a genetic and structural overview'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: CADASIL syndrome is a rare disease that belongs to a group of disorders called leukodystrophies.
      explanation: Deep research cited this publication as relevant literature for CADASIL Type 1.
- reference: DOI:10.3389/fgene.2021.705284
  title: NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients
  found_in:
  - CADASIL_Type_1-deep-research-falcon.md
  findings:
  - statement: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene.
    supporting_text: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene.
    evidence:
    - reference: DOI:10.3389/fgene.2021.705284
      reference_title: NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene.
      explanation: Deep research cited this publication as relevant literature for CADASIL Type 1.
- reference: DOI:10.3389/fneur.2023.1203985
  title: 'Lifelong cerebrovascular disease burden among CADASIL patients: analysis from a global health research network'
  found_in:
  - CADASIL_Type_1-deep-research-falcon.md
  findings:
  - statement: Data reporting on patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) within the United States population is limited.
    supporting_text: Data reporting on patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) within the United States population is limited.
    evidence:
    - reference: DOI:10.3389/fneur.2023.1203985
      reference_title: 'Lifelong cerebrovascular disease burden among CADASIL patients: analysis from a global health research network'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Data reporting on patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) within the United States population is limited.
      explanation: Deep research cited this publication as relevant literature for CADASIL Type 1.
- reference: DOI:10.3390/ijms25168796
  title: 'Phenotypes Associated with NOTCH3 Cysteine-Sparing Mutations in Patients with Clinical Suspicion of CADASIL: A Systematic Review'
  found_in:
  - CADASIL_Type_1-deep-research-falcon.md
  findings:
  - statement: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by NOTCH3 mutations affecting the number of cysteines.
    supporting_text: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by NOTCH3 mutations affecting the number of cysteines.
    evidence:
    - reference: DOI:10.3390/ijms25168796
      reference_title: 'Phenotypes Associated with NOTCH3 Cysteine-Sparing Mutations in Patients with Clinical Suspicion of CADASIL: A Systematic Review'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by NOTCH3 mutations affecting the number of cysteines.
      explanation: Deep research cited this publication as relevant literature for CADASIL Type 1.

📚

References & Deep Research

References

8

DOI:10.1007/s00415-023-12177-0

Prevalence, clinical characteristics, and risk factors of intracerebral haemorrhage in CADASIL: a case series and systematic review

1 finding

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and is characterised by early onset stroke and dementia.

"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and is characterised by early onset stroke and dementia."

Show evidence (1 reference)

DOI:10.1007/s00415-023-12177-0 SUPPORT Human Clinical

"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and is characterised by early onset stroke and dementia."

Deep research cited this publication as relevant literature for CADASIL Type 1.

DOI:10.1055/s-0042-1758756

Clinical and epidemiological profiles from a case series of 26 Brazilian CADASIL patients

1 finding

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cause of ischemic stroke and the most common form of non-atherosclerotic stroke.

"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cause of ischemic stroke and the most common form of non-atherosclerotic stroke."

Show evidence (1 reference)

DOI:10.1055/s-0042-1758756 SUPPORT Human Clinical

"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cause of ischemic stroke and the most common form of non-atherosclerotic stroke."

Deep research cited this publication as relevant literature for CADASIL Type 1.

DOI:10.1177/0271678x221126280

Phenotypic variability in 446 CADASIL patients: Impact of NOTCH3 gene mutation location in addition to the effects of age, sex and vascular risk factors

1 finding

Phenotypic variability in 446 CADASIL patients: Impact of NOTCH3 gene mutation location in addition to the effects of age, sex and vascular risk factors

"The recent discovery that the prevalence of cysteine mutations in the NOTCH3 gene responsible for CADASIL was more than 100 times higher in the general population than that estimated in patients highlighted that the mutation location in EGFr-like-domains of the NOTCH3 receptor could have a major..."

Show evidence (1 reference)

DOI:10.1177/0271678x221126280 SUPPORT Human Clinical

"The recent discovery that the prevalence of cysteine mutations in the NOTCH3 gene responsible for CADASIL was more than 100 times higher in the general population than that estimated in patients highlighted that the mutation location in EGFr-like-domains of the NOTCH3 receptor could have a major..."

Deep research cited this publication as relevant literature for CADASIL Type 1.

DOI:10.1186/s40246-019-0255-x

Investigating diagnostic sequencing techniques for CADASIL diagnosis

1 finding

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene.

"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene."

Show evidence (1 reference)

DOI:10.1186/s40246-019-0255-x SUPPORT Human Clinical

"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene."

Deep research cited this publication as relevant literature for CADASIL Type 1.

DOI:10.14806/ej.24.0.921

NOTCH3 and CADASIL syndrome: a genetic and structural overview

1 finding

CADASIL syndrome is a rare disease that belongs to a group of disorders called leukodystrophies.

"CADASIL syndrome is a rare disease that belongs to a group of disorders called leukodystrophies."

Show evidence (1 reference)

DOI:10.14806/ej.24.0.921 SUPPORT Other

"CADASIL syndrome is a rare disease that belongs to a group of disorders called leukodystrophies."

Deep research cited this publication as relevant literature for CADASIL Type 1.

DOI:10.3389/fgene.2021.705284

NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

1 finding

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene.

"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene."

Show evidence (1 reference)

DOI:10.3389/fgene.2021.705284 SUPPORT Human Clinical

"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene."

Deep research cited this publication as relevant literature for CADASIL Type 1.

DOI:10.3389/fneur.2023.1203985

Lifelong cerebrovascular disease burden among CADASIL patients: analysis from a global health research network

1 finding

Data reporting on patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) within the United States population is limited.

"Data reporting on patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) within the United States population is limited."

Show evidence (1 reference)

DOI:10.3389/fneur.2023.1203985 SUPPORT Human Clinical

"Data reporting on patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) within the United States population is limited."

Deep research cited this publication as relevant literature for CADASIL Type 1.

DOI:10.3390/ijms25168796

Phenotypes Associated with NOTCH3 Cysteine-Sparing Mutations in Patients with Clinical Suspicion of CADASIL: A Systematic Review

1 finding

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by NOTCH3 mutations affecting the number of cysteines.

"CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by NOTCH3 mutations affecting the number of cysteines."

Show evidence (1 reference)

DOI:10.3390/ijms25168796 SUPPORT Human Clinical

"CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by NOTCH3 mutations affecting the number of cysteines."

Deep research cited this publication as relevant literature for CADASIL Type 1.

Deep Research

1

Falcon ▸

CADASIL Type 1 (NOTCH3-related) — Disease Characteristics Research Report

Edison Scientific Literature 36 citations 2026-05-08T10:54:27.497554

CADASIL Type 1 (NOTCH3-related) — Disease Characteristics Research Report

1. Disease information

1.1 Concise overview

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult-onset, autosomal dominant hereditary cerebral small-vessel disease that typically presents in mid-adulthood with ischemic strokes/transient ischemic attacks, migraine (often with aura), mood disturbance, and progressive cognitive impairment leading to vascular dementia. (cerfontaine2024associationofnotch3 pages 1-2, papakonstantinou2019notch3andcadasil pages 1-3, bersano2017cadasiltreatmentand pages 1-3)

A current mechanistic consensus is that CADASIL is “considered to be caused by accumulation of the mutant NOTCH3 extracellular domain (N3ECD)” with possible contribution from impaired Notch signaling; however, “the process leading to N3ECD accumulation and its association with canonical NOTCH3 signaling remain unknown.” (Mizuta et al., 2024-01-18) (mizuta2024progresstoclarify pages 1-2)

1.2 Key identifiers and synonyms (from retrieved evidence)

Preferred name: CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). (bersano2017cadasiltreatmentand pages 1-3)
OMIM: 125310 (explicitly cited as “CADASIL (OMIM 125310)” in multiple sources). (hu2021notch3variantsand pages 1-2, bersano2017cadasiltreatmentand pages 1-3)
Causal gene: NOTCH3 (chr19; NOTCH3 receptor). (hu2021notch3variantsand pages 1-2, bersano2017cadasiltreatmentand pages 1-3)

Not located in the retrieved sources for this run: MONDO ID, Orphanet ORPHA number, ICD-10/ICD-11 codes, MeSH ID. These identifiers should be added by consulting the corresponding terminologies (e.g., MONDO/Orphanet/WHO ICD/MeSH) because they are not directly available in the evidence retrieved here.

1.3 Source types for disease definition

Aggregated, disease-level consensus in peer-reviewed reviews and cohorts. (bersano2017cadasiltreatmentand pages 1-3, mizuta2024progresstoclarify pages 1-2)
Large-scale EMR/network analyses (coded diagnosis; potential for misclassification). (pan2023lifelongcerebrovasculardisease pages 1-2)

2. Etiology

2.1 Disease causal factors

CADASIL is caused primarily by pathogenic NOTCH3 variants. The archetypal CADASIL-causing variants are heterozygous missense mutations in the NOTCH3 extracellular epidermal growth factor-like repeat (EGFr) region that alter the number of cysteines (creating an odd number), leading to misfolding/aggregation of the NOTCH3 extracellular domain and characteristic vessel-wall pathology. (hu2021notch3variantsand pages 1-2, mizuta2024progresstoclarify pages 1-2)

Direct abstract quote (mechanistic framing): “CADASIL … is adult-onset and considered to be caused by accumulation of the mutant NOTCH3 extracellular domain (N3ECD) and, possibly, by an impairment in Notch signaling.” (Mizuta et al., 2024-01-18) (mizuta2024progresstoclarify pages 1-2)

2.2 Risk factors (genetic and non-genetic modifiers)

Genetic (variant-position effects): NOTCH3 variant position in EGFr domains strongly influences phenotype severity; variants in EGFr 1–6 are repeatedly associated with more severe disease than EGFr 7–34, beyond effects of age/sex/vascular risk factors. (dupe2023phenotypicvariabilityin pages 1-2, kaisaridi2025determiningclinicaldisease pages 1-5, cao2024phenotypesassociatedwith pages 13-14)

Non-genetic modifiers: Large cohort analyses identify age, male sex, and vascular risk factors (notably hypertension, hypercholesterolemia; also smoking in progression modeling) as contributors to clinical severity/progression, in addition to NOTCH3 variant position. (dupe2023phenotypicvariabilityin pages 1-2, kaisaridi2025determiningclinicaldisease pages 1-5)

Hemorrhage-related treatment/risk factor signal: In a UK register/systematic review study, anticoagulation was associated with higher intracerebral hemorrhage (ICH) risk in CADASIL (see §11 and §12). (sukhonpanich2024prevalenceclinicalcharacteristics pages 1-2)

2.3 Protective factors and gene–environment interaction

No protective factors or explicit gene–environment interaction models were identified in the retrieved evidence.

3. Phenotypes (with suggested HPO terms)

3.1 Core phenotype spectrum

Across large cohort and registry/EMR studies, CADASIL commonly includes: - Migraine with aura (often early feature). Suggested HPO: HP:0002076 (Migraine); aura can be mapped to HP:0012378 (Aura) (phenotype label). (cerfontaine2024associationofnotch3 pages 1-2, bersano2017cadasiltreatmentand pages 1-3) - Ischemic stroke/TIA, typically lacunar subtype. Suggested HPO: HP:0001297 (Stroke); HP:0002326 (Transient ischemic attack). (cerfontaine2024associationofnotch3 pages 1-2, bersano2017cadasiltreatmentand pages 1-3) - Cognitive impairment/executive dysfunction → vascular dementia. Suggested HPO: HP:0100543 (Cognitive impairment); HP:0000726 (Dementia). (cerfontaine2024associationofnotch3 pages 1-2, bersano2017cadasiltreatmentand pages 1-3) - Psychiatric/mood disturbance (depression/apathy). Suggested HPO: HP:0000716 (Depression); HP:0000741 (Apathy). (cerfontaine2024associationofnotch3 pages 1-2, bersano2017cadasiltreatmentand pages 1-3) - Seizures (minority). Suggested HPO: HP:0001250 (Seizures). (bersano2017cadasiltreatmentand pages 1-3)

3.2 Quantitative phenotype frequencies from recent cohorts/case series

Brazilian genetically confirmed series (n=26): ischemic stroke first symptom 19/26; cognitive impairment 17/26; dementia 6/26; psychiatric manifestations 16/26; recurrent migraine 8/26, aura in 6/8 (75%). (Nogueira et al., online 2023-05-08) (nogueira2023clinicalandepidemiological pages 1-2)
TriNetX EMR network analysis (n=914): 596/914 (65.2%) had documented cerebrovascular events; among CADASIL-stroke patients, 89.4% had ischemic stroke; TIAs co-existed in 27.7%; hemorrhagic strokes 6.2%; first stroke ≤65 years in 71%. (Pan et al., 2023-07-14) (pan2023lifelongcerebrovasculardisease pages 1-2)

3.3 MRI phenotype (selected frequencies)

Brazilian series (n=26): temporal lobe WMH 20/22? reported as 20 patients (91%); external capsule WMH 15 (68%); lacunar infarcts 18 (82%); microbleeds 9 (41%); larger hemorrhages 2 (9%). (nogueira2023clinicalandepidemiological pages 1-2)
Chinese cohort excerpt (probands; MRI): external capsule involvement 77.8% and anterior temporal lobe involvement 37.0% in that cohort; skin biopsy GOM detected in 11/16 tested. (hu2021notch3variantsand pages 1-2)

4. Genetic/molecular information

4.1 Causal gene

NOTCH3 encodes a ~2,321 amino-acid transmembrane receptor with 34 EGF-like repeats in the extracellular domain (EGFr 1–34). (hu2021notch3variantsand pages 1-2)

4.2 Pathogenic variants and variant classes

Most causative variants are cysteine-altering missense variants located in the NOTCH3 EGFr domain, producing an odd number of cysteines. (hu2021notch3variantsand pages 1-2, mizuta2024progresstoclarify pages 1-2)
Pathology is linked to vascular deposition/aggregation of NOTCH3 extracellular domain and extracellular matrix proteins (see §6). (papakonstantinou2019notch3andcadasil pages 1-3, kaisaridi2025determiningclinicaldisease pages 1-5)

Examples of common variants (systematic review): A 1996–2023 systematic review reported the six most common missense mutations globally as p.R75P, p.R133C, p.R141C, p.R169C, p.R182C, and p.R544C. (Boston et al., 2024-06-03) (boston2024mostcommonnotch3 pages 1-2)

4.3 Genotype–phenotype correlations

EGFr position is a major determinant: variants in EGFr 1–6 generally confer higher severity than variants in EGFr 7–34; severity differences appear mediated by differences in ischemic brain lesion accumulation. (dupe2023phenotypicvariabilityin pages 1-2, kaisaridi2025determiningclinicaldisease pages 1-5, cao2024phenotypesassociatedwith pages 13-14)
Risk categorization for NOTCH3-associated SVD: NOTCH3 variants have been categorized as high-, moderate-, or low-risk for early-onset severe small-vessel disease, and this categorization predicts short-term progression in a 2-year prospective CADASIL study (see §8 and artifact table). (cerfontaine2024associationofnotch3 pages 1-2)

4.4 Modifier genes / epigenetics / chromosomal abnormalities

No robust modifier genes, epigenetic mechanisms, or chromosomal abnormalities were identified in the retrieved evidence for this run.

5. Environmental information

No CADASIL-specific environmental toxins or infectious triggers were identified in the retrieved evidence. Vascular risk factors (hypertension, dyslipidemia, smoking) are clinically relevant modifiers rather than primary environmental causes. (kaisaridi2025determiningclinicaldisease pages 1-5)

6. Mechanism / pathophysiology

6.1 Causal chain (current understanding)

1) Germline NOTCH3 EGFr cysteine-altering variant → 2) misfolding and accumulation/aggregation of NOTCH3 extracellular domain (N3ECD) in small-vessel walls → 3) granular osmiophilic material (GOM) deposition and co-aggregation with extracellular matrix/matrisome proteins → 4) progressive small-vessel dysfunction (vascular wall damage, impaired vascular reactivity/perfusion) → 5) chronic ischemic injury and MRI small-vessel disease markers (WMH, lacunes, microbleeds, atrophy) → 6) clinical manifestations (migraine, lacunar strokes/TIA, cognitive decline/dementia, mood symptoms). (papakonstantinou2019notch3andcadasil pages 1-3, kaisaridi2025determiningclinicaldisease pages 1-5, mizuta2024progresstoclarify pages 1-2)

6.2 Cellular/tissue context

CADASIL pathology is centered on vascular smooth muscle cells and pericytes of small arteries/arterioles and capillaries, where NOTCH3 is expressed and where N3ECD deposits and GOM are detected. (papakonstantinou2019notch3andcadasil pages 1-3)

Suggested Cell Ontology (CL) terms (label suggestions): - Vascular smooth muscle cell (e.g., “vascular associated smooth muscle cell”). - Pericyte.

6.3 Molecular pathways and processes (GO suggestions)

Evidence in this run most strongly supports processes related to: - Notch signaling (canonical pathway involvement uncertain in CADASIL relative to other NOTCH disorders). (mizuta2024progresstoclarify pages 1-2) - Protein aggregation / extracellular deposition, extracellular matrix interactions, and vascular wall remodeling. (kaisaridi2025determiningclinicaldisease pages 1-5)

GO term suggestions (label-level): Notch signaling pathway; extracellular matrix organization; protein aggregation; vascular smooth muscle cell differentiation/maintenance; response to hypoxia/ischemia.

6.4 Recent mechanistic emphasis (2024)

Mizuta et al. (2024) explicitly highlight that, despite extensive downstream studies, “the process leading to N3ECD accumulation and its association with canonical NOTCH3 signaling remain unknown,” underscoring an upstream mechanistic gap that is increasingly relevant for designing disease-modifying therapies. (mizuta2024progresstoclarify pages 1-2)

7. Anatomical structures affected

7.1 Organ/system level

Primary: Brain (cerebral small vessels; subcortical ischemic injury; vascular cognitive impairment/dementia). (cerfontaine2024associationofnotch3 pages 1-2, bersano2017cadasiltreatmentand pages 1-3)

Suggested UBERON terms (label suggestions): brain; cerebral cortex; white matter; basal ganglia; thalamus.

7.2 Tissue/cell level

Small arteries/arterioles and capillaries (microvasculature), with vascular smooth muscle cells and pericytes as key cellular sites of pathology. (papakonstantinou2019notch3andcadasil pages 1-3)

7.3 Subcellular level

Extracellular deposition/aggregation of NOTCH3 ectodomain (extracellular compartment/ECM). (kaisaridi2025determiningclinicaldisease pages 1-5)

8. Temporal development

CADASIL is adult-onset with early manifestations such as migraine with aura potentially in young adulthood, while disabling motor/cognitive manifestations often occur later (often after age 50 in clinical descriptions). (bersano2017cadasiltreatmentand pages 1-3, akrich2024geneticdiagnosisof pages 1-2)

Disease progression is heterogeneous; modeling of longitudinal clinical scores identified an early-onset rapidly progressing subgroup vs a later-onset slower subgroup, with variant position (EGFr 1–6), male sex, education, hypertension, and smoking associated with more aggressive progression. (kaisaridi2025determiningclinicaldisease pages 1-5)

9. Inheritance and population

9.1 Inheritance

Autosomal dominant inheritance is consistently reported for classical CADASIL due to pathogenic NOTCH3 variants. (akrich2024geneticdiagnosisof pages 1-2)

9.2 Epidemiology and prevalence

Traditional European prevalence estimates: ~2–5 per 100,000, cited in multiple sources including cohort/review contexts. (cerfontaine2024associationofnotch3 pages 1-2, mizuta2024progresstoclarify pages 1-2)
Population genomics context: NOTCH3 variants may be far more common in the general population than clinically recognized CADASIL prevalence; one 2024 prospective study notes NOTCH3 variants in at least ~1:300 individuals while CADASIL minimal prevalence is 2–5:100,000. (cerfontaine2024associationofnotch3 pages 1-2)

9.3 Sex differences (real-world EMR data)

In TriNetX EMR data, males had higher associated risk of stroke onset (OR 1.37) and higher mortality risk (OR 2.72) compared with females, after adjustment. (pan2023lifelongcerebrovasculardisease pages 1-2)

10. Diagnostics

10.1 Genetic testing (current implementation)

Genetic testing is repeatedly described as the diagnostic gold standard for CADASIL in the retrieved evidence. (hu2021notch3variantsand pages 1-2, bersano2017cadasiltreatmentand pages 1-3)

A real-world diagnostic laboratory evaluation (680 referred samples; 1997 onward) showed a 14.7% mutation detection rate overall, and higher yield using a targeted NGS panel (15.8%) compared with limited Sanger strategies (10.8%), supporting broader sequencing approaches. (Dunn et al., 2020-01; Human Genomics) (dunn2020investigatingdiagnosticsequencing pages 1-2)

10.2 Skin biopsy / pathology

Presence of granular osmiophilic material (GOM) in skin vessels is a characteristic pathological hallmark and is used diagnostically in some workflows, particularly when genetic results are uncertain; in one cohort excerpt, skin biopsy found GOM in 11/16 tested. (papakonstantinou2019notch3andcadasil pages 1-3, hu2021notch3variantsand pages 1-2)

10.3 MRI and imaging markers

Characteristic MRI patterns include extensive white matter hyperintensities (WMH), lacunes, microbleeds, and brain atrophy, with involvement of anterior temporal pole and external capsule often considered suggestive. (bersano2017cadasiltreatmentand pages 1-3, nogueira2023clinicalandepidemiological pages 1-2)

A 2024 prospective study demonstrates trial-sensitive MRI outcomes over 2 years including diffusion MRI (MSMD), WMH volume, lacune volume, and brain parenchymal fraction; variant risk category stratifies progression rates. (cerfontaine2024associationofnotch3 pages 1-2)

Image evidence: Table 2 from Dupé et al. provides a structured summary of clinical and imaging features stratified by NOTCH3 EGFr 1–6 vs 7–34 (including WMH, lacunes, microbleeds, and brain parenchymal fraction), supporting genotype-informed interpretation of MRI patterns. (dupe2023phenotypicvariabilityin media cdee29b5)

11. Outcome / prognosis

CADASIL is progressive and leads to cumulative cerebrovascular injury and vascular cognitive impairment/dementia. (cerfontaine2024associationofnotch3 pages 1-2, bersano2017cadasiltreatmentand pages 1-3)

Recent quantitative prognosis-related signals include: - Two-year prospective worsening in disability, executive function, and multiple MRI measures (MSMD, WMH volume, lacune volume, brain parenchymal fraction), with faster progression in high-risk NOTCH3 variant categories. (cerfontaine2024associationofnotch3 pages 1-2) - ICH occurs in about ~2% of symptomatic cases in a large UK register estimate, with mean onset ~56.6 years and important associations with anticoagulation exposure. (sukhonpanich2024prevalenceclinicalcharacteristics pages 1-2)

12. Treatment

12.1 Current standard of care (symptomatic/risk management)

No disease-modifying therapy is established in the retrieved evidence; management is largely supportive and focused on symptom control and vascular risk factor management. A dedicated treatment review emphasizes that “no proven disease-modifying therapies exist” and management is empiric. (bersano2017cadasiltreatmentand pages 1-3)

12.2 Antithrombotic considerations (evidence relevant to practice)

ICH-focused evidence indicates anticoagulation is associated with increased ICH risk in CADASIL (20.0% vs 1.9% in the UK register comparison), whereas antiplatelet agents were not associated with increased risk in that study. This is relevant to clinical decision-making when considering anticoagulation indications in CADASIL patients. (Sukhonpanich & Markus, published online 2024-01-13) (sukhonpanich2024prevalenceclinicalcharacteristics pages 1-2)

12.3 Clinical trials and observational research (real-world implementation)

Although interventional disease-modifying trials were not identified in the retrieved clinicaltrials.gov set for this run, multiple observational/natural history efforts are active and support biomarker development and future trial readiness: - NCT05677880 (first posted 2023-01-10; recruiting): longitudinal observational study (“Unraveling the Early Phases…”) enrolling individuals with CADASIL family history and known NOTCH3 status; includes neurocognitive assessment, MRI, and biofluids including neurofilament light (NfL). URL: https://clinicaltrials.gov/study/NCT05677880 (NCT05677880 chunk 1) - NCT05072483 (first posted 2021-10-11; recruiting): NIH natural history study with deep phenotyping; may include skin biopsy and lumbar puncture; long follow-up. URL: https://clinicaltrials.gov/study/NCT05072483 (NCT05072483 chunk 1)

Suggested MAXO terms (label suggestions): genetic testing; magnetic resonance imaging; antiplatelet therapy; anticoagulation avoidance/risk assessment; rehabilitation therapy; cognitive assessment.

13. Prevention

No primary prevention strategies specific to CADASIL onset were identified in the retrieved evidence. Secondary/tertiary prevention in practice focuses on aggressive management of vascular risk factors and careful consideration of anticoagulation given ICH risk evidence. (kaisaridi2025determiningclinicaldisease pages 1-5, sukhonpanich2024prevalenceclinicalcharacteristics pages 1-2)

14. Other species / natural disease

No naturally occurring CADASIL-equivalent disease in non-human species was identified in the retrieved evidence.

15. Model organisms and experimental models

A 2024 mechanistic review notes that Notch signaling is conserved across species and that some Drosophila Notch lines harbor cysteine-altering mutations corresponding to CADASIL-causing mutations, but also states that “animal models of CADASIL other than rodent models have not been established,” potentially because Notch signaling is not impaired by most CADASIL-causing mutations. (mizuta2024progresstoclarify pages 1-2)

Recent quantitative findings (2023–2024)

Study (first author, year)	Design/Population	Key quantitative results (include exact numbers)	Interpretation/implication
Cerfontaine, 2024	Prospective 2-year single-center follow-up in genetically confirmed CADASIL; 162 patients total: high-risk (HR) n=90, moderate-risk (MR) n=67, low-risk (LR) n=5	Over 2 years, whole cohort showed progression in MSMD β=0.20 (95% CI 0.17–0.23; p=7.0×10⁻²⁴), normalized lacune volume β=0.13 (0.080–0.19; p=2.1×10⁻⁶), normalized WMH volume β=0.092 (0.075–0.11; p=8.8×10⁻²⁰), brain parenchymal fraction β=−0.22 (−0.26 to −0.19; p=3.2×10⁻²²), plus increased disability (p=0.002) and executive decline (β=−0.15; 95% CI −0.30 to −3.4×10⁻⁵; p=0.05). HR variants had higher 2-year incident stroke risk than MR variants: hazard ratio 4.3 (95% CI 1.4–13.5; p=0.011); also greater increase in MSMD β=0.074 (0.013–0.14; p=0.017) and lacune volume β=0.14 (0.034–0.24; p=0.0089). Significant MSMD progression was detectable even in young n=17 and premanifest n=24 subgroups. (cerfontaine2024associationofnotch3 pages 1-2)	Strong evidence that NOTCH3 risk category predicts short-term clinical and radiologic worsening; supports MSMD as a trial-sensitive biomarker, including in premanifest disease.
Dupé, 2023	Large phenotyping study of 446 CADASIL patients assessing effects of NOTCH3 EGFr mutation location plus age, sex, and vascular risk factors	The study confirmed that mutation location in EGFr 1–6 vs 7–34 strongly influences disease severity; effects were “mainly driven” by differential development of ischemic tissue lesions. The cohort analysis showed severity differences beyond the effects of aging, male sex, hypertension, and hypercholesterolemia. MRI outcomes included WMH, lacunes, microbleeds, and brain parenchymal fraction; mutation location was a major determinant of clinical/imaging profile. (dupe2023phenotypicvariabilityin pages 1-2, dupe2023phenotypicvariabilityin pages 2-3, dupe2023phenotypicvariabilityin media cdee29b5)	Establishes variant position as one of the most important predictors of phenotype and a key stratifier for prognosis and trial design.
Sukhonpanich, 2024	Retrospective review of UK prospective CADASIL register plus systematic review; 516 symptomatic registry patients	10 ICH cases identified in the UK register, giving estimated point prevalence 1.9%. Systematic review added 119 cases, for 129 total cases and 142 ICH events. Mean age at ICH onset 56.6 ± 15.7 years; 57.4% male. ICH was the first manifestation in 32 patients (38.1%) and recurred in 16 (12.4%). Commonest sites were thalamus 58/142 (40.8%) and basal ganglia 34/142 (23.9%). Anticoagulation was associated with higher ICH risk (20.0% vs 1.9%; p=0.006), whereas antiplatelets were not. (sukhonpanich2024prevalenceclinicalcharacteristics pages 1-2)	ICH is uncommon but clinically important in CADASIL; the anticoagulation signal is highly relevant to real-world management decisions.
Pan, 2023	TriNetX global health research network analysis; 914 CADASIL patients identified in US-based EMR data	Median age 60 [IQR 50–69]; 61.3% female. 596/914 (65.2%) had documented cerebrovascular events. Among CADASIL-stroke patients, 89.4% had ischemic stroke, 27.7% had co-existing TIA, and 6.2% had hemorrhagic strokes. Initial stroke occurred at age ≤65 years in 71%. Male sex was associated with higher stroke risk (OR 1.37, 95% CI 1.01–1.86) and higher mortality (OR 2.72, 95% CI 1.53–4.84). (pan2023lifelongcerebrovasculardisease pages 1-2)	Demonstrates a high lifetime cerebrovascular burden in real-world practice and suggests sex-specific risk stratification may be important.
Dunn, 2020	Clinical diagnostic sequencing evaluation; 680 patient samples, 764 tests across Sanger, targeted NGS panel, and WES	Overall mutation detection rate was 14.7% (100/680). By method: Sanger 10.8% (44/407), targeted NGS panel 15.8% (56/354), and WES 1/3 identifying a likely non-NOTCH3 pathogenic variant. Sanger-positive variants clustered mainly in exon 4 (n=36), then exon 3 (n=3), exon 11 (n=3), exon 18 (n=1), exon 19 (n=1). (dunn2020investigatingdiagnosticsequencing pages 1-2)	Supports current practice favoring broader NGS-based testing over limited exon-first Sanger approaches for CADASIL diagnostics.
Nogueira, 2023	Brazilian multicenter case series with genetic confirmation; 26 patients	16/26 female; mean disease onset 45 years. Ischemic stroke was first symptom in 19/26. Cognitive impairment occurred in 17/26, dementia in 6/26, psychiatric manifestations in 16/26. Recurrent migraine in 8/26, with aura in 6/8 (75%). MRI: temporal lobe WMH in 20 patients (91%), external capsule WMH in 15 (68%), lacunar infarcts in 18 (82%), microbleeds in 9 (41%), larger hemorrhages in 2 (9%). (nogueira2023clinicalandepidemiological pages 1-2)	Confirms that core CADASIL clinical-radiologic patterns generalize to an admixed Brazilian cohort, while microbleed/hemorrhage rates may vary by population.
Mizuta, 2024	Mechanistic review of NOTCH3/CADASIL biology	CADASIL is described as adult-onset and driven primarily by mutant NOTCH3 extracellular domain (N3ECD) accumulation, with possible contribution from impaired Notch signaling. The review emphasizes that all known causative mutations are in the EGFr domain, most are cysteine-altering missense variants, and that N3ECD accumulation with downstream vascular pathology remains the dominant current mechanistic framework. (mizuta2024progresstoclarify pages 1-2)	Provides current expert consensus for the field: disease-modifying strategies will likely need to target early N3ECD aggregation/vascular injury, not just downstream stroke consequences.

Table: This table compiles recent quantitative and clinically actionable findings in CADASIL, emphasizing cohort sizes, exact effect estimates, and why each study matters for prognosis, diagnosis, and trial design.

Expert analysis and current gaps (2023–2024 emphasis)

1) Variant position and risk categorization are now central to prognosis and trial design. Large cohorts show EGFr 1–6 vs 7–34 effects on severity, and 2024 prospective data show that risk category predicts 2-year clinical and MRI progression (including incident stroke HR 4.3 for HR vs MR). (cerfontaine2024associationofnotch3 pages 1-2, dupe2023phenotypicvariabilityin pages 1-2) 2) A key upstream mechanistic gap remains: despite strong evidence that N3ECD aggregation and GOM are core to pathogenesis, the “process leading to N3ECD accumulation” remains unresolved, complicating rational targeting for disease-modifying therapies. (mizuta2024progresstoclarify pages 1-2) 3) Real-world diagnosis and early-stage identification are increasingly operationalized via NGS testing and longitudinal biomarker studies. Diagnostic laboratories report improved detection with targeted NGS panels, while large observational studies now recruit pre-symptomatic carriers to define early biomarkers and endpoints. (dunn2020investigatingdiagnosticsequencing pages 1-2, NCT05677880 chunk 1)

URLs and publication dates (from retrieved sources)

Cerfontaine et al., Neurology — published 2024-05 (DOI landing): https://doi.org/10.1212/WNL.0000000000209310 (cerfontaine2024associationofnotch3 pages 1-2)
Dupé et al., J Cereb Blood Flow Metab — 2023-10: https://doi.org/10.1177/0271678X221126280 (dupe2023phenotypicvariabilityin pages 1-2)
Mizuta et al., Biomolecules — published 2024-01-18: https://doi.org/10.3390/biom14010127 (mizuta2024progresstoclarify pages 1-2)
Sukhonpanich & Markus, Journal of Neurology — published online 2024-01-13: https://doi.org/10.1007/s00415-023-12177-0 (sukhonpanich2024prevalenceclinicalcharacteristics pages 1-2)
Pan et al., Frontiers in Neurology — published 2023-07-14: https://doi.org/10.3389/fneur.2023.1203985 (pan2023lifelongcerebrovasculardisease pages 1-2)
Dunn et al., Human Genomics — 2020-01: https://doi.org/10.1186/s40246-019-0255-x (dunn2020investigatingdiagnosticsequencing pages 1-2)
Nogueira et al., Arquivos de Neuro-Psiquiatria — published online 2023-05-08: https://doi.org/10.1055/s-0042-1758756 (nogueira2023clinicalandepidemiological pages 1-2)
Boston et al., Cerebral Circulation - Cognition and Behavior — 2024-06-03: https://doi.org/10.1016/j.cccb.2024.100227 (boston2024mostcommonnotch3 pages 1-2)
ClinicalTrials.gov NCT05677880 — first posted 2023-01-10: https://clinicaltrials.gov/study/NCT05677880 (NCT05677880 chunk 1)
ClinicalTrials.gov NCT05072483 — first posted 2021-10-11: https://clinicaltrials.gov/study/NCT05072483 (NCT05072483 chunk 1)

References

(cerfontaine2024associationofnotch3 pages 1-2): Minne N. Cerfontaine, Remco J. Hack, Benno Gesierich, Marco Duering, Marie-Noëlle W. Witjes-Ané, Mar Rodríguez-Girondo, Gido Gravesteijn, Julie Rutten, and Saskia A.J. Lesnik Oberstein. Association of notch3 variant risk category with 2-year clinical and radiologic small vessel disease progression in patients with cadasil. Neurology, May 2024. URL: https://doi.org/10.1212/wnl.0000000000209310, doi:10.1212/wnl.0000000000209310. This article has 12 citations and is from a highest quality peer-reviewed journal.
(papakonstantinou2019notch3andcadasil pages 1-3): Eleni Papakonstantinou, Flora Bacopoulou, Dimitrios Brouzas, Vasileios Megalooikonomou, Domenica D'Elia, Erik Bongcam-Rudloff, and Dimitrios Vlachakis. Notch3 and cadasil syndrome: a genetic and structural overview. EMBnet.journal, 24:e921, May 2019. URL: https://doi.org/10.14806/ej.24.0.921, doi:10.14806/ej.24.0.921. This article has 50 citations.
(bersano2017cadasiltreatmentand pages 1-3): Anna Bersano, Gloria Bedini, Joshua Oskam, Caterina Mariotti, Franco Taroni, Silvia Baratta, and Eugenio Agostino Parati. Cadasil: treatment and management options. Current Treatment Options in Neurology, 19:1-15, Jul 2017. URL: https://doi.org/10.1007/s11940-017-0468-z, doi:10.1007/s11940-017-0468-z. This article has 58 citations and is from a peer-reviewed journal.
(mizuta2024progresstoclarify pages 1-2): Ikuko Mizuta, Yumiko Nakao-Azuma, Hideki Yoshida, Masamitsu Yamaguchi, and Toshiki Mizuno. Progress to clarify how notch3 mutations lead to cadasil, a hereditary cerebral small vessel disease. Biomolecules, 14:127, Jan 2024. URL: https://doi.org/10.3390/biom14010127, doi:10.3390/biom14010127. This article has 25 citations.
(hu2021notch3variantsand pages 1-2): Yacen Hu, Qiying Sun, Yafang Zhou, Fang Yi, Haiyun Tang, Lingyan Yao, Yun Tian, Nina Xie, Mengchuan Luo, Zhiqin Wang, Xinxin Liao, Hongwei Xu, and Lin Zhou. Notch3 variants and genotype-phenotype features in chinese cadasil patients. Frontiers in Genetics, Jul 2021. URL: https://doi.org/10.3389/fgene.2021.705284, doi:10.3389/fgene.2021.705284. This article has 39 citations and is from a peer-reviewed journal.
(pan2023lifelongcerebrovasculardisease pages 1-2): Alan P. Pan, Thomas Potter, Abdulaziz Bako, Jonika Tannous, Sudha Seshadri, Louise D. McCullough, and Farhaan S. Vahidy. Lifelong cerebrovascular disease burden among cadasil patients: analysis from a global health research network. Frontiers in Neurology, Jul 2023. URL: https://doi.org/10.3389/fneur.2023.1203985, doi:10.3389/fneur.2023.1203985. This article has 13 citations and is from a peer-reviewed journal.
(dupe2023phenotypicvariabilityin pages 1-2): Charlotte Dupé, Stéphanie Guey, Lucie Biard, Sokhna Dieng, Jessica Lebenberg, Lina Grosset, Nassira Alili, Dominique Hervé, Elisabeth Tournier-Lasserve, Eric Jouvent, Sylvie Chevret, and Hugues Chabriat. Phenotypic variability in 446 cadasil patients: impact of notch3 gene mutation location in addition to the effects of age, sex and vascular risk factors. Journal of Cerebral Blood Flow & Metabolism, 43:153-166, Oct 2023. URL: https://doi.org/10.1177/0271678x221126280, doi:10.1177/0271678x221126280. This article has 40 citations and is from a highest quality peer-reviewed journal.
(kaisaridi2025determiningclinicaldisease pages 1-5): Sofia Kaisaridi, Dominique Herve, Aude Jabouley, Sonia Reyes, Carla Machado, Stéphanie Guey, Abbas Taleb, Fanny Fernandes, Hugues Chabriat, and Sophie Tezenas Du Montcel. Determining clinical disease progression in symptomatic patients with cadasil. Neurology, Jan 2025. URL: https://doi.org/10.1212/wnl.0000000000210193, doi:10.1212/wnl.0000000000210193. This article has 3 citations and is from a highest quality peer-reviewed journal.
(cao2024phenotypesassociatedwith pages 13-14): Yuan Cao, Ding-Ding Zhang, Fei Han, Nan Jiang, Ming Yao, and Yi-Cheng Zhu. Phenotypes associated with notch3 cysteine-sparing mutations in patients with clinical suspicion of cadasil: a systematic review. International Journal of Molecular Sciences, 25:8796, Aug 2024. URL: https://doi.org/10.3390/ijms25168796, doi:10.3390/ijms25168796. This article has 7 citations.
(sukhonpanich2024prevalenceclinicalcharacteristics pages 1-2): Nontapat Sukhonpanich and Hugh S. Markus. Prevalence, clinical characteristics, and risk factors of intracerebral haemorrhage in cadasil: a case series and systematic review. Journal of Neurology, 271:2423-2433, Jan 2024. URL: https://doi.org/10.1007/s00415-023-12177-0, doi:10.1007/s00415-023-12177-0. This article has 13 citations and is from a domain leading peer-reviewed journal.
(nogueira2023clinicalandepidemiological pages 1-2): Renata Nogueira, Christian Marques Couto, Pérola de Oliveira, Bernardo José Alves Ferreira Martins, and Vinícius Viana Abreu Montanaro. Clinical and epidemiological profiles from a case series of 26 brazilian cadasil patients. Arquivos de Neuro-Psiquiatria, 81:417-425, May 2023. URL: https://doi.org/10.1055/s-0042-1758756, doi:10.1055/s-0042-1758756. This article has 10 citations and is from a peer-reviewed journal.
(boston2024mostcommonnotch3 pages 1-2): Georgina Boston, Dan Jobson, Toshiki Mizuno, Masafumi Ihara, and Raj N Kalaria. Most common notch3 mutations causing cadasil or cadasil-like cerebral small vessel disease: a systematic review. Cerebral Circulation - Cognition and Behavior, 6:100227, Jun 2024. URL: https://doi.org/10.1016/j.cccb.2024.100227, doi:10.1016/j.cccb.2024.100227. This article has 31 citations.
(akrich2024geneticdiagnosisof pages 1-2): Madeleine Akrich, Vololona Rabeharisoa, Florence Paterson, and Hugues Chabriat. Genetic diagnosis of individuals at risk of cadasil: prospect for future therapeutic development. Journal of Neurology, 271:6912-6922, Sep 2024. URL: https://doi.org/10.1007/s00415-024-12640-6, doi:10.1007/s00415-024-12640-6. This article has 4 citations and is from a domain leading peer-reviewed journal.
(dunn2020investigatingdiagnosticsequencing pages 1-2): P. J. Dunn, N. Maksemous, R. A. Smith, H. G. Sutherland, L. M. Haupt, and L. R. Griffiths. Investigating diagnostic sequencing techniques for cadasil diagnosis. Human Genomics, Jan 2020. URL: https://doi.org/10.1186/s40246-019-0255-x, doi:10.1186/s40246-019-0255-x. This article has 23 citations and is from a peer-reviewed journal.
(dupe2023phenotypicvariabilityin media cdee29b5): Charlotte Dupé, Stéphanie Guey, Lucie Biard, Sokhna Dieng, Jessica Lebenberg, Lina Grosset, Nassira Alili, Dominique Hervé, Elisabeth Tournier-Lasserve, Eric Jouvent, Sylvie Chevret, and Hugues Chabriat. Phenotypic variability in 446 cadasil patients: impact of notch3 gene mutation location in addition to the effects of age, sex and vascular risk factors. Journal of Cerebral Blood Flow & Metabolism, 43:153-166, Oct 2023. URL: https://doi.org/10.1177/0271678x221126280, doi:10.1177/0271678x221126280. This article has 40 citations and is from a highest quality peer-reviewed journal.
(NCT05677880 chunk 1): Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Study. University of Wisconsin, Madison. 2022. ClinicalTrials.gov Identifier: NCT05677880
(NCT05072483 chunk 1): Natural History Study of CADASIL. National Heart, Lung, and Blood Institute (NHLBI). 2022. ClinicalTrials.gov Identifier: NCT05072483
(dupe2023phenotypicvariabilityin pages 2-3): Charlotte Dupé, Stéphanie Guey, Lucie Biard, Sokhna Dieng, Jessica Lebenberg, Lina Grosset, Nassira Alili, Dominique Hervé, Elisabeth Tournier-Lasserve, Eric Jouvent, Sylvie Chevret, and Hugues Chabriat. Phenotypic variability in 446 cadasil patients: impact of notch3 gene mutation location in addition to the effects of age, sex and vascular risk factors. Journal of Cerebral Blood Flow & Metabolism, 43:153-166, Oct 2023. URL: https://doi.org/10.1177/0271678x221126280, doi:10.1177/0271678x221126280. This article has 40 citations and is from a highest quality peer-reviewed journal.

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Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Source YAML

References & Deep Research

References

Deep Research

CADASIL Type 1 (NOTCH3-related) — Disease Characteristics Research Report

1. Disease information

1.1 Concise overview

1.2 Key identifiers and synonyms (from retrieved evidence)

1.3 Source types for disease definition

2. Etiology

2.1 Disease causal factors

2.2 Risk factors (genetic and non-genetic modifiers)

2.3 Protective factors and gene–environment interaction

3. Phenotypes (with suggested HPO terms)

3.1 Core phenotype spectrum

3.2 Quantitative phenotype frequencies from recent cohorts/case series

3.3 MRI phenotype (selected frequencies)

4. Genetic/molecular information

4.1 Causal gene

4.2 Pathogenic variants and variant classes

4.3 Genotype–phenotype correlations

4.4 Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 Causal chain (current understanding)

6.2 Cellular/tissue context

6.3 Molecular pathways and processes (GO suggestions)

6.4 Recent mechanistic emphasis (2024)

7. Anatomical structures affected

7.1 Organ/system level

7.2 Tissue/cell level

7.3 Subcellular level

8. Temporal development

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology and prevalence

9.3 Sex differences (real-world EMR data)

10. Diagnostics

10.1 Genetic testing (current implementation)

10.2 Skin biopsy / pathology

10.3 MRI and imaging markers

11. Outcome / prognosis

12. Treatment

12.1 Current standard of care (symptomatic/risk management)

12.2 Antithrombotic considerations (evidence relevant to practice)

12.3 Clinical trials and observational research (real-world implementation)

13. Prevention

14. Other species / natural disease

15. Model organisms and experimental models

Recent quantitative findings (2023–2024)

Expert analysis and current gaps (2023–2024 emphasis)

URLs and publication dates (from retrieved sources)