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PubMed This is a summary of 13 peer-reviewed journal articles Updated
Neurology

The NOTCH3 Gene and How CADASIL Works

At a Glance

CADASIL is caused by a mutation in the NOTCH3 gene that makes proteins clump on the walls of small brain blood vessels. This makes the vessels stiff and prone to blockage or small strokes. As a genetic condition, there is a 50% chance of passing it to children.

Understanding the biology of CADASIL helps shift the perspective from a mysterious illness to a manageable genetic condition. At its core, CADASIL is a disease of the brain’s “plumbing,” caused by a single instruction error in your DNA [1].

The NOTCH3 Mutation: A Protein Misstep

The NOTCH3 gene provides the blueprint for a protein that is essential for the health of your vascular smooth muscle cells (VSMCs) [2]. These cells wrap around your small blood vessels like a muscular sleeve, helping them constrict and relax to control blood flow [1].

In CADASIL, the mutation usually causes a change in a specific building block called cysteine [3]. This error makes the NOTCH3 protein “sticky.” Instead of doing its job, the protein breaks and clumps together on the outside of the muscle cells [4][5]. Over time, these clumps form dark, grainy deposits that doctors call GOM (Granular Osmiophilic Material) [6][7].

How Vessels Lose Their Way

As these protein clumps (GOM) accumulate, the blood vessels in your brain undergo two major changes:

  1. Loss of Elasticity: The vessels become stiff and “crunchy” rather than flexible. They lose their ability to expand when your brain needs more oxygen [1][8].
  2. Wall Degeneration: The muscle cells that line the vessels begin to die off [9]. This weakens the vessel wall, making it prone to two different problems:
    • Ischemia (Blockage): The vessel wall becomes so thick that the opening (lumen) narrows, eventually blocking blood flow and causing a small “lacunar” stroke [8][10].
    • Microbleeds (Leakage): The weakened wall can develop tiny leaks, leading to “microbleeds” that doctors can see on specialized MRI scans [11][12].

CADASIL vs. “Regular” Stroke

It is a common misunderstanding that CADASIL is the same as the strokes most people hear about. They are biologically very different:

Feature CADASIL Strokes “Regular” (Atherosclerotic) Strokes
Root Cause A structural failure of the vessel wall itself due to the faulty NOTCH3 protein [1]. Caused by plaque—a buildup of fat and cholesterol inside the vessel [1].
Location Tiny, deep small vessels of the brain [2]. Larger arteries in the neck or brain [1].
Primary Drivers Genetics (NOTCH3 mutation) [1]. Diet, lack of exercise, high cholesterol, lifestyle factors [1].

Family Planning and Pregnancy Risks

CADASIL follows an autosomal dominant inheritance pattern, which means if one parent has the gene, there is a 50% chance of passing it to each child [1]. This does not skip generations [1].

For individuals in their childbearing years, this diagnosis brings up crucial considerations:

  • Family Planning Pathways: You have medical options to have children without passing on the NOTCH3 mutation. Techniques like Preimplantation Genetic Testing for Monogenic disorders (PGT-M) used alongside IVF allow doctors to screen embryos for the mutation before pregnancy [13].
  • Pregnancy Safety: Because CADASIL causes structural changes to your blood vessels, the major cardiovascular shifts that occur during pregnancy can put extra stress on your body. If you become pregnant, it is vital to have your care managed by a high-risk Maternal-Fetal Medicine (MFM) specialist to closely monitor your blood pressure and vascular health.

Common questions in this guide

How does the NOTCH3 gene mutation cause CADASIL?
The mutation makes the NOTCH3 protein clump together on the outside of the muscle cells of small blood vessels in the brain. Over time, these clumps cause the vessels to become stiff and degenerate, restricting blood flow and leading to small strokes.
Is a CADASIL stroke the same as a regular stroke?
No, they are biologically very different. Regular strokes are usually caused by a buildup of plaque inside larger arteries. CADASIL strokes happen in tiny, deep brain vessels because of a genetic structural failure in the vessel wall itself.
What is the chance I will pass CADASIL to my children?
CADASIL is an autosomal dominant condition, meaning if one parent has the gene, there is a 50% chance of passing the NOTCH3 mutation to each child. This inheritance pattern does not skip generations.
Can I have children without passing on the CADASIL gene?
Yes. Medical techniques like Preimplantation Genetic Testing (PGT-M) paired with in vitro fertilization (IVF) can screen embryos for the NOTCH3 mutation before pregnancy. This allows individuals to have children who will not inherit the disease.
Is it safe to get pregnant if I have CADASIL?
Pregnancy causes major cardiovascular changes that can put extra stress on blood vessels weakened by CADASIL. It is highly recommended to have your pregnancy managed by a high-risk Maternal-Fetal Medicine specialist to closely monitor your vascular health.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Exactly how does the NOTCH3 mutation affect the proteins in my blood vessels?
  2. 2.Is my specific mutation one that alters a 'cysteine' residue, and what does that mean for my prognosis?
  3. 3.Since this is 'autosomal dominant,' at what age should my children or siblings consider genetic testing or counseling?
  4. 4.What are my options for family planning, such as PGT-M or IVF, if I want to ensure I don't pass the gene to my future children?
  5. 5.If I become pregnant, will the vascular changes in my body require monitoring by a high-risk maternal-fetal medicine specialist?

Questions For You

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References

References (13)
  1. 1

    Cadasil syndrome: A case report with a literature review.

    Lahkim M, Laamrani FZ, Andour H, et al.

    Radiology case reports 2021; (16(11)):3540-3543 doi:10.1016/j.radcr.2021.08.023.

    PMID: 34584593
  2. 2

    Role of NOTCH3 Mutations in the Cerebral Small Vessel Disease Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

    Coupland K, Lendahl U, Karlström H

    Stroke 2018; (49(11)):2793-2800 doi:10.1161/STROKEAHA.118.021560.

    PMID: 30355220
  3. 3

    Top-NOTCH3 Variants in the Population at Large.

    Kalaria RN, Kittner SJ

    Stroke 2020; (51(12)):3482-3484 doi:10.1161/STROKEAHA.120.031609.

    PMID: 33161845
  4. 4

    Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases.

    Schoemaker D, Arboleda-Velasquez JF

    The American journal of pathology 2021; (191(11)):1856-1870 doi:10.1016/j.ajpath.2021.03.015.

    PMID: 33895122
  5. 5

    The role of NOTCH3 in CADASIL pathogenesis: insights into novel therapies.

    Felix-Ilemhenbhio F, Kocsy K, Azzouz M, Majid A

    Brain research 2025; (1863()):149754 doi:10.1016/j.brainres.2025.149754.

    PMID: 40456481
  6. 6

    Most common NOTCH3 mutations causing CADASIL or CADASIL-like cerebral small vessel disease: A systematic review.

    Boston G, Jobson D, Mizuno T, et al.

    Cerebral circulation - cognition and behavior 2024; (6()):100227 doi:10.1016/j.cccb.2024.100227.

    PMID: 38966425
  7. 7

    Clinical presentation of Y189C mutation of the NOTCH3 gene in the Polish family with CADASIL.

    Dorszewska J, Kowalska M, Grzegorski T, et al.

    Folia neuropathologica 2020; (58(1)):83-92 doi:10.5114/fn.2020.94009.

    PMID: 32337960
  8. 8

    Acute bilateral multiple subcortical infarcts as manifestation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

    Huang H, Xie W, Hu F, et al.

    Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2023; (44(12)):4391-4399 doi:10.1007/s10072-023-06949-9.

    PMID: 37458844
  9. 9

    ER stress and Rho kinase activation underlie the vasculopathy of CADASIL.

    Neves KB, Harvey AP, Moreton F, et al.

    JCI insight 2019; (4(23)).

    PMID: 31647781
  10. 10

    Mechanisms regulating cerebral hypoperfusion in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

    Yan X, Shang J, Wang R, et al.

    Journal of biomedical research 2022; (36(5)):353-357 doi:10.7555/JBR.36.20220208.

    PMID: 36165325
  11. 11

    Intracerebral Hemorrhage in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Prevalence, Clinical and Neuroimaging Features and Risk Factors.

    Liao YC, Hu YC, Chung CP, et al.

    Stroke 2021; (52(3)):985-993 doi:10.1161/STROKEAHA.120.030664.

    PMID: 33535780
  12. 12

    Occurrence of Intracranial Hemorrhage and Associated Risk Factors in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: A Systematic Review and Meta-Analysis.

    Lai QL, Zhang YX, Wang JJ, et al.

    Journal of clinical neurology (Seoul, Korea) 2022; (18(5)):499-506 doi:10.3988/jcn.2022.18.5.499.

    PMID: 36062766
  13. 13

    Hereditary Haemorrhagic Cerebrovascular Disease: Implications for Clinical Management.

    Hou W, Hou Y, Ren X, Liu J

    Annals of neurosciences 2025; 09727531241308346 doi:10.1177/09727531241308346.

    PMID: 40115281

This page explains the biology and inheritance of CADASIL for educational purposes only. Always consult a genetic counselor or neurologist regarding your specific mutation and family planning options.

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