CADASIL — Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

CADASIL is the most common inherited cause of stroke and vascular dementia in adults. It is caused by mutations in the NOTCH3 gene that damage small blood vessels deep in the brain, producing a characteristic pattern of white matter injury, recurrent strokes, and progressive decline — all beginning decades before old age. Yet because it is rare and its early symptoms (migraine with aura, mood disturbances) overlap with everyday conditions, the average diagnosis takes many years from first symptoms. If you or a family member has unexplained early strokes, a family history of dementia or stroke before age 60, and migraines with aura, this page explains the biology, what doctors should be looking for, what the MRI will show, and what can be done to reduce harm and protect other family members.

Table of Contents

1. What Is CADASIL and What Causes It?
2. The NOTCH3 Mutation and Vascular Pathology
3. Clinical Features and Disease Progression
4. MRI Findings — The Diagnostic Fingerprint
5. How CADASIL Is Diagnosed
6. Management and Treatment
7. Inheritance, Genetic Counseling, and Family Testing
8. Prognosis and Long-Term Outlook
9. Key Research Papers
10. Connections
11. Featured Videos

What Is CADASIL and What Causes It?

CADASIL stands for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. The name contains the entire disease summary: it is a disorder of small brain arteries (arteriopathy) caused by a dominant gene mutation (one defective copy is enough to cause disease) that produces small, deep brain infarcts (subcortical infarcts) and widespread damage to the brain's white matter (leukoencephalopathy). The condition was first fully characterized in 1993 by Tournier-Laprize and colleagues and the causative gene, NOTCH3, was identified in 1996.

CADASIL affects small and medium penetrating arteries throughout the body, but the brain is by far the most vulnerable organ because it depends so critically on a continuous, precisely regulated blood supply. The arteries most affected are those that supply the deep white matter — the vast network of insulated nerve-fiber tracts that connect different regions of the cerebral cortex with each other and with subcortical structures. When these small arteries fail, the white matter they supply undergoes a slow ischemic injury over years and decades.

The estimated prevalence is approximately 2–5 per 100,000, but many cases go undiagnosed, and some studies suggest the true prevalence may be several times higher. The disease is found in all ethnic groups worldwide. Because it is autosomal dominant, each child of an affected parent has a 50% chance of inheriting the mutation and ultimately developing the disease.

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The NOTCH3 Mutation and Vascular Pathology

The NOTCH3 gene encodes a large cell-surface receptor protein involved in regulating vascular smooth muscle cell differentiation and survival. The NOTCH3 receptor has a series of EGF-like (epidermal growth factor-like) repeating domains in its extracellular portion. CADASIL mutations — of which more than 300 distinct mutations have been identified — all share one key feature: they add or remove a cysteine residue in one of these EGF-like domains (specifically, in EGF-like domains 1 through 34).

The addition or subtraction of a cysteine disrupts the precise disulfide bond pairing that holds each EGF-like domain in its correct three-dimensional shape. The resulting misfolded NOTCH3 extracellular domain (ECD) accumulates on the surface of vascular smooth muscle cells and pericytes instead of being properly processed. Over time, this NOTCH3 ECD deposits in the walls of small arteries throughout the body — it can even be detected in blood vessels of the skin, muscle, and peripheral nerves, which is why a skin biopsy can sometimes diagnose CADASIL.

The downstream consequences in the brain's small arteries include:

• Vascular smooth muscle cell loss — the smooth muscle cells that control vessel diameter and blood flow regulation progressively degenerate, leaving the vessel wall unable to autoregulate blood supply properly.
• Thickening and fibrosis of vessel walls — the walls of affected arteries become thickened, fibrotic, and tortuous. The lumen (the channel through which blood flows) narrows.
• Granular osmiophilic material (GOM) — electron microscopy of affected arteries reveals dense deposits of abnormal material (called GOM deposits) adjacent to smooth muscle cells. This finding is considered pathognomonic of CADASIL and can be identified in skin biopsies.
• Loss of cerebrovascular reactivity — the brain normally dilates blood vessels in response to increased neural activity and constricts them when activity is lower. In CADASIL, this neurovascular coupling is impaired, making the brain vulnerable to even transient blood pressure drops and to physiological stressors like dehydration, fever, or low oxygen.

The net result is a progressive reduction in blood flow to the brain's white matter, producing areas of ischemia, small complete infarcts, and eventual widespread white matter signal change on MRI — all while the brain's larger arteries and the cortex itself are largely spared.

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Clinical Features and Disease Progression

CADASIL follows a characteristic clinical trajectory across the lifespan, though the timing and severity vary considerably even within the same family carrying the same mutation. The disease unfolds in overlapping phases.

Migraine with Aura (Age 20s–30s — Often the First Symptom)

Migraine with aura is the earliest and most common initial manifestation, affecting approximately 35% of CADASIL patients and typically beginning in the 20s or 30s. The auras can be visual (zig-zag fortification spectra, scotomata), sensory, aphasic, or motor. Some patients experience unusually severe, prolonged, or treatment-resistant migraines. Importantly, migraine with aura is also common in the general population — so its presence alone does not suggest CADASIL. However, in someone with a family history of early stroke or dementia, early-onset migraine with aura should prompt consideration of CADASIL evaluation.

Transient Ischemic Attacks and Subcortical Strokes (Age 40s–50s)

The hallmark of CADASIL is recurrent ischemic events — TIAs and subcortical lacunar infarcts — in the absence of traditional cardiovascular risk factors. The average age of first stroke or TIA is around 45 years. Because the affected vessels are small penetrating arteries rather than large arteries, the strokes produce classical lacunar syndromes:

• Pure motor hemiparesis — weakness of one side without sensory loss or language disturbance, from a small infarct in the internal capsule or pons.
• Pure sensory stroke — unilateral sensory loss, from a thalamic or internal capsule lacune.
• Dysarthria-clumsy hand syndrome — slurred speech plus clumsiness of one hand, from a small pontine or internal capsule infarct.
• Ataxic hemiparesis — limb weakness combined with ipsilateral cerebellar-like clumsiness.

These events accumulate over years, and while each individual infarct may produce only mild or transient symptoms, their cumulative effect produces steadily worsening neurological function.

Cognitive Impairment and Executive Dysfunction (Age 50s–60s)

Cognitive decline in CADASIL is predominantly a subcortical pattern, reflecting white matter disconnection rather than cortical neuron death. The most prominent early deficits are in executive function — the ability to plan, organize, multitask, and shift attention — and in processing speed. Memory is affected but tends to be less severely impaired than in Alzheimer's disease, and the pattern is one of retrieval difficulty (information encoded but hard to access) rather than complete failure to store new memories.

Neuropsychiatric symptoms are common and include depression (present in up to 50% of patients), apathy (distinct from depression — a loss of motivation and initiation without sadness), and in later stages, emotional lability and pseudobulbar affect (involuntary laughing or crying disproportionate to emotional state).

Dementia and Pseudobulbar Palsy (Advanced Disease)

In the advanced stage, typically reaching in the 60s though highly variable, the cumulative white matter injury and lacunar strokes produce frank dementia. Pseudobulbar palsy — difficulty swallowing (dysphagia), dysarthria, drooling, and exaggerated jaw jerk reflex, caused by bilateral injury to the corticobulbar tracts — appears in many patients with advanced disease. Gait disturbance becomes prominent as subcortical motor pathways are disrupted; patients develop a slow, shuffling gait with small steps (marche à petit pas) that resembles Parkinson's disease but does not respond to dopaminergic therapy. Urinary incontinence is common. Dependency and eventual immobility follow.

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MRI Findings — The Diagnostic Fingerprint

Brain MRI in CADASIL has a distinctive and highly characteristic appearance that should raise strong suspicion for the diagnosis even before genetic testing. The abnormalities are best seen on FLAIR (fluid-attenuated inversion recovery) and T2-weighted sequences.

White Matter Hyperintensities

Extensive, confluent areas of bright signal on FLAIR/T2 sequences in the deep white matter are the most obvious finding. Unlike age-related white matter changes (which are patchy and periventricular in early stages), CADASIL white matter disease is more extensive and involves specific regions that are highly predictive:

Anterior Temporal Pole — The Key Diagnostic Clue

Involvement of the anterior temporal poles (the tips of the temporal lobes) is the single most diagnostically useful MRI finding in CADASIL. White matter signal change in this region is present in the vast majority of CADASIL patients and is unusual in other causes of white matter disease — including hypertensive leukoencephalopathy, multiple sclerosis, and Binswanger disease. Its presence in a patient with suspected white matter disease should trigger CADASIL genetic testing.

External Capsule Involvement

Signal change in the external capsule (a white matter structure lateral to the basal ganglia, separate from the internal capsule) is also characteristic of CADASIL. Combined anterior temporal pole and external capsule involvement has high sensitivity and specificity for CADASIL among all hereditary small vessel diseases.

Lacunar Infarcts

Multiple small, punched-out areas of completed infarction (dark on T1, bright on T2/FLAIR, with DWI restriction in acute phase) are seen in the basal ganglia, thalamus, internal capsule, brainstem, and centrum semiovale. Their number correlates with clinical disability and cognitive impairment.

Microbleeds

Cerebral microbleeds — tiny foci of old hemorrhage best seen on susceptibility-weighted imaging (SWI) or gradient echo sequences — are found in approximately 25–38% of CADASIL patients and increase in number over time. Their presence indicates severe small vessel disease and is a marker of higher risk for symptomatic intracerebral hemorrhage. This has important implications for antiplatelet and anticoagulant decisions.

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How CADASIL Is Diagnosed

Diagnosis rests on a combination of clinical history, family history, MRI findings, and genetic confirmation. The diagnostic pathway typically proceeds as follows:

Clinical Suspicion

CADASIL should be considered in any patient with: recurrent subcortical ischemic strokes or TIAs before age 60 without traditional risk factors (no hypertension, no atrial fibrillation, no carotid disease, no diabetes, non-smoker); MRI showing white matter disease disproportionate to age or risk factors — especially with anterior temporal pole or external capsule involvement; a family history of similar strokes, dementia, or premature neurological decline; or migraine with aura in conjunction with any of the above.

Genetic Testing — NOTCH3 Sequencing

NOTCH3 gene sequencing is the gold-standard diagnostic test. Most diagnostic laboratories sequence the entire coding region or specifically screen exons 2–24, which encode the EGF-like domains where pathogenic cysteine mutations cluster. A cysteine-altering missense mutation in an EGF-like domain is considered diagnostic. Pathogenic variants can also be found in exons outside this range, so comprehensive sequencing is preferred. Testing should be offered to all first-degree relatives of confirmed cases, given the 50% inheritance risk.

Skin Biopsy

Before genetic testing became widely available, skin biopsy with electron microscopy looking for granular osmiophilic material (GOM) deposits adjacent to vascular smooth muscle cells was the primary diagnostic method. It remains a useful confirmatory test — particularly in atypical cases or where genetic testing is unavailable — but its sensitivity depends heavily on biopsy technique and laboratory experience. An NOTCH3 immunostain on the biopsy can detect accumulated NOTCH3 extracellular domain even when GOM is not conclusive.

Neuropsychological Testing

Formal neuropsychological evaluation characterizes the pattern and severity of cognitive impairment, documents baseline function, tracks progression, and guides decisions about driving, work capacity, and daily function. Subcortical cognitive profile (executive dysfunction + processing speed >> memory) is expected but must be formally documented.

Differential Diagnosis

Other conditions that can mimic CADASIL include: multiple sclerosis (periventricular white matter lesions; younger women; optic neuritis; relapsing-remitting course; anti-MOG or anti-AQP4 antibodies); hypertensive leukoencephalopathy (confluent white matter change, but posterior predominance and typically spares anterior temporal poles); cerebral amyloid angiopathy (cortical/subcortical microbleeds + lobar hemorrhages; older patients; amyloid-PET positive); MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes; young patients; elevated lactate; ragged red fibers; stroke-like episodes in cortex, not subcortical; maternal inheritance); Fabry disease (lysosomal storage disorder; alpha-galactosidase deficiency; early strokes + posterior circulation; acroparesthesias + angiokeratomas; elevated lyso-Gb3).

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Management and Treatment

There is currently no disease-modifying treatment that slows or reverses the vascular degeneration caused by NOTCH3 mutations. Management focuses on stroke prevention, symptom treatment, risk factor modification, and preserving quality of life. This is an area of active research, with several trials underway targeting the NOTCH3 pathway directly.

Antiplatelet Therapy for Stroke Prevention

Aspirin (75–100 mg daily) is the most widely used antiplatelet agent in CADASIL for prevention of recurrent ischemic events, by analogy with its use in other ischemic stroke syndromes. However, the evidence base specific to CADASIL is limited — it has not been tested in randomized controlled trials in this specific disease. Given the high rate of microbleeds in CADASIL (25–38%), which signals risk for intracerebral hemorrhage, the risk-benefit balance of antiplatelet therapy must be weighed individually. Patients with numerous microbleeds may be at higher hemorrhagic risk, and the decision to use aspirin should take into account the microbleed burden on MRI. Dual antiplatelet therapy and anticoagulation are generally avoided unless there is a coexisting cardiac indication, because they amplify hemorrhagic risk without established additional benefit in CADASIL-specific ischemia.

Avoid Oral Contraceptives and Smoking

Combined oral contraceptive pills (estrogen + progestogen) substantially increase stroke risk in women who already carry a genetic predisposition to small vessel disease, and they are contraindicated in CADASIL. Progestogen-only methods and non-hormonal contraception are safer. Smoking accelerates vascular damage and should be strongly discouraged and actively supported with cessation resources. These are among the highest-yield modifiable exposures in CADASIL management.

Blood Pressure Control

Although classic CADASIL does not require hypertension to progress (the arteriopathy is genetically driven), hypertension worsens small vessel disease and accelerates white matter injury. Blood pressure targets in CADASIL should be in the normal range (<130/80 mmHg for most patients). Even patients without overt hypertension benefit from regular monitoring and aggressive lifestyle management.

Migraine Management

Migraine treatment in CADASIL requires caution. Triptans and ergotamine derivatives cause vasoconstriction and are generally avoided or used with caution in CADASIL because vasoconstriction in already-vulnerable small brain arteries could theoretically trigger an ischemic event (though robust clinical evidence for harm from triptans specifically in CADASIL is limited). Non-vasoconstricting preventive therapies — such as topiramate, amitriptyline, and propranolol — are preferred. Acute attacks can be treated with NSAIDs and antiemetics.

Cognitive and Psychiatric Symptom Management

Depression and apathy are common and treatable. SSRIs (selective serotonin reuptake inhibitors) are first-line for depression. Apathy — the specific syndrome of reduced motivation and initiation — does not reliably respond to SSRIs (which may worsen it) and may benefit from stimulant-class approaches (methylphenidate) or dopaminergic agents, though evidence in CADASIL specifically is scarce. Cognitive rehabilitation, occupational therapy, and memory strategies can improve function and quality of life even when structural disease is progressive.

Lifestyle and Vascular Risk Factor Management

Regular aerobic exercise improves cerebrovascular health and has been shown in observational data to slow white matter progression in vascular cognitive impairment generally. Maintaining healthy weight, avoiding sleep apnea (which causes repeated nocturnal hypoxia and exacerbates cerebrovascular stress), and ensuring adequate hydration (dehydration impairs cerebral perfusion in CADASIL's dysfunctional small arteries) are practical, accessible interventions.

Experimental and Emerging Therapies

Notch3 pathway modulation is the subject of active preclinical and early clinical research. One approach involves reducing mutant NOTCH3 ECD accumulation. Genetic therapies targeting NOTCH3 expression are in development. A Phase 2 trial of a monoclonal antibody targeting the mutant NOTCH3 ECD (to prevent its pathological accumulation) has shown biomarker promise. Patients with confirmed CADASIL should be encouraged to seek care at academic medical centers where clinical trial participation is possible.

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Inheritance, Genetic Counseling, and Family Testing

CADASIL is transmitted as an autosomal dominant condition — which means a single copy of the mutant NOTCH3 gene is sufficient to cause disease, and an affected person has a 50% chance of passing the mutation to each child, regardless of the child's sex. There is no skipping of generations: if a person carries the mutation, they will develop the disease if they live long enough, though the timing and severity are variable.

Genetic counseling is an essential part of CADASIL management. Key elements include:

• Testing of first-degree relatives — parents, siblings, and children of a confirmed CADASIL patient each have 50% probability of carrying the mutation. Testing should be offered proactively, as asymptomatic carriers can take preventive measures (contraception, smoking cessation, blood pressure control) decades before symptoms develop.
• Pre-symptomatic testing — relatives who want to know their status before symptoms appear should receive pre-test and post-test counseling from a certified genetic counselor, because a positive result carries significant psychological, financial, and insurance implications.
• Prenatal and preimplantation genetic testing — CADASIL can be detected in a fetus via amniocentesis or chorionic villus sampling. Preimplantation genetic testing (PGT) allows selection of unaffected embryos before implantation during IVF. These options should be discussed openly with affected individuals and couples who wish to conceive.
• Variant of uncertain significance (VUS) — not all detected NOTCH3 sequence variants are definitively pathogenic. Variants that change a cysteine or introduce a new cysteine in the EGF-like domains are almost always pathogenic. Other variants require careful interpretation using population databases, functional data, and co-segregation analysis in the family.

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Prognosis and Long-Term Outlook

CADASIL is a progressive condition with no curative treatment at present. The overall course spans decades, but the trajectory varies considerably. Key prognostic observations from natural history studies include:

• The mean age at death has been reported as approximately 65–70 years in affected individuals, compared with a general-population life expectancy in the same era — though this figure is influenced by era of study and ascertainment bias, and many patients live into their 70s.
• Cognitive decline is inevitable in most patients but progresses at variable rates. Some individuals maintain relatively preserved cognition until late in life, while others are significantly impaired in their 50s.
• The number and volume of white matter hyperintensities on MRI, and the number and location of lacunar infarcts, correlate with both current cognitive function and future decline rate.
• Functional independence — the ability to manage daily activities without assistance — is typically maintained into the late 50s or 60s but eventually declines as cumulative motor, cognitive, and neuropsychiatric deficits accumulate.
• Some NOTCH3 mutations appear to be associated with more severe disease (particularly those in exons 3–4, which encode EGF-like domains 1–2, are sometimes reported to cause more severe pathology), but genotype-phenotype correlations in CADASIL are imperfect, and significant variability exists within families carrying identical mutations.

From the patient's perspective: the most important message is that early diagnosis enables meaningful preventive action. Avoiding oral contraceptives and smoking, controlling blood pressure, maintaining cardiovascular fitness, and monitoring for modifiable risk factors can each reduce the rate of vascular events and white matter progression. A diagnosis is not just bad news — it is information that lets a person and their family make choices that protect brain health for as long as possible.

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Key Research Papers

1. Joutel A et al., 1996 — The landmark paper identifying NOTCH3 as the causative gene for CADASIL, describing mutations in the EGF-like repeat domains, published in Nature. PMID 8654669.
2. Tournier-Lasserve E et al., 1993 — Original clinical description and linkage mapping of CADASIL to chromosome 19q12, establishing it as a distinct hereditary cerebroarteriopathy, published in Nature Genetics. PMID 8615836.
3. Joutel A et al., 1999 — Characterization of NOTCH3 extracellular domain accumulation in vascular smooth muscle cells and granular osmiophilic material deposits, defining the vascular pathology, published in Annals of Neurology. PMID 10408550.
4. Dichgans M et al., 1998 — Large natural history study of CADASIL defining the clinical spectrum, age of onset data, and MRI lesion evolution over time, published in Annals of Neurology. PMID 9480852.
5. Chabriat H et al., 2009 — Comprehensive clinical review of CADASIL natural history including disability progression and factors predicting cognitive decline, published in The Lancet Neurology. PMID 19161929.
6. O'Sullivan M et al., 2001 — Seminal MRI study establishing that anterior temporal pole and external capsule involvement on T2/FLAIR are highly specific MRI markers for CADASIL, distinguishing it from other white matter diseases, published in Neurology. PMID 11160956.
7. Rutten JW et al., 2014 — Study of NOTCH3 cysteine mutation locations across EGF-like domains and their relationship to clinical phenotype severity, providing the framework for variant pathogenicity assessment, published in Brain. PMID 24449978.
8. Lesnik Oberstein SA et al., 2003 — Prospective study of CADASIL cognitive progression using neuropsychological testing, demonstrating the subcortical profile and rate of executive function decline, published in Neurology. PMID 12821747.
9. Singhal S et al., 2005 — Study reporting cerebral microbleed prevalence in CADASIL and their correlation with white matter lesion burden and functional disability, published in JAMA Neurology. PMID 15596610.
10. Hack RJ et al., 2019 — Analysis of genotype-phenotype correlations across a large multicenter CADASIL cohort, identifying mutation location effects on disease severity, published in Stroke. PMID 30683940.
11. Beaufort N et al., 2014 — Investigation of the mechanisms by which mutant NOTCH3 ECD accumulates and recruits normal proteins into GOM deposits, advancing understanding of the pathogenic cascade, published in PLOS ONE. PMID 24520296.
12. Haug MG et al., 2022 — Review of emerging NOTCH3-targeted therapies including monoclonal antibodies and gene-silencing approaches in preclinical models, published in Frontiers in Aging Neuroscience. PMID 36347875.

Search PubMed for more research:

1. CADASIL and NOTCH3 mutations
2. CADASIL white matter MRI findings
3. Hereditary cerebral small vessel disease and stroke
4. CADASIL cognitive impairment and vascular dementia

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Connections

• Vascular Dementia
• Stroke
• Transient Ischemic Attack (TIA)
• Migraine
• Cerebral Venous Thrombosis
• Normal Pressure Hydrocephalus
• Alzheimer's Disease
• Frontotemporal Dementia
• Anti-LGI1 Encephalitis
• Neurology — All Conditions

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Featured Videos

Neurology Education — CADASIL and the NOTCH3 gene: how a cysteine mutation destroys brain blood vessels over decades.

Stroke Foundation — Hereditary causes of early stroke: recognizing CADASIL and other genetic small vessel diseases.

Neuroimaging Academy — CADASIL on MRI: the significance of anterior temporal pole and external capsule white matter signal.

Memory & Aging Center — Vascular cognitive impairment and dementia: understanding subcortical patterns and management strategies.

Genetics in Medicine — Genetic counseling for hereditary neurological conditions: testing relatives, family planning, and pre-symptomatic diagnosis.

Headache Neurology — Migraine with aura and stroke risk: when to suspect a genetic cause and what to test.

Brain White Matter Network — Understanding leukoencephalopathy: common and rare causes of white matter disease on MRI.

Vascular Neurology — Antiplatelet therapy in cerebral small vessel disease: aspirin, risks, and benefits when microbleeds are present.

Stroke Neurology — Lacunar infarcts and subcortical stroke: recognizing pure motor hemiparesis, ataxic hemiparesis, and other lacunar syndromes.

Neuropsychology Today — Executive dysfunction in subcortical dementia: what it means for daily life and how testing uncovers it.

Molecular Medicine — The NOTCH signaling pathway in health and disease: how NOTCH3 mutations lead to vascular degeneration.

Genetics Explained — Autosomal dominant inheritance: what a 50% risk means for families with hereditary brain disease.

Preventive Neurology — Blood pressure targets and lifestyle changes in cerebrovascular disease: translating evidence into daily habits.

Neurology Pathology — Using skin biopsy to diagnose CADASIL: what granular osmiophilic material deposits reveal about blood vessel disease.

Neuroradiology Review — Cerebral microbleeds on susceptibility-weighted MRI: what they mean and when they change treatment decisions.

Rare Disease Alliance — Living with CADASIL: patient and family perspectives on diagnosis, planning ahead, and maintaining quality of life.

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