CADASIL disease

Overview of CADASIL disease

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) represents the most prevalent monogenic form of cerebral small vessel disease, primarily manifesting through neurological symptoms that progressively impair quality of life.

First described in the 1970s and genetically characterized in the 1990s, CADASIL arises from mutations in the NOTCH3 gene, leading to pathological changes in small and medium-sized arteries, predominantly in the brain. This results in chronic hypoperfusion, ischemic events, and white matter degeneration.

Epidemiological data indicate a prevalence of approximately 2-5 per 100,000 individuals, though recent genomic studies suggest it may be underdiagnosed, with mutation carriers potentially reaching 3.4 per 1,000 in general populations, particularly higher among Asian ancestries.

The condition affects men and women equally, with onset typically in early to middle adulthood, and it carries a high risk of disability due to recurrent strokes and cognitive decline.

Unlike common vascular diseases, CADASIL is non-atherosclerotic and non-amyloid, distinguishing it pathologically. This section draws from peer-reviewed sources to provide a detailed exploration, emphasizing its clinical relevance for patients, families, and healthcare providers.

What Is CADASIL?

CADASIL is a hereditary vascular disorder characterized by the progressive degeneration of small cerebral arteries, leading to subcortical infarcts (small strokes) and leukoencephalopathy (damage to the brain’s white matter). It was initially reported in European families in 1977 as a familial arteriopathy causing early-onset strokes and dementia, but the term “CADASIL” was coined in the early 1990s following genetic mapping.

The disease is inherited in an autosomal dominant manner, meaning a single mutated gene copy from one parent is sufficient for manifestation, with a 50% transmission risk to offspring. Rare de novo mutations occur without family history.

Pathologically, CADASIL involves the accumulation of abnormal protein deposits in vessel walls, resulting in thickening, fibrosis, and narrowing of arterial lumens. This impairs blood flow, particularly to deep brain regions, causing ischemic damage. Systemic involvement is possible, but symptoms are largely neurological due to the brain’s vulnerability. Prevalence estimates vary: traditional studies report 1.3-4.6 per 100,000 in Europeans, but large-scale genomic databases like gnomAD reveal cysteine-altering mutations in up to 11.78 per 1,000 in some ethnic groups, with Asians showing the highest rates (e.g., 0.85% for specific mutations in Taiwanese populations). No sex predilection exists, though men may experience slightly more severe outcomes and shorter lifespans (mean death age 64.4 years for men vs. 70.7 for women). The disease’s progressive nature often leads to dependency by age 60-65, with causes of death including pneumonia, sudden events, or asphyxia.

This table summarizes core epidemiological and defining characteristics, aiding quick reference for clinicians.

Symptoms of CADASIL

The clinical spectrum of CADASIL is broad and heterogeneous, with symptoms emerging gradually and varying in intensity even among family members sharing the same mutation. Core manifestations include migraines, ischemic events, cognitive impairment, and psychiatric disturbances, often progressing over decades.

Migraines with aura affect 40-75% of patients (lower in Asian cohorts at 2.7-28.4%), typically onsetting around age 30. These are severe, unilateral headaches preceded by visual disturbances (e.g., scintillating scotoma), sensory changes, or aphasia, lasting 20-30 minutes or longer. Rare “CADASIL coma” episodes involve prolonged confusion, fever, or coma-like states.

Ischemic events, occurring in 60-85% of cases, manifest as transient ischemic attacks (TIAs) or subcortical strokes, usually starting at 40-50 years. Symptoms include sudden weakness, numbness, speech difficulties, visual loss, or ataxia, resolving within 24 hours for TIAs but persisting in strokes. Recurrent events lead to cumulative damage, with “silent” infarcts detectable on MRI in some. East Asian patients show higher rates of intracerebral hemorrhages (17-25%) and microbleeds.

Cognitive impairment develops in 50-60% by ages 50-60, featuring deficits in attention, executive function, processing speed, memory, and visuospatial skills. This progresses to vascular dementia, interfering with daily activities. Psychiatric symptoms affect 25-30%, including depression, anxiety, apathy, bipolar disorder, or schizophrenia-like features. Other less common issues include seizures (5-10%), parkinsonism, gait instability, urinary incontinence, and pseudobulbar palsy.

This table outlines symptom profiles for practical assessment.

Causes of CADASIL

CADASIL is genetically driven by mutations in the NOTCH3 gene on chromosome 19p13, which encodes a transmembrane receptor crucial for vascular smooth muscle cell (VSMC) development and maintenance. Over 280 pathogenic variants have been identified, predominantly missense mutations (95%) altering cysteine residues in one of the 34 epidermal growth factor-like repeats (EGFRs), resulting in an odd number of cysteines and protein misfolding.

Mutations cluster in exons 2-24, with hotspots varying by ethnicity: exons 3-4 in Europeans, exon 11 in Dutch/Chinese, and specific founder mutations like p.Arg544Cys in East Asians (prevalent in 0.85% of Taiwanese). Rare cysteine-sparing or de novo mutations occur.

The autosomal dominant inheritance ensures high penetrance, though expressivity varies due to modifiers like hypertension or smoking.

Why CADASIL happens: pathogenesis

The precise mechanism remains incompletely understood, but key hypotheses involve aberrant NOTCH3 signaling, toxic protein aggregation, and extracellular matrix (matrisome) dysregulation.

Mutant NOTCH3 leads to extracellular accumulation of its ectodomain (N3ECD), forming granular osmiophilic material (GOM) deposits around VSMCs and pericytes. GOM sequesters proteins like TIMP3, vitronectin, LTBP-1, serum amyloid P, annexin 2, and periostin, disrupting vessel homeostasis, TGF-β signaling, and intramural periarterial drainage.

It causes VSMC degeneration, impaired autophagy, endoplasmic reticulum stress, arterial wall thickening, lumen narrowing, and hypoperfusion. Endothelial dysfunction and reduced neurovascular coupling exacerbate ischemia. White matter changes arise from chronic hypoperfusion and gliovascular unit disruption. Modifier factors like oxidative stress or comorbidities amplify damage.

What patients feel and how it starts

Patients often describe CADASIL as a “slow thief,” with insidious onset disrupting life unpredictably. It typically begins subtly in the 20s-30s with migraines feeling like intense, throbbing pain with visual flashes or numbness, severely impacting work and daily routines.

As it progresses, stroke-like episodes bring sudden fear—arm weakness, slurred speech, or confusion—resolving but leaving anxiety about recurrence.

Cognitive fog develops further as frustration with forgotten tasks or decision-making, evolving to profound isolation in dementia stages. Emotional toll includes depression from lost independence, with physical symptoms like unsteady gait adding to vulnerability. Pregnancy may trigger symptoms in women, heightening stress.

Progression spans 20-40 years, from mild headaches to full dependency, emphasizing early support needs.

First symptoms

The earliest indicators are often migraines with aura in 40-75% of cases, onsetting around age 30, characterized by severe headaches preceded by sensory or visual disturbances. In some, psychiatric changes like apathy or mood swings precede, while others experience subtle cognitive slips. Family history prompts vigilance, as MRI changes may appear presymptomatically by age 30.

How CADASIL is diagnosed

Diagnosis integrates family history, clinical symptoms, neuroimaging, and confirmatory testing.

• MRI reveals characteristic white matter hyperintensities in anterior temporal lobes, external capsules, and superior frontal regions (present in nearly all over 35), plus lacunes, microbleeds, and atrophy.
• Genetic testing for NOTCH3 mutations is the gold standard (detecting 96% of cases), while skin biopsy confirms GOM with 45-100% sensitivity.
• Differential includes multiple sclerosis, Fabry disease, CARASIL, and sporadic small vessel disease.
• Biomarkers like serum neurofilament light chain aid screening.

Treatment of CADASIL

No disease-modifying therapy exists; management is symptomatic and preventive.

• Migraines are treated with analgesics (acetaminophen, NSAIDs); avoid vasoconstrictors like triptans.
• For strokes, tPA may be considered acutely if no contraindications (e.g., microbleeds).

Long-term: control hypertension, cholesterol with statins, antiplatelets (though role debated due to non-thrombotic pathology), and smoking cessation. Antidepressants address psychiatric issues; cognitive therapies support function. New research explores antisense oligonucleotides or immunotherapy targeting NOTCH3. Genetic counseling is essential.