Polymerase Chain Reaction/Sequencing
- Preferred test for genetic confirmation of a clinical diagnosis of CADASIL
- Informed consent is required for testing
- See ARUP Genetics Consent Forms
- Testing of asymptomatic minors (<18 years of age) is not available at ARUP
Related Tests
Polymerase Chain Reaction/Sequencing
Useful when a pathogenic familial variant identifiable by sequencing is known
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by pathogenic variants in the NOTCH3 gene. This condition is primarily characterized by subcortical ischemic events, such as transient ischemic attacks (TIAs) and strokes. Individuals with CADASIL may also present with cognitive impairment and dementia, migraines, psychiatric and mood disorders, and epilepsy. Age of onset and clinical presentation are highly variable.
Disease Overview
Prevalence
2-4/100,000
Age of Onset
Variable and age dependent; symptoms may present from the 3rd-8th decade
Symptoms
- Subcortical ischemic events (85% of affected individuals)
- TIAs
- Strokes
- Cognitive defects/dementia (75% of affected individuals)
- Migraines (35% of affected individuals)
- Psychiatric disorders (33% of affected individuals)
- Epilepsy (10% of affected individuals)
Prognosis
- CADASIL is a progressive disease with no known effective treatment
- Disease progression is more rapid in males than females
- Median age for loss of ambulation is 60 years
- Median age of death is 68 years
Diagnostic Criteria
- Clinical signs
- Family history
- Brain imaging
- White matter hyperintensities first appear in anterior temporal lobes
- May be visible by magnetic resonance imaging (MRI) as early as 21 years of age
- Cerebral microbleeds may be detected by echo imaging
- White matter hyperintensities first appear in anterior temporal lobes
- Skin biopsy
- Immunohistochemistry demonstrating a positive NOTCH3 staining of the vessel wall
- Electron microscopy showing granular osmophilic material within vascular media close to vascular smooth muscle cells
Pathophysiology
Reduced cerebral blood flow leads to degeneration of vascular smooth muscle and neurological and psychiatric impairment.
Genetics
Gene
NOTCH3
Inheritance
Autosomal dominant
Penetrance
100%, with variable expressivity and age of onset
De novo Variants
Rare
Variants
>300 pathogenic variants identified; the majority are missense
Test Interpretation
Sensitivity/Specificity
Results
- Positive
- One copy of a pathogenic NOTCH3 gene variant detected predicts a diagnosis of CADASIL
- Negative
- No pathogenic NOTCH3 gene variant detected; CADASIL diagnosis unlikely, but not excluded
- Inconclusive
- NOTCH3 gene variant of uncertain significance detected; whether variant is benign or pathogenic is unknown
Limitations
- Diagnostic errors may occur due to rare sequence variations
- Large deletions and duplications are not detected
- Deep intronic and promoter variants will not be detected
11706120
Dichgans M, Herzog J, Gasser T. NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL. Neurology. 2001;57(9):1714-1717.
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Dichgans M, Mayer M, Uttner I, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol. 1998;44(5):731-739.
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Markus HS, Martin RJ, Simpson MA, et al. Diagnostic strategies in CADASIL. Neurology. 2002;59(8):1134-1138.
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Opherk C, Peters N, Herzog J, et al. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004;127(Pt 11):2533-2539.
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Peters N, Opherk C, Bergmann T, et al. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. 2005;62(7):1091-1094.