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CADASIL: hereditary disease of arteries causing brain infarcts and dementia
H Kalimo1, M Viitanen, K Amberla
1Department of Pathology; Division of Geriatric Medicine, Karolinska Institutet, Huddinge Hospital, Huddinge, Sweden.
Insights
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic condition causing strokes and dementia. It results from Notch3 gene mutations affecting blood vessels, with no current cure.
Area of Science:
- Neurology
- Genetics
- Vascular Biology
Background:
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disorder.
- It often presents with migraine with aura and progresses to recurrent strokes, cognitive decline, and dementia between ages 30-50.
Purpose of the Study:
- To summarize the key features, diagnostic markers, underlying pathology, and genetic basis of CADASIL.
- To highlight the diagnostic potential of skin biopsy due to generalized arteriopathy.
Main Methods:
- Review of clinical, imaging (T2-weighted MRI), pathological, and genetic findings in CADASIL patients.
- Description of arteriopathy in cerebral and dermal arteries.
Main Results:
- CADASIL is characterized by subcortical infarcts and leukoencephalopathy, stemming from thickened, fibrotic penetrating artery walls.
- Diagnostic MRI shows characteristic hyperintensities; skin biopsy reveals abnormal material in dermal arteries.
- The condition is caused by missense mutations in the Notch3 gene, altering the protein's structure.
Conclusions:
- CADASIL is a generalized arteriopathy with significant neurological manifestations, including stroke and dementia.
- Early diagnosis is possible through characteristic MRI findings and skin biopsy.
- Current understanding points to Notch3 gene mutations as the cause, but its exact function and pathogenesis remain unclear; no specific therapy is available.
Abstract:
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) begins with migraine with aura in approximately one-third of the patients. More severe symptoms of recurrent strokes usually appear at 30-50 years of age. However, well before the first stroke, CADASIL may be diagnosed on the basis of characteristic hyperintensities in T2-weighted magnetic resonance images. Multiple lacunar infarcts located mainly in the basal ganglia and frontal white matter lead to a cognitive decline and finally to dementia. These infarcts result from a thickening and fibrosis of the walls of the small and medium-sized penetrating arteries with consequent obliteration and/or thrombosis. Although the symptoms are almost exclusively neurological, the arteriopathy is generalized. Thus, basophilic, periodic acid-Schiff-positive and, in electron microscopy, osmiophilic material accumulates between degenerating smooth muscle cells. This occurs even in dermal arteries, which renders skin a useful target for diagnostic biopsy. Presently, no specific therapy is available. CADASIL is caused by missense point mutations in the Notch3 gene, which encodes a transmembrane receptor protein. Each gene defect leads to either a gain or loss of a cysteine residue in the extracellular, N-terminal domain of the molecule, which most probably results in conformational alteration. The function of Notch3 in adults and the pathogenesis of CADASIL are still unknown.