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CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia
Hannu Kalimo1, Marie-Magdaleine Ruchoux, Matti Viitanen
1Department of Pathology, Turku University Hospital, Finland. hkalimo@utu.fi
Insights
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic brain disorder causing stroke and dementia. Mutations in the Notch3 gene disrupt blood vessels, leading to these severe neurological symptoms.
Area of Science:
- Neuroscience
- Genetics
- Vascular Biology
Background:
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease.
- It leads to cognitive decline, dementia, and often begins with migraine, followed by strokes between ages 30-50.
Purpose of the Study:
- To describe the clinical, pathological, and genetic features of CADASIL.
- To understand the underlying mechanisms of Notch3 gene mutations in vascular pathology.
Main Methods:
- Review of clinical cases and diagnostic criteria for CADASIL.
- Pathological examination of arterial walls, including dermal biopsies.
- Genetic analysis to identify mutations in the Notch3 gene.
Main Results:
- CADASIL is characterized by white matter hyperintensities on MRI and granular osmiophilic material in arterial walls.
- Vascular smooth muscle cell destruction leads to arterial wall thickening, fibrosis, and luminal narrowing.
- Notch3 gene mutations, affecting cysteine residues, are the cause, but the precise pathway disruption remains unclear.
Conclusions:
- CADASIL results from Notch3 gene mutations affecting cerebral arteries.
- Understanding the Notch3 signaling pathway is crucial for elucidating CADASIL pathogenesis.
- Early diagnosis is possible through characteristic imaging and pathological findings.
Abstract:
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to cognitive decline and dementia. CADASIL usually begins with migraine in about one third of the patients. More severe manifestations, transient ischemic attacks or recurrent strokes, appear between 30 and 50 years of age. CADASIL, however, may be diagnosed well before the first stroke on the basis of characteristic white matter hyperintensities upon magnetic resonance imaging and presence of pathognomonic granular osmiophilic material in arterial walls, including dermal arteries, since the arteriopathy is generalized. Gradual destruction of vascular smooth muscle cells (VSMC) leads to progressive wall thickening and fibrosis and luminal narrowing in small and medium-sized penetrating arteries. The reduced cerebral blood flow finally causes lacunar infarcts, mainly in the basal ganglia and fronto-temporal white matter, which lead to cognitive deficits and dementia of the subcortical vascular type. CADASIL is caused by single missense mutations or small deletions in Notch3 gene encoding a transmembrane receptor Notch3, of which upon ligand binding a nuclear signaling protein is generated by regulated intramembrane proteolysis. Notch signaling is essential during development, regulating cellular differentiation. In adults Notch3 is expressed only in VSMCs and it may promote cell survival by inhibiting apoptosis, but its exact function is unknown. Mutations result in either a gain or loss of one (or rarely, 3) cysteine residue(s) in one of the 34 epidermal growth factor-like repeats in the extracellular amino-terminal region of Notch3. It is as yet unclear which disturbance in the Notch signaling pathway leads to the characteristic vascular pathology of CADASIL.