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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Author
Martin Dichgans, MD
Section Editor
Scott E Kasner, MD
Deputy Editor
John F Dashe, MD, PhD

INTRODUCTION

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited angiopathy caused by mutations in the NOTCH3 gene on chromosome 19 [1]. CADASIL is now recognized as an important cause of stroke in the young [2,3].

Stroke and vascular cognitive impairment remain the main causes of morbidity and mortality in patients with CADASIL. Previous descriptions of families with "hereditary multi-infarct dementia," "chronic familial vascular encephalopathy," and "familial subcortical dementia" represent early reports of the same condition.

PATHOPHYSIOLOGY

CADASIL is caused by pathogenic mutations in the NOTCH3 gene, which lead to vasculopathic changes predominantly involving small penetrating arteries, arterioles, and brain capillaries.

Molecular mechanisms — The NOTCH3 gene on chromosome 19p13.2-p13.1 is one of four mammalian homologs of the Drosophila NOTCH gene [4]. NOTCH genes code for large transmembrane receptors involved in cell fate decisions during embryonic development [5]. The protein product Notch3 is critical for vascular smooth muscle cell (VSMC) differentiation and vascular development [6]. In adults, expression of NOTCH3 is largely restricted to VSMCs and capillary pericytes.

Like all Notch receptors, the Notch3 receptor is proteolytically processed in the trans-Golgi network as it traffics from the endoplasmic reticulum to the plasma membrane. Proteolytic cleavage results in a large extracellular fragment and a small intracellular fragment that contains the transmembrane region.

                        

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Literature review current through: Nov 2016. | This topic last updated: Thu Oct 13 00:00:00 GMT 2016.
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References
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