Pathophysiological Mechanisms and Potential Therapeutic Targets in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL).

Martina Locatelli,Alessandro Padovani,Alessandro Pezzini

doi:10.3389/fphar.2020.00321

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a hereditary small-vessels angiopathy caused by mutations in the NOTCH 3 gene, located on chromosome 19, usually affecting middle-ages adults, whose clinical manifestations include migraine with aura, recurrent strokes, mood disorders, and cognitive impairment leading to dementia and disability. In this review, we provide an overview of the current knowledge on the pathogenic mechanisms underlying the disease, focus on the corresponding therapeutic targets, and discuss the most promising treatment strategies currently under investigations. The hypothesis that CADASIL is an appropriate model to explore the pathogenesis of sporadic cerebral small vessel disease is also reviewed.

Highlights

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a hereditary small-vessels angiopathy that usually affects middle-ages adults (Opherk et al, 2004)
A genotype-phenotype correlation analysis revealed that EGFR10-11 and EGFR2-5 mutations are associated with different phenotypes, with EGFR10–11 mutants usually presenting with milder cognitive deficits, lower volume of lacunar infarcts, and higher volume of white matter hyperintensities at Magnetic Resonance Imaging (MRI), suggesting different pathological processes related to different NOTCH3 mutations (Joutel, 2011)
Molecular Findings NOTCH3 consists of exons, but approximately 98% of CADASIL mutations occur in exons 2–23, which encode the epidermal growth factor-like repeats (EGFR) on the extracellular domain (ECD)

Summary

INTRODUCTION

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a hereditary small-vessels angiopathy that usually affects middle-ages adults (Opherk et al, 2004). Typical clinical manifestations include migraine with aura, recurrent strokes, mood disorders, and cognitive impairment leading to dementia and disability (Chabriat et al, 2009). Despite the well-established etiology, uncertainties regarding pathogenesis have delayed development of effective treatment, and specific therapy is still unavailable. We provide an overview of the current knowledge on the pathogenic mechanisms underlying the disease, focus on the corresponding therapeutic targets, and discuss the most promising treatment strategies currently under investigations. Whether an increased understanding of the pathophysiology and innovations in the therapeutic approach to CADASIL will benefit patients with sporadic cerebral small-vessel disease (SVD) is discussed

CADASIL and Cerebral Small Vessel Disease

Clinical Features

Therapeutic Approach

CADASIL as a Model of Sporadic SmallVessel Disease

CONCLUSION