Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a genetic cause of cerebral small vessel disease

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder of the cerebral small blood vessels caused by mutations in the Notch3 gene. The exact prevalence of this disorder was unknown currently, and the number of reported CADASIL families is steadily increasing as the clinical picture and diagnostic examinations are becoming more widely known. The main clinical manifestations are recurrent stroke, migraine, psychiatric symptoms, and progressive cognitive impairment. The clinical course of CADASIL is highly variable, even within families. The involvement of the anterior temporal lobe and the external capsule on brain magnetic resonance imaging was found to have high sensitivity and specificity in differentiating CADASIL from the much more common sporadic cerebral small-vessel disease (SVD). The pathologic hallmark of the disease is the presence of granular osmiophilic material in the walls of affected vessels. CADASIL is a prototype single-gene disorder that has evolved as a unique model for studying the mechanisms underlying cerebral SVD. At present, the incidence and prevalence of CADASIL seem to be underestimated due to limitations in clinical, neuroradiological, and genetic diagnoses of this disorder.

Keywords: Notch3; cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; ischemic stroke; migraine; small-vessel disease.

Fig. 1

Characteristic pathologic findings in CADASIL on electron microscopy. An arteriole obtained during a skin biopsy shows multiple GOMs (arrow) between the basement membranes of VSMC (Courtesy of Sung-Hye Park, MD, PhD). CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, GOMs: granular osmiophilic materials, VSMC: vascular smooth-muscle cell.

Fig. 2

Typical brain MRI findings in CADASIL. FLAIR images demonstrate HSI lesions in the anterior temporal lobe (A) and bilateral external capsules (B). Multiple lacunar infarctions (C) are noted in bilateral periventricular and deep white matter with punctate HSI lesions. CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, FLAIR: fluid attenuated inversion recovery, HSI: high-signal-intensity.