CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
Incidence
CADASIL is inherited in an autosomal dominant manner. The prevalence of CADASIL is unknown. Some 205 families have been described from all continents, but so far most families described are of European origin.
Clinical Characteristics
CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is characterized by a history of migraine headaches (30-40% of patients), mid-adult (30s-60s) onset of cerebrovascular disease progressing to dementia, and diffuse white matter lesions and subcortical infarcts on neuroimaging. Clinical Description: CADASIL is a microangiopathy mainly affecting the brain. Affected individuals experience transient ischemic attacks (TIAs) and stroke beginning, on average, at 45 years of age. Cognitive decline can start as early as age 35 years. The extent of cognitive impairment is variable. Most patients over age 65 are demented or have severe cognitive deficits. Almost 40% of patients with CADASIL suffer from migraine, predominantly with aura, with attacks being the initial symptom of CADASIL in almost half of the patients. Psychiatric disturbances occur in about 30% of patients with CADASIL. Epilepsy is present in 10% of patients.
Precipitants
none
Provocation Tests
none
Diagnostic Procedures
Diagnosis/testing: The pathological hallmark of CADASIL is electron dense granules in the media of arterioles that can often be identified by electron microscopic (EM) evaluation of skin biopsies. More than 90% of patients have mutations in the NOTCH3 gene (chromosomal locus 19p13.2-p13.1). Molecular genetic testing is available on a clinical basis. Schroder et al. (1995) demonstrated pathologic findings on sural nerve biopsy in individuals from a family with 4 affected members in 3 successive generations. Light microscopic abnormalities were very mild. However, by electron microscopy, they were able to demonstrate characteristic electron dense, extracellular granular deposits in close association with smooth muscle cells and to a lesser degree with pericytes and endothelial cells. They found focal pinocytotic vesicles at the site of close contact between the extracellular deposit and the surface membrane of the smooth muscle cell, suggesting exocytosis of abnormal material. The authors stated that this was the first demonstration that the diagnosis of CADASIL could be verified by sural nerve biopsy. Joutel et al. (2001) established whether immunostaining skin biopsy samples with a monoclonal antibody specific for NOTCH3 could form the basis of a reliable and easy diagnostic test. Their immunostaining technique, based on the abnormal accumulation of NOTCH3 within small vessels, was judged to be highly sensitive (96%) and specific (100%) for the diagnosis of CADASIL. The presence of granular osmiophilic material on skin biopsy is diagnostic but can be negative. Skin biopsy, performed in 18 cases, had a sensitivity of 45% and specificity of 100%.