CADASIL Syndrome

At a glance

A polymorphic neurologic syndrome with recurrent infarctions in the white matter resulting in a wide range of neurologic symptoms (depression, dementia, seizures, pseudobulbar paralysis). CADASIL is an acronym that stands for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts, and Leukoencephalopathy.

Synonyms

Hereditary Multi-Infarct Dementia; Chronic Familial Vascular Encephalopathy; Familial Vascular Leukoencephalopathy.

Incidence

The prevalence is unknown, but has been estimated to range between 1 and 2 in 50,000. No sexual predilection has been reported. It has been estimated that more than 500 families are affected worldwide.

Genetic inheritance

Autosomal dominant. Almost all cases are caused by missense mutations in the NOTCH3 gene that has been mapped to chromosome 19p13.2-p13.1 and encodes a transmembrane receptor with a large number of epidermal growth factor-like repeats and is mainly expressed in vascular smooth muscle cells.

Pathophysiology

CADASIL mainly affects the small to medium-sized arteries in the brain. Intimal thickening and expansion of the extracellular matrix in these cerebral vessels result in narrowing of the lumen. This is accompanied by widespread disruption and degeneration of smooth muscle cells in the vessel walls and the deposition of granular osmiophilic material (GOM). This dense GOM is in close contact with arteriolar smooth muscle cells and can be revealed by electron microscopy. The pathologic changes in the cerebral vasculature result in significantly reduced cerebral blood flow (CBF) and volume, impaired cerebral vasoreactivity to CO₂ (most likely related to vascular smooth muscle cell dysfunction), decreased cerebral glucose utilization, and possibly increased fragility of small cerebral vessels.

Diagnosis

Based on the clinical findings characterized by the acronymic association and a positive family history (most affected patients have an affected parent as de novo mutations seem to be rare). MR imaging is the most important tool for monitoring the cerebral status in CADASIL patients, as it is able to detect signal anomalies associated with white matter and microangiopathic patterns, ischemic infarcts, lacunes, and diffuse leukoencephalopathy. Prominent signal abnormalities on MRI include hyperintense lesions on T2-weighted images of the subcortical white matter, especially in the anterior part of the temporal lobes, the periventricular portion of the occipital lobes, and the basal ganglia. Small linear and punctate lacunas can be detected in the periventricular white matter, brainstem, thalamus, external capsule, and corpus callosum. In fact, reduced CBF can already be detected in the white matter of yet asymptomatic individuals, thus highlighting the importance of CBF anomalies early in the onset of the disorder. Based on the abnormal accumulation of NOTCH3-positive material within small vessels, immunostaining of skin biopsy samples using a monoclonal antibody specific for NOTCH3 forms the basis for a reliable and easy diagnostic test. Ultrastructural examination (electron microscopy) of small arterioles ...