Phenotypic variability of CADASIL and novel morphologic findings

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a non-arterio-atherosclerotic, non-amyloidotic arteriopathy affecting preferentially the small arteries and arterioles of the brain. The morphologic hallmark is the presence of a characteristic granular alteration of the arterial media that ultrastructurally corresponds to the accumulation of electron-dense material surrounding the smooth muscle cells. Although the presence of this granular osmiophilic material (GOM) was originally described as limited to brain vessels, identical electron microscopic findings have been demonstrated in the media of peripheral tissue arteries, allowing for a pathologic diagnosis of the disease by a simple skin, muscle or nerve biopsy. We report some atypical features identified in our CADASIL patients that broaden the phenotypic expression of this disease. Firstly, we identified a cortical infarct in an otherwise typical CADASIL patient. Secondly, we observed GOM in skin arteries of a 30-year-old man with hemiplegic migraine, the son of a woman who had died with CADASIL. This confirms that it may be possible to diagnose the disease at a preclinical stage by the ultrastructural evaluation of peripheral tissue biopsy material, particularly for individuals for whom there is a supporting family history. Thirdly, ultrastructural examination of the skin, and subcutaneous and striated muscle of an unrelated and apparently sporadic patient with neuropathologic and neuroradiologic evidence of CADASIL in meningeal and cerebral vessels failed to reveal diagnostic lesions in peripheral arteries. Thus, the possibility of a false-negative pathologic diagnosis in patients with a clinicoradiologic diagnosis of CADASIL, if one relies solely on a peripheral tissue biopsy, does exist. Additionally, we have identified heat shock proteins (Hsp70 and alphaB crystallin) and ubiquitin in the vascular myocytes of affected arteries. <alpha>B crystallin also seemed to be deposited extracellularly, which suggests that GOM also might be immunoreactive for alphaB crystallin.

Arg133Cys Mutation of Notch3 in Two Unrelated Japanese Families with CADASIL.

“…The electron microscopic demonstration of GOMwithin the basal lamina of vascular smooth-muscle cells in arterioles is specific for the diagnosis of CADASIL (4,6,(18)(19)(20)(21)(22). As shown in our demonstration, GOMwas also present within the basement membrane of pericyte in the capillaries.…”

Conserved signal peptide of Notch3 inhibits interaction with proteasome

“…We are currently evaluating whether CADASIL mutations indeed result in proteasome inhibition. Consistent with this hypothesis, some investigators have detected increased ubiquitinated protein in pathological CADASIL samples [25].…”

Transgenic Mice Expressing Mutant Notch3 Develop Vascular Alterations Characteristic of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

“…In addition, as in human patients, vessels in transgenic mice showed a disruption of the normal smooth muscle cell anchorage to cells and extracellular matrix (PB, MMR, and AJ; unpublished observations). 16,17,27,28 As in human patients, endothelial cells, in addition to smooth muscle cells, showed degenerative changes. 17,26 However, these transgenic mice did not show evidence of brain parenchyma damages.…”