Identification of the characteristic vascular changes in a sural nerve biopsy of a case with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy' (CADASIL) has recently been identified as a hereditary disorder with characteristic fine structural changes of small intracerebral arteries and arterioles. Electron microscopically there are characteristic perivascular deposits of granular electron-dense material resembling immunoglobulin deposits. The present case from a family with four affected members in three successive generations shows that similar vascular changes as described in the central nervous system are present in blood vessels of the sural nerve, although less pronounced and, therefore, affording electron microscopy for their unequivocal detection. Nevertheless it has been shown for the first time that the diagnosis of CADASIL can be verified by a sural nerve biopsy. Occasional focal accumulation of pinocytotic vesicles opposite the granular deposits suggests exocytosis as one of the possible pathomechanisms for their production.

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.…”

“…Abnormal patches of a granular osmiophilic material (GOM)within the basal membranes of vascular smooth-musclecells are a specific hallmark (4). The nature of systemic involvement allows the presence of GOMin the muscle (4,5), sural nerve (6), and skin (4,5), but is less evident than that in cerebral small arteries. There have been at least 80 unrelated CADASIL patients with Notch3 mutations identified from various communities around the world (7)(8)(9)(10)(11)(12), however all were Caucasian.…”

Blood vessel ultrastructural picture in a CADASIL patient diagnosed at an advanced age

“…In irregularly thickened suben dothelial space, large aggregates mainly of elastin were observed. In CADASIL patients, increased pro duction of elastin [4], as well as fibrous and hyaline thickening of the vessel walls, was observed [6,24]. On the other hand, hyaline is observed in different processes, such as aging and hypertension [20], and it is not specific for CADASIL pathology such as col lagen fibres usually visible in the form of clusters scattered throughout the basement membrane of our patient.…”

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

“…[12][13][14] Examination of heart, muscle, skin, and many other peripheral organs revealed vessel changes, including the presence of GOM deposits, that were identical, although less severe, to those of cerebral arteries, providing evidence that CADASIL is indeed a systemic arteriopathy. [15][16][17] GOM deposits are highly specific of CADASIL and their detection in cerebral and peripheral vessels from skin or muscle biopsy material has been widely used as a diagnostic marker of this disease. 15,18,19 Importantly, VSMC alterations and GOM deposits have been detected in skin vessels of asymptomatic mutation carriers having a normal brain magnetic resonance imaging, indicating that arterial lesions are present at a very early stage of the disease before brain parenchyma damages and clinical symptoms occurrence (MMR, ETL, and AJ; unpublished data).…”