CADASIL and CARASIL

Abstract

CADASIL and CARASIL are hereditary small vessel diseases leading to vascular dementia. CADASIL commonly begins with migraine followed by minor strokes in mid-adulthood. Dominantly inherited CADASIL is caused by mutations (n > 230) in NOTCH3 gene, which encodes Notch3 receptor expressed in vascular smooth muscle cells (VSMC). Notch3 extracellular domain (N3ECD) accumulates in arterial walls followed by VSMC degeneration and subsequent fibrosis and stenosis of arterioles, predominantly in cerebral white matter, where characteristic ischemic MRI changes and lacunar infarcts emerge. The likely pathogenesis of CADASIL is toxic gain of function related to mutation-induced unpaired cysteine in N3ECD. Definite diagnosis is made by molecular genetics but is also possible by electron microscopic demonstration of pathognomonic granular osmiophilic material at VSMCs or by positive immunohistochemistry for N3ECD in dermal arteries.In rare, recessively inherited CARASIL the clinical picture and white matter changes are similar as in CADASIL, but cognitive decline begins earlier. In addition, gait disturbance, low back pain and alopecia are characteristic features. CARASIL is caused by mutations (presently n = 10) in high-temperature requirement. A serine peptidase 1 (HTRA1) gene, which result in reduced function of HTRA1 as repressor of transforming growth factor-β (TGF β) -signaling. Cerebral arteries show loss of VSMCs and marked hyalinosis, but not stenosis.

Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGFβ expression

“…The TGFβ family implication in fibrosis is most interesting as fibrotic thickening of small vessels in CADASIL is widely reported 38. It has been suggested that the damage of VSMCs in CADASIL induces secondary fibrosis with consequent thickening of the walls and narrowing of the lumen of cerebral arteries 19. In this study, we found elevated expression level of TGF β isoforms ( TGF β 1, TGF β 2 and TGF β 3 ) in Pla‐ and CerVSMCs, where the increased level of TGF β 3 was more obvious as compared to the TGF β 1 or TGF β 2 .…”

“…NOTCH3 is a type I transmembrane receptor belonging to the Notch signalling family, one of a group of “elite” intracellular signalling pathways 17, 18. Currently, more than 230 different CADASIL‐causing mutations in the NOTCH3 gene have been detected,19 which are either missense mutations or small in‐frame deletions in the epidermal growth factor repeats of NOTCH3 . These mutations affect the number of cysteine residues, leading to an unpaired cysteine residue 20, 21, 23, 24…”

Consensus statement for diagnosis of subcortical small vessel disease

“…Eventually, multiple strokes cause gait problems, urinary incontinence, depression, and pseudobulbar palsy. 45,46 Leukoaraiosis Leukoaraiosis was derived from the Greek words for 'white' and 'rarified', and was originally proposed to describe the low signal seen on CT in the white matter for which a concise etiology was lacking. 47 The attenuated signal on CT corresponds to high signal on T2-weighted MRI.…”

Current Pathogenetic Concepts of Vascular Cognitive Impairment

“…Within CVD, the most common contribution is likely central SVD, which involves tissue injury in both cortical and subcortical gray and white matter, but may coexist with atherosclerosis involving large extracranial vessels and embolic disease [4,17,41]. Vessel wall changes such as arteriolosclerosis and CAA were proposed to be the most earliest and common changes, followed by perivascular spacing with lacunar and regional microinfarcts progressing from frontal to temporal lobe and basal ganglia [52].…”