Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain

Abstract

Advances in molecular genetics have enabled identification of several monogenic conditions involving small vessels predisposing to ischaemic and haemorrhagic strokes and diffuse white matter disease. With emphasis on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we review the molecular pathogenesis of recently characterized disorders including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and the Collagen type IV, alpha 1 (COL4A1)-related disorders. CADASIL remains the most common hereditary small vessel disease (SVD) caused by >190 different mutations in the NOTCH3 gene, which encodes a cell-signalling receptor. Mutant NOTCH3 instigates degeneration of vascular smooth muscle cells in small arteries and arterioles leading to recurrent lacunar infarcts. Mutations in the serine protease HTRA1 gene are associated with CARASIL. Aberrant HTRA1 activity results in increased transforming growth factor-β signalling provoking multiple actions including vascular fibrosis and extracellular matrix synthesis. The RVCL disorders characterized by profound retinopathy are associated with mutations in TREX1, which encodes an abundant 3'-5' DNA-specific exonuclease. TREX1 mutations lead to detrimental gain-of-function or insufficient quantities of enzyme. The COL4A1-related disorders are highly variable comprising four major phenotypes with overlapping systemic and central nervous system features including SVD with cerebral haemorrhages in children and adults. Mutant COL4A1 likely disrupts the extracellular matrix resulting in fragile vessel walls. The hereditary SVDs albeit with variable phenotypes demonstrate how effects of different defective genes converge to produce the characteristic arteriopathy and microvascular disintegration leading to vascular cognitive impairment.

Notch3 Arg170Cys Knock-In Mice Display Pathologic and Clinical Features of the Neurovascular Disorder Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

“…33 It is tempting to speculate that these findings may reflect stages of GOM development 33 or may relate to a postulated defective ubiquitin-dependent (trans)endocytosis of mutant Notch3. 16,39,50,51 The latter is a plausible scenario, implying the presence of Notch3 ECD in GOM. This remains controversial, however, as the detection of Notch3 ECD in GOM by immunoelectron microscopy on patient material was not confirmed by mass spectrometry analysis.…”

“…[13][14][15] Thus far, more than 180 mutations are known, nearly 60% of which cluster in exon 4. 3,[13][14][15][16] In vitro and in vivo studies have highlighted a role of Notch3 in artery maturation, responses to vascular injury or ischemia, and regulation of SMC proliferation and apoptosis. [17][18][19][20][21][22][23][24][25] How the various Notch3 mutations effectuate arteriopathy and CADASIL disease development remains enigmatic.…”

Anesthetic Management and Postoperative Care of a Patient with CADASIL (Cerebral Arteriopathy, Autosomal Dominant, with Subcortical Infarcts and leukoencephalopathy) for Cesarean Section

“…It is interesting that the locus of the Notch -3 gene is near that of the Cacnl1a4 calcium channel gene, which carries the causal mutation of familial hemiplegic migraine and type II familial episodic ataxia (2,5). At the histological level, the characteristic that is considered specific for CADASIL-type arteriopathy is the presence, on electronic microscopy, of dense osmophilic granular material in contact with the smooth muscular cells of the arterioles (7). This material is observed in brain tissue, in nerves and also in the dermis.…”

Poststroke cognitive impairment and dementia

“…Вероятно, наряду с собственно церебральным повреждением вслед-ствие инсульта и наличием неройденегеративных изме-нений, эти факторы делают мозг в большей степени под-верженным деменции. Не до конца выяснена и роль генетических факторов: отчетливых доказательств связи определенных генетич еских вариантов с развитием ког-нитивных нарушений не установлено, однако на него могут влиять нуклеотидные последовательности, связан-ные с развитием различных подтипов ишемического инсульта и изменений белого вещества вследствие пора-жения сосудов мелкого калибра [14,53]. Ряд биомаркеров, таких как маркеры воспаления (интерлейкин-6, C-реак-тивный белок), B-секретаза, наличие аллелей DD АПФ и аполипротеина E4, изучаются в качестве возможных пре-дикторов деменции и когнитивных нарушений [5].…”