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Journal of Advanced Research logoLink to Journal of Advanced Research
. 2024 Jan 2;66:223–235. doi: 10.1016/j.jare.2024.01.001

CADASIL: A NOTCH3-associated cerebral small vessel disease

Lamei Yuan a,b,c,d, Xiangyu Chen b,c,e, Joseph Jankovic f, Hao Deng a,b,c,d,
PMCID: PMC11674792  PMID: 38176524

Graphical abstract

graphic file with name ga1.jpg

Keywords: CADASIL, Hereditary cerebral small vessel disease, NOTCH3, Predictive approach, Targeted prevention

Highlights

  • Progress of CADASIL like clinical, pathological, genetic, and therapeutic aspects is presented.

  • The role of NOTCH3 mutations in CADASIL is highlighted in this review.

  • Genetic testing is very important for diagnosis of CADASIL and CADASIL-like phenotypes.

  • The viewpoint CADASIL should be revisited as a NOTCH3-associated CSVD was proposed.

  • Hereditary CSVD caused by NOTCH3 mutations may be better understood with advanced research.

Abstract

Background

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease (CSVD), pathologically characterized by a non-atherosclerotic and non-amyloid diffuse angiopathy primarily involving small to medium-sized penetrating arteries and leptomeningeal arteries. In 1996, mutation in the notch receptor 3 gene (NOTCH3) was identified as the cause of CADASIL. However, since that time other genetic CSVDs have been described, including the HtrA serine peptidase 1 gene-associated CSVD and the cathepsin A gene-associated CSVD, that clinically mimic the original phenotype. Though NOTCH3-associated CSVD is now a well-recognized hereditary disorder and the number of studies investigating this disease is increasing, the role of NOTCH3 in the pathogenesis of CADASIL remains elusive.

Aim of review

This review aims to provide insights into the pathogenesis and the diagnosis of hereditary CSVDs, as well as personalized therapy, predictive approach, and targeted prevention. In this review, we summarize the current progress in CADASIL, including the clinical, neuroimaging, pathological, genetic, diagnostic, and therapeutic aspects, as well as differential diagnosis, in which the role of NOTCH3 mutations is highlighted.

Key scientific concepts of review

In this review, CADASIL is revisited as a NOTCH3-associated CSVD along with other hereditary CSVDs.

Introduction

Cerebral small vessel disease (CSVD) is a range of neurological diseases with different pathogenic mechanisms involving cerebral small arteries, capillaries, and small veins. These intracranial vascular diseases have different clinical symptoms and neuroimaging characteristics as a result of the functional and structural abnormalities [1], [2]. CADASIL (OMIM 125310, also termed as CADASIL1), the acronym for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is the most common monogenic CSVD, characterized as a non-atherosclerotic and non-amyloid diffuse angiopathy primarily involving small to medium-sized penetrating arteries and leptomeningeal arteries [3], [4], [5]. Despite well-established involvement of systemic vasculature, CADASIL mainly leads to brain parenchyma lesions [6].

Between 1977 and 1994, multiple published reports described a group of inherited intracranial vascular disorders causing stroke and dementia in several European pedigrees [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. In 1993, Tournier-Lasserve et al. formally introduced the acronym CADASIL to designate this separate disease entity and mapped the disease-causing gene locus to chromosome 19 [15]. In 1996, the notch receptor 3 gene (NOTCH3, OMIM 600276) located on chromosome 19p13.12 was identified as the causative gene for CADASIL (Fig. 1) [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. CADASIL has an early estimated prevalence of 2 to 5 cases per 100,000 worldwide, which varies geographically (<1 cases per 100,000 in most provinces of Canada and 1.98 cases per 100,000 in west Scotland, 4 cases per 100,000 in Finland, and 14 cases per 100,000 in the Spanish island Gran Canaria), and may be substantially underestimated with a predicted mutation frequency of 4.1 to 10.7 carriers per 100,000 [3], [21], [22].

Fig. 1.

Fig. 1

Milestones in understanding of NOTCH3-associated CSVD.

Typical CADASIL symptoms include migraine with aura, transient ischemic attacks (TIAs), recurrent ischemic strokes, psychiatric disturbances, and cognitive impairment, even progressing to severe dementia, contributing to disability and life-threatening condition [5], [21].

Because of heterogeneous presentation, with or without family history, CADASIL is frequently misdiagnosed and underdiagnosed. The clinical diagnosis of CADASIL is often suspected when a patient presents with a combination of typical clinical symptoms, an autosomal dominant inheritance, and distinctive brain magnetic resonance imaging (MRI) abnormalities [23]. Brain MRI is a routine imaging test designed to document small vessel disease characterized by white matter hyperintensities (WMHs) on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, lacunar infarcts, and cerebral microbleeds (CMBs) [2], [24]. The pathological characteristics of CADASIL include an arteriopathy manifested by the degeneration of vascular smooth muscle cells (VSMCs) and deposition of granular osmiophilic material (GOM) within the plasma membrane of VSMCs and pericytes [23], [25].

Currently, genetic testing identifying the characteristic cysteine-altering mutations in the NOTCH3 gene is the gold standard for the CADASIL diagnosis, while cysteine-sparing mutations in the NOTCH3 gene and heterozygous mutations in the HtrA serine peptidase 1 gene (HTRA1, OMIM 602194) have also been reported in patients with CADASIL-like clinical and neuroimaging phenotypes [22], [26]. The HTRA1-associated autosomal dominant CSVD was documented in the Online Mendelian Inheritance in Man (OMIM) database as CADASIL type 2 (CADASIL2, OMIM 616779). Classifying the phenotype caused by cysteine-sparing NOTCH3 mutations and heterozygous HTRA1 mutations as CADASIL is still debated [25], [26]. In this article, we comprehensively review the clinical, neuroimaging, pathological, genetic, diagnostic, and therapeutic aspects of CADASIL, as well as differential diagnosis of HTRA1-associated autosomal dominant CSVD, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL, OMIM 600142), and cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL) (Table 1). This review should contribute to a better understanding of CADASIL and provide insights into diagnosis and personalized pathogenesis-targeted therapy for this inherited cerebrovascular disease, as well as predictive approach and targeted prevention.

Table 1.

Clinical, genetic, neuroimaging, and pathologic features of CADASIL, CADASIL2, CARASIL, and CARASAL, as well as potential therapeutic strategies.

Disorder CADASIL CADASIL2 CARASIL CARASAL
OMIM 125310 616779 600142 /
Causative gene NOTCH3 HTRA1 HTRA1 CTSA
Inheritance pattern Autosomal dominant Autosomal dominant Autosomal recessive Autosomal dominant



Main symptoms
 Migraine Yes Yes Yes Yes
 TIA/stroke Yes Yes Yes Yes
 Cognitive impairment Yes Yes Yes Yes
 Psychiatric disturbances Yes Yes Yes Yes
 Movement disorders Yes Yes Yes Yes
 Intracerebral hemorrhage Yes Yes Yes Yes
 Acute encephalopathy Yes No No No
 Epilepsy Yes Yes Yes No
 Spondylosis No Yes Yes No
 Alopecia No Yes Yes No
 Therapy-resistant hypertension No No No Yes



MRI abnormalities
 WMHs Yes Yes Yes Yes
 Lacunar infarcts Yes Yes Yes Yes
 CMBs Yes Yes Yes Yes



GOM deposits Yes No No No



Therapeutic strategies Symptomatic and prophylactic treatment like antiplatelet, analgesic, and psychiatric drugs, vascular risk factor reduction like hypertension control and smoking cessation, and novel potential pathogenesis-targeted interventions like gene silencing and immunotherapy / No available effective treatment No available causal treatment

Abbreviations: CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASAL, cathepsin A-related arteriopathy with strokes and leukoencephalopathy; CARASIL, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; CMBs, cerebral microbleeds; CTSA, the cathepsin A gene; GOM, granular osmiophilic material; HTRA1, the HtrA serine peptidase 1 gene; MRI, magnetic resonance imaging; NOTCH3, the notch receptor 3 gene; OMIM, Online Mendelian Inheritance in Man; TIA, transient ischemic attack; WMHs, white matter hyperintensities.

Clinical manifestations

Despite variable phenotypes of CADASIL within and among families, a set of core manifestations characterize this disease, including migraine with aura, TIAs, recurrent ischemic strokes, psychiatric disturbances, and cognitive impairment, progressing to dementia [24], [27]. The classic CADASIL phenotype is composed of migraine with aura as the first symptom occurring around in the third decade, the ischemic event often occurring in the fourth decade, dementia occurring in the fifth to sixth decade, and death occurring in the sixth to seventh decade, with an average disease duration ranging from 20 to 30 years. In addition to the above clinical characteristics, some uncommon manifestations comprising intracerebral hemorrhage, epilepsy, acute encephalopathy, territorial infarcts, parkinsonism, and deafness are also exhibited in some patients [3], [28].

Migraine with aura

Migraine with aura is the most common inaugural symptom of CADASIL with a mean age at onset of 30 years, and typically precedes onset of other symptoms by at least a decade [29], [30]. The prevalence of migraine with aura in CADASIL patients varies, and the range has been reported to be as high as 67.7% [31]. Generally, 20% to 40% of patients with CADASIL were estimated to experience migraine with aura, five times more prevalent than it in the general population, while it appears to be no difference in prevalence of migraine without aura between CADASIL patients and the general population [28]. Most migraine headaches in patients with CADASIL are manifested by typical aura with visual or sensory symptoms lasting 20 to 30 min preceding a headache that lasts several hours. A high frequency of atypical auras has also been reported, including basilar, hemiplegic, prolonged aura, acute-onset aura, aura without headache, confusion, and fever [28], [29], [30]. Majority of patients experienced more than one type of aura and most patients experienced no more than one migraine attack a month [29], [31]. The prevalence of migraine is higher in female patients than in male patients, and European patients suffered from it more frequently than Asian patients [31], [32]. Patients with migrainous aura were reported to have a reduced risk of stroke. Migraines seem to go into remission and even cease in some CADASIL patients after their first ischemic strokes, which may be partly explained by a recall bias by the stroke cases [33].

TIAs and ischemic strokes

CADASIL is the most common genetic cause for stroke, responsible for disability and death [34]. TIAs are usually followed by ischemic strokes and may be confused with severe migrainous aura. These two subcortical ischemic events are the most frequent clinical manifestations in CADASIL, involving up to 85% of symptomatic patients. The age at onset of these ischemic events ranges between 20 and 70 years of age with an average age of 40 to 50 years. CADASIL patients may experience these ischemic events without conventional cardiovascular disease risk factors such as hypertension, diabetes, hypercholesterolaemia, hyperhomocysteinemia, or smoking [35], [36]. However, factors like hypertension and smoking may influence the clinical expression and increase the risk of ischemic strokes in these patients. Smoking is associated with earlier age at onset, suggesting that it triggers or aggravates occlusion of perforating arteries in CADASIL patients [33], [35]. Ischemic events almost invariably occur in subcortical areas and most present as lacunar syndromes such as pure motor strokes, pure sensory strokes, dysarthria-clumsy hand syndrome, expressive dysphasia, or visual field defects [36]. A CADASIL patient suffers on average 2 to 5 ischemic events in lifetime, often resulting in gait difficulty, urinary urgency, pseudobulbar palsy, and ambulation loss [4].

Cognitive impairment and dementia

Recurrent subcortical ischemic events in CADASIL patients often result in a stepwise, progressive cognitive impairment and a dementia [37]. Cognitive impairment is the second most common clinical manifestation in CADASIL, frequently leading to disability [38]. Subtle cognitive impairment including deteriorations in executive function and working memory/attention, occurs in patients long before the presence of subcortical ischemic events or dementia, which can be detected using various neuropsychological tests such as Wisconsin Card Sorting Test, Trail Making Test, Rey-Osterreith Complex Figure Test, Brief Memory and Executive Test, and Montreal Cognitive Assessment [38], [39]. The pattern of cognitive impairment seems different between patients under the age of 60 years compared to older patients. Early cognitive impairment is variable but deterioration in executive function is the most frequent cognitive impairment in patients younger than 50 years. Patients 60 years old or older, however, have impairments in all cognitive domains including executive function, memory, attention, visuospatial ability, and reasoning [37]. Dementia in CADASIL is a pure subcortical vascular dementia, and it is characterized by executive dysfunction, processing speed impairment, and frontal lobe features. One third of CADASIL patients are demented at the end stage of the disease, and approximately 60% of demented patients are older than 60 years [38], [39], [40]. The pattern of memory impairment in dementia of CADASIL differs from that in Alzheimer’s disease. For example, demented CADASIL patients often display improved memory with cues, suggesting that the encoding process is relatively preserved even during the end stage of CADASIL [37].

Psychiatric disturbances

The reported prevalence of psychiatric disturbances in CADASIL patients ranges from 20% to 41% [41]. Although psychiatric disturbances are typically observed after diagnosis, they may be the initial manifestation of CADASIL in up to 15% of cases, particularly in young patients, often underdiagnosed or misdiagnosed. Therefore, CADASIL should be considered in the initial differential diagnosis of psychiatric symptoms [42]. Mood disorders including major depression, bipolar disorders and mania, dysthymia, and suicidal attempts, are the most frequently reported psychiatric disturbances, noted in 9% to 41% of CADASIL patients. Depression is the most common and serious mood disorder, and major depression was manifested in 21% of patients [36], [41]. Apathy is also commonly observed in CADASIL patients, and a frequency of 41% was observed in a large CADASIL cohort [43]. Other psychiatric disturbances reported in CADASIL patients include anxiety disorders, adjustment disorders, agoraphobia, behavioural and personality disorders, psychotic disorders and delusion, panic disorders, drug addiction or alcoholism, hallucinations, and schizophrenia [38], [41].

Parkinsonism and other movement disorders

Up to 9% of patients with Parkinson’s disease may have NOTCH3 mutations, typically associated with WMHs on MRI [44]. Some cases diagnosed as CADASIL associated with NOTCH3 mutations, present with parkinsonism, consistent clinically with vascular parkinsonism [45], [46]. In addition to vascular parkinsonism, CADASIL may be associated with other atypical parkinsonian phenotypes including progressive supranuclear palsy and multiple system atrophy [47]. Besides hypokinetic disorders, hyperkinetic movement disorders such as chorea and dystonia have been reported in association with CADASIL [48], [49].

Atypical clinical manifestations

CADASIL patients are at increased risk for intracerebral hemorrhage, which was once considered to be rare and was observed in over 20% of CADASIL patients [50]. Acute encephalopathy, also referred to as CADASIL coma, is an acute episode of reduced consciousness as a manifestation of generalized brain dysfunction. The encephalopathic event occurs in over 10% of CADASIL patients, and is self-terminated within days to weeks in the absence of specific therapy [51]. Approximately one tenth of CADASIL patients present with epileptic seizures, most of which occur at late stage of the disease [52]. Cardiac involvement including ischemic heart disease was observed in CADASIL patients, as a heavy disease burden in younger sufferers [53]. Reduced heart rate variability was reported in 23 CADASIL patients, which may be associated with life-threatening arrhythmias and sudden death [54]. However, in another case-control study involving 23 CADASIL patients, no evidence for increased rate of myocardial infarcts or arrhythmias in CADASIL was found [55]. A high prevalence of cardiac right-to-left shunt was described in a CADASIL population, which may be due to the role of notch receptor family in the development of cardiovascular system [56].

MRI features

Brain MRI, particularly the T2-weighted and the FLAIR sequences, is the most important radiologic method for the diagnosis and evaluation of CADASIL patients [42], [57]. The main characteristic MRI presentations in CADASIL patients include symmetrical WMHs, lacunar infarcts, and CMBs. Other MRI features include lacunes, increased ventricular volume, brain atrophy, and dilated perivascular spaces [23], [24], [58]. Development of neuroimaging can be of benefit to the early diagnosis, therapy, and mechanistic studies, as well as predictive approach [58], [59], [60].

WMHs

WMHs represent the earliest and most common MRI changes of CADASIL typically manifested as punctate, patchy, or confluent white matter high signal intensities on T2-weighted and FLAIR sequences [57], [61]. WMHs, also termed periventricular leukoencephalopathy, are the radiological manifestation of underlying leukoaraiosis, reflecting white matter lesions with the degenerated macromolecular structure and the water-rich contents [62], [63]. These lesions are frequently detected in presymptomatic stage of CADASIL patients, increasing with age. The youngest mutant carrier displaying subcortical increased T2 high signal intensities of white matter lesions was only 8 years old [60], [64].

WMHs in CADASIL often bilaterally and symmetrically involve the periventricular region, anterior temporal pole, frontal and parietal areas, as well as external capsule. WMHs in the anterior temporal pole may have an important diagnostic significance with a high specificity and sensitivity [62], [65]. However, sensitivity of anterior temporopolar WMHs in Chinese CADASIL populations was reported to be 42.9% to 46%, much lower than the sensitivity of 89% to 95% in Caucasian patients [32]. WMHs in the corpus callosum on FLAIR sequences, but not WMHs in general, were found to be associated with clinical severity [66].

MRIs in patients with CARASIL typically show WMHs that are more homogeneously confluent, with the typical hyperintensities in the pons (“split pons sign”) developing later in the course [67]. In contrast, CARASAL-associated WMHs are more likely to involve the basal ganglia rather than the anterior temporal region [65], [68].

The pathophysiological mechanisms underlying WMHs in CADASIL remain to be elucidated. In addition to prevailing hypothesis of hypoperfusion and disruption of the blood–brain barrier, decreased cerebrovascular reactivity is also considered an important contributor to the development of WMHs in CADASIL [59], [61], [63]. It has been suggested that WMHs in CADASIL are composed of distinct subsets but the mechanisms of WMHs in different areas may vary. WMHs in anterior temporal poles and superior frontal areas are related to milder clinical phenotype, and they are attributed to mechanisms different from WMHs in other white matter areas [69]. WMHs in temporal poles predominantly ascribe to dilated perivascular space and degenerated myelin with insufficient drainage of the interstitial fluid [70].

Lacunar infarcts and lacunes

Though terms “lacunar infarct” and “lacune” are often used interchangeably, they are actually distinct [71]. Lacunar infarcts, also known as recent small subcortical infarcts, are small subcortical ischemic lesions in variable shapes such as rounded, ovoid, or tubular, with an axial diameter no more than 20 mm [72]. Blockage of cerebral penetrating arteries is presumed to be the primary cause for lacunar infarcts. They can present as lacunar syndromes, but may symptomatically silent [73]. An acute lacunar infarct has a similar signal intensity to white matter lesion on T2-weighted and FLAIR sequences, and can be identified by hyperintense signal on diffusion-weighted imaging (DWI) sequence [71], [73]. A proportion of acute lacunar infarcts, whether symptomatic or silent, may progress to lacunes with time, while some leave small lesions still retaining a signal characteristic resembling WMHs or disappear completely [72].

Lacunes are cerebrospinal fluid (CSF)-containing cavities located in the deep gray or white matter with a diameter of 3 to 15 mm, and most have a volume far less than 500 mm3 in CADASIL [72], [74]. Most lacunes are clinically silent and detected incidentally by neuroimaging, with a similar signal intensity to CSF in all sequences of MRI and surrounded by a hyperintense rim on FLAIR sequence. Since the hyperintense rim on FLAIR sequence is sometimes absent in lacune, and a perivascular space can also be surrounded by a hyperintense rim when passing through an area of WMH, over 3 mm in diameter is recommended as the criterion to discriminate lacunes from dilated perivascular space. In addition to the cavitation of acute lacunar infarcts, lacunes may also result from intracerebral hemorrhages. The proportion of cavitation after acute lacunar infarcts varies from 28% to 94% in different studies [73]. Therefore, epidemiologic and pathophysiologic studies that simply counted lacunes as lacunar infarcts and extrapolated from lacunar infarcts to lacunes may establish spurious associations between lacunar infarcts and other dysfunctions in CADASIL [71]. In CADASIL, lacunes appear to have a preference to occur at the edge of WMHs, possibly indicating shared mechanisms of lacunes and WMHs [75].

CMBs

CMBs are ovoid, spherical, round, or dot-like, and well-demarcated lesions easily recognized on T2*-weighted gradient-recalled echo and susceptibility-weighted imaging (SWI) with a hypointense signal and a diameter of 2 to 10 mm [76], [77]. The blooming effect of CMBs is displayed on MRI by focal areas of signal voids on T2*-weighted gradient-recalled echo planar images larger than those on T2-weighted spin echo images, which can be used to differentiate them from areas of signal voids originating from vascular flow voids [78]. They result from the rupture of vessels with a diameter less than 0.2 mm, and histopathologically they are perivascular focal accumulations of hemosiderin-laden macrophages [78], [79]. In CADASIL, CMBs are observed in 34% of patients and occur throughout the deep subcortical, lobar, and infratentorial regions. A history of hemorrhagic stroke, dementia, and urge incontinence appear to be related to the increased number of CMBs. Patients with migraine were reported to have a reduced number of CMBs compared to those without migraine [77]. The presence of CMBs strongly increases with advanced age and may be associated with intracerebral hemorrhage, and hypertension may exert a region-dependent effect on CMB volume [50], [77], [80].

Other features

Another feature of CADASIL is increased ventricular volume, attributed to damage to brain parenchyma surrounding the ventricles, particularly deep white matter tracts or gray matter, associated with WMHs, lacunar infarcts, and CMBs. Increased ventricular volume, as well as lacunar infarcts and CMBs, is associated with cognitive impairment in patients with CADASIL [81]. Brain atrophy in CADASIL may occur as a consequence of accumulated lacunar lesions and cerebral tissue microstructural damages [82]. Dilated perivascular spaces are round, ovoid, or linear fluid-filled spaces with a CSF-similar signal intensity on all MRI sequences with a diameter smaller than 3 mm, and predominantly located within the temporal pole and basal ganglia, paralleling the vessel’s course. The severity was found to increase with age and be related to cognitive decline in CADASIL patients [83]. Abnormalities of cerebral small vessel function, including lower blood flow velocity and higher pulsatility index, were demonstrated within perforating arteries of the centrum semiovale and basal ganglia using 7T-MRI [59]. These may explain a relatively high prevalence of parkinsonism with or without dementia in patients with CADASIL-related CSVD [44], [45], [84].

Pathological features

Pathological changes include cystic softening in the white matter, corpus callosum, internal capsule, basal ganglia, thalamus, and brainstem, a diffuse myelin loss in the hemispheric white matter (with the U fibers preserved), and widespread neuronal apoptosis in the cerebral cortex [85], [86]. CADASIL may cause a specific arteriopathy characterized by progressive degeneration and loss of VSMCs, thickening and occasional splitting of arteriolar wall due to fibrosis and hyalinization, lumen stenosis and occlusion of some arterioles [87], [88]. VSMCs of CADASIL patients displayed increased proliferation and apoptosis, and cytoskeleton disorganization [89]. This arteriopathy is systemic but mainly affects cerebral small to medium-sized penetrating arteries and leptomeningeal arteries. The most characteristic ultrastructural change of CADASIL is the GOM accumulating close to the membrane infoldings of VSMCs and pericytes [85], [87], [88]. GOM is periodic acid-Schiff (PAS)-positive, but also stains eosinophilic or basophilic. Under electron microscopy (EM), GOM deposits are visible as particles of tightly aggregated and fine electron-dense granule materials with a size of 10–15 nm. In most of CADASIL patients, GOMs are immunoreactive for NOTCH3 extracellular domain (NOTCH3ECD), suggesting NOTCH3ECD is an important component of GOM. However, GOM was found to be negative for extracellular domains [85], [87], [90]. Skin biopsy to detect GOM has a sensitivity varying from 45% to 90%, and recently GOM has also been observed in the collagen beta(1-O)galactosyltransferase 1 gene-associated CSVD [91], [92]. Therefore, the presence of GOM is characteristically present in the brains of patients with CADASIL but is not considered a pathognomonic feature to differentiate it from other similar CSVD.

Genetic diagnosis of NOTCH3-associated CSVD

In 1996, the NOTCH3 gene, a member of NOTCH gene family and mapped to chromosome 19p13.12, was first identified as the causative gene for CADASIL [17]. It has 33 exons and codes for a transmembrane receptor protein of 2,321 amino acids, predominantly expressed in VSMCs and pericytes [90], [93]. It plays an important role in the vascular development and function by regulating the proliferation, differentiation, maturation, migration, and apoptosis of VSMCs, as well as the proliferation of pericytes [94], [95]. After synthesized in the endoplasmic reticulum (ER), the full-length NOTCH3 protein (∼280 kDa) is subject to proteolytic cleavages, and releases a NOTCH3ECD and an intracellular domain (NOTCH3ICD). The NOTCH3ECD is composed of 34 epidermal growth factor-like repeat (EGFr) domains encoded by exons 2 to 24 and three lin12/notch repeats (Fig. 2A) [90]. Each EGFr domain contains six cysteines with a conserved number and position, and these six cysteines form three disulphide pairwise bridges, which stabilize the EGFr domain and contribute to the protein’s tertiary structure [96].

Fig. 2.

Fig. 2

Schematic representation of the wild-type and mutant NOTCH3 protein, and missense NOTCH3 mutations in 34 EGFr domains. Schematic diagrams were created by Illustrator for Biological Sequences software (version 1.0, https://ibs.biocuckoo.org/) referred to Universal Protein Knowledgebase Q9UM47. (A) Main conserved domains of human NOTCH3 protein and distribution of missense NOTCH3 mutations causing NOTCH3-associated CSVD in 34 EGFr domains. NOTCH3ECD contains a signal peptide and 34 EGFr domains followed by LNR. NOTCH3ICD contains ANK repeats. Locations of S1, S2, and S3 cleavage sites as well as TMD are indicated. The cysteine-altering and cysteine-sparing missense mutations from Human Gene Mutation Database are shown. (B) The cysteine-altering missense mutation (e.g., previously identified p.G111C mutation in EGFr domain 2 [22]) results in an unpaired cysteine residue and is predicted to disrupt disulphide bridge formation in the EGFr domain by ScanProsite (https://prosite.expasy.org/scanprosite/). ANK, ankyrin; LNR, lin12/notch repeat; TMD, transmembrane domain.

Over 350 mutations throughout the EGFr domains, especially EGFr domains 2 to 5, have been reported according to the Human Gene Mutation Database (HGMD), and more than 76% of these mutations are missense mutations changing the number of cysteines (Fig. 2A). Missense, nonsense, insertion, deletion, and splice-site mutations, causing a numerical change of cysteines in the EGFr domain, are well-known to cause CADASIL [94], [96]. The frequency of cysteine-changing mutations in the general population is about 1/300, more common than expected. However, the genotype-phenotype association has not been firmly established. Mutations in EGFr domains 1 to 6 may cause a more severe phenotype with earlier age at stroke onset, lower survival time, and greater brain MRI lesions than mutations in EGFr domains 7 to 34, with lower vascular NOTCHECD aggregates [20], [97]. Based on genotype-phenotype correlative analyses, CADASIL cohorts, and population databases, the three-tiered EGFr risk classification found a high-risk group linked to the EGFr domains 1–6, 8, 11, and 26 [98]. Cysteines and disulphide bonds exert a critical role in normal protein structure maintenance, and the alternation-induced unpaired cysteine residue is unable to form disulphide bridge, which may lead to EGFr domain misfolding (Fig. 2B). The mutant NOTCH3ECD with enhanced multimerization properties accumulate around VSMCs and brain pericytes resulting in accumulation of wild-type NOTCH3 protein and other functionally important extracellular matrix proteins such as tissue inhibitor of metalloproteinases 3 (TIMP3), vitronectin (VTN), and latent TGF-β binding protein 1. These recruited proteins may be required for VSMCs, or have toxic effects on vascular cells, finally resulting in brain vessel dysfunction [99], [100], [101]. This toxic gain-of-function mechanism was further validated by NOTCH3ECD aggregates detected at a very early stage of the disease both in patients and mouse models [102]. The accumulation of TIMP3 and VTN due to NOTCH3ECD aggregates play a role in cerebral blood flow deficits and white matter lesions, respectively [103]. The abnormal TIMP3-ADAM17 (a disintegrin and metalloproteinase domain-containing protein 17) signaling increases in the number of voltage-dependent potassium channels in the membrane of VSMC, which may impair the pressure-induced vasoconstriction of brain arterioles [104], [105]. NOTCH3ICD can mediate transcriptional activation of target genes via interacting with recombination signal binding protein for immunoglobulin kappa J region (Fig. 3) [106].

Fig. 3.

Fig. 3

Schematic representation of the canonical NOTCH3 signaling pathway and aberrant NOTCH3-NOX5/ER stress/ROCK signaling pathway in CADASIL. After synthesized in ER, NOTCH3 is cleaved by furin at S1 in the trans-Golgi. NOTCH3ECD is non-covalently linked to NOTCH3TMIC at HD. Upon ligand (DLL1, 3, and 4/JAG 1 and 2) binding at EGFr domains 10–11, the NOTCH3 receptor is activated. The bound ligand and NOTCH3ECD are trans-endocytosed into the signal-sending cell, which perhaps dissociates the HD and exposes S2 to ADAM 10/17 cleavage. The γ-secretase cleavage occurs at the intramembranous S3 and releases NOTCH3ICD which translocates to the nucleus. In the absence of NOTCH3ICD, RBPJ interacts with transcription Co-Rs to repress transcription of target genes. NOTCH3ICD displaces the co-repressor complex from RBPJ and recruits transcription Co-As, resulting in transcriptional activation of target genes. Increased NOTCH3 signaling promotes ROCK activity, and increases ER stress through inducing NOX5-derived ROS. ADAM, a disintegrin and metalloproteinase domain-containing protein; Co-As, co-activators; Co-Rs, co-repressors; DLL, delta like canonical notch ligand; HD, heterodimerization domain; JAG, jagged canonical notch ligand; NOTCH3TMIC, NOTCH3 transmembrane and intracellular domain; RBPJ, recombination signal binding protein for immunoglobulin kappa J region; ROS, reactive oxygen species.

In vitro studies have demonstrated that CADASIL-causing NOTCH3 mutations have variable impacts on NOTCH3 signaling activity. Most of them seemed to retain normal canonical NOTCH3 function, but some may impair NOTCH3 signaling activity [106], [107]. Similar results were presented in some in vivo studies. In CADASIL mouse model, the p.R90C mutation retained normal signaling activity, while the p.C428S, p.C455R, and p.R1031C mutations decreased the signaling activity [108], [109], [110]. Interestingly, the p.R169C mutation seemed to increase NOTCH3 signaling activity [111]. One explanation is that both increased and reduced NOTCH3 signaling may act as a modifier to the CADASIL phenotype via Goldilock pathway [112]. Some cysteine-sparing mutations may also change NOTCH3 signaling activity, and a missense mutation p.L1515P was reported to cause CADASIL-like phenotype via destabilizing the heterodimer and hyperactivating NOTCH3 activity [113]. Moreover, in CADASIL VSMCs, hyperactive NOTCH3 signaling was found to promote Rho associated coiled-coil containing protein kinase (ROCK) activity and ER stress by driving expression of NADPH oxidase 5 (NOX5), and this NOTCH3-NOX5/ER stress/ROCK signaling is related to the altered growth and cytoskeletal organization of VSMCs [89].

Loss-of-function mutation including nonsense and frameshift mutations are reported in some patients with partial CADASIL features [18]. Skin biopsy performed in some cases revealed the absence of GOM deposits and/or NOTCH3 accumulation [114], [115], [116]. In a consanguineous family, a homozygous NOTCH3 nonsense mutation c.2898C>A (p.C966X) was identified in a patient with early-onset arteriopathy and cavitating leukoencephalopathy, and CADASIL-like VSMCs degeneration without GOM deposits was observed in this patient. The heterozygous parents are asymptomatic but displayed a lesser vessel degeneration [117]. Biallelic cysteine-sparing NOTCH3 mutations, a homozygous frameshift mutation c.29_53del (p.R10HfsX16) and compound heterozygous mutations, c.5830C>T (p.H1944Y) and c.5926dup (p.L1976PfsX11), were reported in three patients from two unrelated pedigrees with early-onset vascular leukoencephalopathy, different from CADASIL [116]. Notch3−/− mice lacked GOM deposits and CADASIL phenotype, but displayed an arteriopathy characterized by progressive degeneration and VSMCs loss in cerebral arteries [102], [118]. These reported cysteine-sparing NOTCH3 mutations may contribute to an incomplete CADASIL phenotype via altering NOTCH3 signaling activity. More clinical and functional studies are needed to reveal the accurate pathogenesis of this NOTCH3-associated CSVD.

Some patients were clinically suspected of CADASIL but sequencing analysis of 2–24 exons or all exons of the NOTCH3 gene revealed a negative result [119], [120]. Incomplete NOTCH3 exon-sequencing analysis may miss the NOTCH3 activity-altering mutations outside of the EGFr-encoding exons, and intronic mutations, large deletions, multiplications, or large rearrangements in the NOTCH3 gene might be missed due to technical limitation of direct sequencing [18]. Additionally, CADASIL phenotype may also have other potential genetic causes besides NOTCH3, especially other NOTCH family member genes.

Mutations in the NOTCH3 gene can also result in Mendelian disorder(s) unrelated to CADASIL, which may due to pleiotropy [121], [122]. Nine heterozygous truncating mutations in the last exon of the NOTCH3 gene can cause lateral meningocele syndrome which is characterized by meningoceles, facial abnormalities, and hypotonia. These mutations lead to the loss of sequences for NOTCH3ICD degradation and thus increasing NOTCH3 signaling effects [122], [123]. A heterozygous NOTCH3 c.4556T>C (p.L1519P) variant was reported to co-segregate with infantile myofibromatosis in a family, and point mutations in exon 25 were further identified in nine pericytic tumors with variable morphology [124], [125].

Differential diagnosis

HTRA1-associated CSVD

Heterozygous mutations in the HTRA1 gene located on chromosome 10q26.13 were identified in patients with a hereditary CSVD phenotype characterized by recurrent cerebral infarction, cognitive decline, gait disturbance, and white matter lesions, which raised the possibility that heterozygous HTRA1 mutation may be a genetic cause for a portion of the NOTCH3-negative CADASIL-like disorders [19], [126]. The OMIM database classified this HTRA1-associated autosomal dominant CSVD as a subtype of CADASIL, named CADASIL2, but there is no consensus on this classification. In most studies, this disorder was considered as a separate disease entity although it mimics the clinical features of NOTCH3-associated CSVD [126], [127]. HTRA1-associated autosomal dominant CSVD is reported to be clinically distinguished from CADASIL by late-onset age and rare migraine with aura, and some HTRA1-associated autosomal dominant CSVD patients manifested with extraneurological symptoms including spondylosis and alopecia [127], [128]. Homozygous and compound heterozygous mutations in the HTRA1 gene account for CARASIL. Pathological studies on patients with heterozygous HTRA1 mutations revealed vascular changes characterized by intimal proliferation, hyaline degeneration of media, splitting of the internal elastic lamina, and loss of smooth muscle cells without GOM deposits in small vessels, which is similar to those in CARASIL patients caused by homozygous or compound heterozygous HTRA1 mutations [129], [130], [131], [132]. The impaired HTRA1 protease activity caused by a dominant-negative effect or nonsense-mediated mRNA decay seems to play an important role in HTRA1-associated autosomal dominant CSVD [127]. In fact, the HTRA1-associated autosomal dominant CSVD seems to be manifested as a mild phenotype of CARASIL, and these two disorders can be termed as HTRA1-associated CSVD (Table 1) [131], [132], [133].

At least 23 homozygous and two compound heterozygous HTRA1 mutations have been reported in 30 CARASIL families including 20 consanguineous families. Up to now, no less than 80 heterozygous HTRA1 mutations have been reported to cause a CADASIL-like phenotype in 122 different families. Thirteen HTRA1 mutations including p.A20V, p.E42DfsX173, p.R166C, p.A252T, p.P275L, p.E277VfsX61, p.P285L, p.G295R, p.V297M, p.R302X, p.D320N, p.A321T, and p.R370X cause CSVD in both heterozygote and homozygote/compound heterozygote within or among families (Supplementary Table S1) [132]. Thus, HTRA1-causing CADASIL-like disorder and CARASIL may be classified as HTRA1-associated CSVD inherited in an autosomal-dominant manner based on the convergence of genetic, clinical, neuroimaging, and pathologic evidence.

Recently, HTRA1 was found to accumulate within cerebral vessels of CADASIL patients and colocalize with NOTCH3ECD. Moreover, a portion of enriched HTRA1 substrates were observed in cerebral vessels of clinically diagnosed CADASIL patients, indicating that a loss of HTRA1 activity may have a certain relationship with the deposition of NOTCH3ECD, further leading to the overlaps in the phenotypes of NOTCH3-associated CSVD and HTRA1-associated CSVD, possibly via shared molecular pathways [134].

CARASAL

CARASAL is another CADASIL-like disorder. It is an ultra-rare monogenic CSVD caused by heterozygous mutations in the cathepsin A gene (CTSA). To yet, only 16 CARASAL patients with c.973C>T (p.R325C) mutation as well as five clinically suspected patients without genetic confirmation have been reported [135], [136], [137], [138], [139]. The relationship between CTSA and CARASAL needs to be confirmed, and this disorder has not been recorded in the OMIM currently. Phenotypic spectrum of CARASAL mainly include migraine, TIA, ischemic stroke, cognitive impairment, movement disorder, gait disturbance, therapy-resistant hypertension, and depression [138], [139]. MRI scanning reveals that WMHs involve the brainstem, periventricular and deep white matter with the U-fibers sparing, while lacunes and CMBs are rare [138]. The vasculopathy is characterized by diffuse angiosclerosis of arterioles without GOM deposits [135].

The CTSA gene is located on chromosome 20q13.12 and codes for cathepsin A protein. In CARASAL patients, cathepsin A-expressing astrocytes were present throughout the white matter. Cathepsin A is a carboxypeptidase mainly expressed in lysosomes and can promote the stabilization of lysosomal enzymes β-galactosidase and neuraminidase-1 [140], [141]. It was postulated that p.R325C mutation causing additional disulphide bridge may interfere with stabilization, folding, and structure of cathepsin A, producing a toxic effect [135]. Moreover, cathepsin A mediates the inactivation of endothelin-1 and the p.R325C mutation may decrease cathepsin A activity, which can increase endothelin-1 levels and contribute to white matter lesions. Diagnosis of CARASAL and analysis of the CTSA gene should be considered for CADASIL-like patients without mutations in NOTCH3 and HTRA1 [141].

Therapy

Currently, no definitive treatment of proven efficacy has been established for CADASIL. Most therapies for CADASIL empirically follow regular treatment practices that focus on mitigating symptoms and managing vascular risk factors by pharmacological approaches [6], [142]. Antiplatelet therapy may be considered as a prophylactic treatment for prevention of recurrent ischemic strokes, but anticoagulants should be avoided as they may increase the risk of cerebral hemorrhage. Secondary prevention by the control of vascular risk factors, such as hypertension, diabetes, hypercholesterolaemia, hyperhomocysteinemia, and smoking, is the cornerstone of treatment designed to minimize the risk of cerebrovascular events. Symptomatic treatment with common analgesics and prophylactic strategies of migraines may be considered, particularly in patients with high-frequency attacks, as well as regular psychiatric drugs for clinical benefits [4], [6], [142], [143], [144].

Pathogenesis-targeted therapeutic interventions, including antisense oligonucleotides-based NOTCH3 cysteine corrective exon skipping, growth factor administration, and immunotherapy by agonist NOTCH3 antibody to prevent loss of VSMCs and pericytes, have been explored, which are meaningful for the potential application of experimental approaches in the therapy for CADASIL, as well as targeted prevention in the future [27], [96], [145]. Silencing the NOTCH3 gene in VSMCs using short hairpin RNA (shRNA) can lead to actin cytoskeletons alterations similar to those in CADASIL VSMCs, which provide insights into silencing the mutated NOTCH3 gene by shRNA to inhibit its toxic gain-of-function [146]. Active immunization therapy targeting NOTCH3ECD aggregation was well tolerated and reduced NOTCH3 deposition in brain capillaries, increased microglia activation, and lowered serum NOTCH3ECD levels in a CADASIL mouse model with human NOTCH3 R182C mutation, suggesting a potential therapy with beneficial clinical application [147]. Several potential drugs for targeting molecules such as TIMP3 and VTN involving in NOTCH3 deposition were found by omic techniques [5].

Conclusions and future perspectives

CADASIL is a term for a CSVD phenotype comprising several and heterogeneous manifestations. Though CADASIL has been extensively studied during the past several decades with the development of diagnostic and experimental techniques, its exact pathogenesis remains enigmatic [27], [148]. The discovery of NOTCH3 as the genetic cause for CADASIL paved the way for facilitating the diagnosis of CADASIL and a better understanding of its pathogenesis [149]. Genetic studies have identified at least 354 NOTCH3 mutations causing NOTCH3-associated CSVD, and about 78% of them are pathogenic by altering cysteine residues in 34 EGFr domains. Thus, toxic gain-of-function effect by accumulation of NOTCH3ECD appears to be the predominant pathogenic mechanism for NOTCH3-associated CSVD. Genetic testing to identify NOTCH3 mutations is presently the only gold standard for the diagnosis of NOTCH3-associated CSVD [97], [119].

Though NOTCH3-associated CSVD is well studied, there are many reports of GOM-negative and NOTCH3-negative CADASIL-like cases [119]. The heterozygous HTRA1 and CTSA mutations were reported to account for a portion of these NOTCH3-negative cases with CADASIL-like phenotype [19], [138]. HTRA1-causing CADASIL-like and CARASIL may be classified as a specific novel genetic disorder, HTRA1-associated CSVD, based on family history, clinical phenotype, neuroimaging, and pathology. Compromised HTRA1 protease activity may underlie HTRA1-associated CSVD [129], [130], [131]. Phenotypic overlap between NOTCH3-associated CSVD and HTRA1-associated CSVD may be attributed to the potential association between HTRA1 loss of function and the accumulation of NOTCH3ECD [134]. The potential pathogenesis for CARASAL may be the additional disulphide bridge and decreased cathepsin A activity by the CTSA cysteine-altering mutation [141]. Genetic screening focusing on HTRA1 and on CTSA in large CADASIL-like cohorts without NOTCH3 mutations will help clarify the prevalence, clinical phenotype, and mutation spectrum of HTRA1-associated and CTSA-associated CSVDs. HTRA1-associated and CTSA-associated CSVDs deserve more attention as they may provide insights into the mechanisms and pathophysiology of ischemic strokes, vascular parkinsonism and dementia, and other brain vascular disorders [142], [149].

Gene diagnosis based on molecular genetics facilitates differentiating NOTCH3-associated CSVD from HTRA1-associated CSVD and CTSA-associated CSVD. In the future, translational research combining functional and clinical studies should concentrate on the role of NOTCH3 protein aggregation and signaling activity in NOTCH3-associated CSVD and the functional relationship between NOTCH3 and HTRA1, which may provide insights into the exact pathogenesis of the NOTCH3-associated CSVD, and further facilitate the diagnosis and development of pathogenesis-targeted therapies tailored to the individual needs, as well as a multi-disciplinary predictive, preventive, and personalized approach for effective disease management [145], [150], [151], [152], [153], [154].

Funding

This work was supported by National Natural Science Foundation of China (81873686 and 81800219), Natural Science Foundation of Hunan Province (2020JJ3057 and 2020JJ4830), the Key Scientific Research Project of Health Commission of Hunan Province (A202303018385), the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University (YX202109), and Distinguished Professor of the Lotus Scholars Award Program of Hunan Province, China.

CRediT authorship contribution statement

Lamei Yuan: Conceptualization, Visualization, Writing – original draft, Funding acquisition. Xiangyu Chen: Conceptualization, Visualization, Writing – original draft. Joseph Jankovic: Conceptualization, Writing – review & editing. Hao Deng: Conceptualization, Writing – original draft, Writing – review & editing, Supervision, Funding acquisition.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Biographies

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LameiYuan is the Associate Professor of Center for Experimental Medicine, the Third Xiangya Hospital, Central South University. She obtained her Ph.D. at the Central South University. Her current research focuses on the molecular biology and diagnostics of human genetic disorders. She is a (co)author of over 80 papers in international peer-reviewed journals.

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XiangyuChen is currently in residency training at Department of Pathology, Changsha Maternal and Child Health Care Hospital. He obtained his Master’s degree at the Central South University. His current research focuses on the pathogenesis of human genetic disease.

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JosephJankovic is the Professor of Neurology, Distinguished Chair in Movement Disorders, and Founder and Director of the Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine. He obtained his M.D. from University of Arizona College of Medicine, and completed his neurology training at Columbia University. He joined the Baylor College of Medicine faculty in 1977. His current research focuses on the etiology, pathophysiology, and experimental therapeutics of neurological disorders. He is a member of many scientific and medical advisory boards. He is a (co)author of over 1200 papers in international peer-reviewed journals and over 50 books.

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HaoDeng is the Professor and Director of Center for Experimental Medicine, the Third Xiangya Hospital, Central South University. He obtained his Ph.D. at the Central South University, and completed his postdoctoral training at Baylor College of Medicine. His current research focuses on the molecular biology and diagnostics of human genetic disorders. He is a member of the Editorial Board of several international journals and a reviewer of more than 40 international journals. He is a (co)author of over 200 papers in international peer-reviewed journals.

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jare.2024.01.001.

Appendix A. Supplementary data

The following are the Supplementary data to this article:

Supplementary data 1
mmc1.doc (530KB, doc)

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