A number sign (#) is used with this entry because of evidence that autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 1 (CADASIL1) is caused by heterozygous mutation in the NOTCH3 gene (600276) on chromosome 19p13. Some patients with the same phenotype have homozygous or compound heterozygous mutations in the NOTCH3 gene.

Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy-1 (CADASIL1) is an adult-onset progressive disorder of the small arterial vessels of the brain manifest by migraine, strokes, and white matter lesions, with resultant cognitive impairment in some patients (review by Kalimo et al., 1999). The disorder shows incomplete penetrance and variable expressivity. Although CADASIL1 is classically associated with heterozygous mutations, many patients with an indistinguishable phenotype carry biallelic NOTCH3 variants, usually variants involving cysteine residues (Iruzubieta et al., 2024). CADASIL1 thus appears to follow the classic definition of an autosomal dominant disease, in which the phenotypes of heterozygous and homozygous patients are indistinguishable (Zlotogora, 1997). Phenotypic variability of CADASIL1 may be due to incomplete penetrance and additional genetic or non-genetic factors.

Genetic Heterogeneity of Autosomal Dominant Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

CADASIL2 (616779) is caused by mutation in the HTRA1 gene (602194) on chromosome 10q26.

Stevens et al. (1977) reported an English family with onset of recurrent cerebral ischemic strokes between 39 and 57 years resulting in progressive neurologic dysfunction and eventual dementia. Affected individuals did not have hypertension, diabetes, or increased cholesterol, but neuropathologic investigation showed abnormalities of the cerebral vasculature; the authors suggested that it was a form of 'vascular encephalopathy.' Low et al. (2007) provided a follow-up of the family reported by Stevens et al. (1977), including confirmation of the CADASIL diagnosis by identification of a pathogenic mutation in the NOTCH3 gene.

In a family originating from northern France, Mas et al. (1992) described a genetic disorder characterized by recurrent attacks of focal brain dysfunction starting in mid-adulthood and leading in some to severe motor disability with pseudobulbar palsy and dementia of the subcortical type. Neuroimaging evidence of leukoencephalopathy and well-circumscribed lesions consistent with small deep infarcts were found in clinically affected individuals as well as in some asymptomatic members of the family. Although there was an instance of first-cousin marriage in the family, Mas et al. (1992) thought that the pedigree pattern suggested autosomal dominant inheritance. Members of 4 successive generations were thought to be affected. The only instance of male-to-male transmission was from a deceased father who was probably affected and an asymptomatic son who was affected by evidence on neuroimaging. Although Mas et al. (1992) thought their family represented a distinct disorder, it is quite possible that all of these reports related to the same condition. See also the large family reported by Tournier-Lasserve et al. (1991) in which of 45 subjects studied, 9 were clinically affected and 8 others, although clinically asymptomatic, had MRI signs of leukoencephalopathy.

Baudrimont et al. (1993) reported the pathologic findings in 1 of the affected members of the family reported by Tournier-Lasserve et al. (1991). A previously healthy woman was 40 years old when she first experienced a grand mal seizure. Twelve years later she suffered 2 other grand mal seizures and thereafter had recurrent strokes as well as psychiatric disturbances (depression, manic episodes, and dementia). After a stroke at the age of 57, she became tetraplegic with severe pseudobulbar palsy and died 2 years later. Pathologic examination demonstrated a recent capsulolenticular hematoma, multiple small deep infarcts, diffuse myelin loss and pallor of the hemispheric white matter, and a widespread vasculopathy of the small arteries penetrating the white matter. The arterial wall was markedly thickened with an extensive nonamyloid eosinophilic deposit in the media and reduplication of the internal elastic lamella. Baudrimont et al. (1993) concluded that the underlying lesion in this disorder is located in the small arteries. It differs from both arterial sclerosis and amyloid angiopathies but is similar to that described in some cases of hereditary multiinfarct dementia.

Chabriat et al. (1995) used MRI and genetic linkage analysis to study 148 subjects belonging to 7 families. They concluded that 45 family members (23 males and 22 females) were clinically affected. Recurrent subcortical ischemic events (in 84%), progressive or stepwise subcortical dementia with pseudobulbar palsy (in 31%), migraine with aura (in 22%), and mood disorders with severe depressive episodes (in 20%) were the main features. All symptomatic subjects had prominent signal abnormalities on MRI with hyperintense lesions on T2-weighted images in the subcortical white matter and basal ganglia; the same findings were present in 19 asymptomatic subjects. The mean age at onset of symptoms was 45 years (SD = 10.6), with attacks of migraine with aura occurring earlier in life, at a mean age of 38.1 (SD = 8.03) then ischemic events at a mean age 43.9 years (SD = 10.7). The mean age of death was 64.5 (SD = 10.6) years. On the basis of MRI data, the penetrance of the disease appeared complete between 30 and 40 years of age. Genetic analysis showed strong linkage to chromosome 19 in all 7 families, suggesting genetic homogeneity.

Hutchinson et al. (1995) used MRI to study 15 members of an Irish family, 10 of whom had evidence of CADASIL. Five members of this family had hemiplegic migraine. They proposed that hemiplegic migraine (141500) may be an allelic disorder to CADASIL. However, within this pedigree was a 36-year-old woman who did not have CADASIL by MRI criteria and did not have the CADASIL affected alleles in her haplotype. The authors suggested that this anomalous individual was either a double recombinant or that her hemiplegic migraine was a phenocopy, due to an unrelated mechanism.

Verin et al. (1995) studied the clinical features of 20 symptomatic individuals in a 4-generation pedigree with CADASIL. Verin et al. (1995) believed that this pedigree was distinguished from those previously published by the high frequency of migraine in psychotic mood disorders with early neurologic manifestations. They proposed that the natural history of the phenotype could be viewed in 3 stages. Stage 1 (between 20 and 40 years) is characterized by frequent migraine-like episodes, as well as well-delineated lesions of the white matter; stage 2 (between 40 and 60 years) presents with stroke-like episodes, affective disorders, and coalescent lesions of the white matter lacunae of the basal ganglia; and stage 3 is characterized by subcortical dementia and pseudobulbar palsy.

Glusker et al. (1998) presented the clinical, imaging, and neuropathologic data for a family with an autosomal dominant, nonhypertensive, progressive cerebral arteriopathy and leukoencephalopathy. Clinical presentation was characterized by progressive dementia, gait abnormalities, and, in some, Parkinson-like symptoms. MRI abnormalities, consisting of white matter T2 hyperintensities and cystic-appearing T1 hypointensities, were present in 7 family members. The basal ganglia also showed cystic abnormalities. Neuropathologic examination in 2 cases revealed numerous lacunar infarct-like lesions, extensive demyelination, and widespread hyalinization of arteriolar walls with karyolysis and granular deposits within the media. Affected members occurred in 4 generations. The index patient was referred at the age of 52 years for evaluation of suspected multiple sclerosis. He had right-sided hemiparesis, left-central facial weakness, diffuse bradykinesia, retropulsion, truncal ataxia, and dementia. The mother of the index case was referred at age 71 years. She had mild bradykinesia and diffuse hyperreflexia in all 4 extremities. The family was of Central American ancestry.

Dichgans et al. (1998) described the phenotypic spectrum of 102 biopsy-proven cases of CADASIL in 29 German and Austrian families. The most consistent finding was ischemic episodes, usually classic transient ischemic attacks or lacunar strokes, but occasionally insidious deficits that developed over several days. Cognitive deficits were seen in 59%, migraine in 38%, and epilepsy in 10%. Mean age at death was 53.2 +/- 10.9 years for males and 59.3 +/- 8.8 years for females.

Rufa et al. (2004) described a patient with CADASIL whose first symptom of the disorder was acute unilateral visual loss at age 27 years. The patient was diagnosed as having nonarteritic anterior ischemic optic neuropathy (NAION; 258660) caused by infarction of the optic nerve resulting from local vascular impairment. Electrophysiologic studies showed abnormal visual evoked potentials (VEPs) and electroretinogram (ERG) in the affected eye. His affected son had less severe ocular involvement. Rufa et al. (2004) noted that acute ocular involvement in CADASIL is uncommon.

In 5 patients with CADASIL confirmed by genetic analysis, Rufa et al. (2004) found a reduction in optic nerve head, temporal inferior, and temporal superior blood flow and volume compared to controls. None of the 5 patients had visual symptoms at the time of examination, but all showed abnormal electroretinograms, and 3 showed narrowed retinal arteriolar vessels.

Golomb et al. (2004) reported a 14-year-old girl with a 3-year history of severe headaches, 3 episodes of right hemiparesis (at ages 11, 12, and 14 years) with residual symptoms, persistent hypertension, depression, and a mutation in the NOTCH3 gene. She had no relevant family history. Although several cranial MRI studies were normal, Golomb et al. (2004) suggested that the patient had unusually early-onset CADASIL.

Roine et al. (2005) found that 12 (48%) of 25 Finnish mothers with CADASIL caused by the R133C NOTCH3 mutation (600276.0008) experienced neurologic symptoms in 17 of their 43 pregnancies. The most common symptoms were hemiparesthesia (65%), hemiparesis (36%), aphasia (65%), and visual disturbance (47%). In 82% of the patients with complicated pregnancies, the symptoms were the first manifestations of CADASIL, and they were most common during puerperium and in patients older than 30 years. Roine et al. (2005) concluded that CADASIL may be a risk factor for complicated pregnancies and that CADASIL should be considered in the differential diagnosis of neurologically complicated pregnancies.

Peters et al. (2005) conducted a cross-sectional study of 65 NOTCH3 mutation carriers and 30 matched comparison subjects utilizing a series of assessments that included ratings of global cognition, the cognitive portion of the Vascular Dementia Assessment Scale, and specific tests of executive function and attention with measures of processing speed and error monitoring. CADASIL subjects had pronounced impairments of the timed measures as well as measures of error monitoring. Prominent deficits in verbal fluency and ideational praxis were observed, while recall, orientation, and receptive language skills were largely preserved. Peters et al. (2005) noted that this profile of cognitive impairment was present at an early stage.

Saiki et al. (2006) reported a Japanese family in which 6 members had CADASIL caused by a heterozygous mutation in the NOTCH3 gene (600276.0009). All affected individuals had a history of ischemic episodes and variable features of dementia, hemiparesis, urinary incontinence, dysarthria/dysphagia, migraine, and mood disorders. MRI studies showed lacunar infarctions and subcortical white matter changes. No affected individuals had involvement of the anterior temporal lobes. All affected individuals also had varicose veins that developed between ages 14 and 30. Biopsies of varicose veins from 3 individuals showed marked intimal hypertrophy, localized thinning of smooth muscle layers, and infiltrated fibrous tissue. Venous smooth muscle cells were irregularly shaped and contained granular osmiophilic material. Saiki et al. (2006) noted that varicose veins had not previously been reported in CADASIL.

In a study of 27 Korean patients with CADASIL from 9 unrelated families, Kim et al. (2006) found that clinical features were similar to those reported in other populations, except for the relatively uncommon finding of migraine, which occurred in only 8.3% of patients.

Choi et al. (2006) found that 5 (25%) of 20 patients with genetically confirmed CADASIL had intracranial hemorrhages (ICH), and that ICH was the initial neurologic presentation in 2 patients. All patients had hypertension as a risk factor, and all had been taking antiplatelet agents, except for the 2 who presented with ICH; however these factors were not significantly different from CADASIL patients without ICH. Brain MRI results showed a significant correlation between the development of ICH and the number of cerebral microbleeds.

Pantoni et al. (2010) performed a retrospective analysis and comparison of clinical features in a cohort of 81 patients suspected of having CADASIL, including 16 (20%) who had NOTCH3 mutations and 65 without NOTCH3 mutations. Patients with genetically confirmed CADASIL had a higher frequency of migraine (73% vs 39%), stroke before the age of 60 among relatives (71% vs 32%), severe leukoencephalopathy (94% vs 62%), white matter changes in the anterior temporal lobes (93% vs 45%), external capsule involvement (100% vs 50%), and presence of lacunar infarcts (100% vs 65%), compared to those without mutations. However, the frequency of vascular risk factors was similar between the 2 groups, and no feature was peculiar to either group.

Chitnis and Hollmann (2012) reported a 26-year-old man of Portuguese descent who was found to carry a heterozygous NOTCH3 mutation inherited from his affected mother. Before identification of the mutation, his clinical presentation was similar to that of Balo concentric sclerosis, a rare disorder associated with demyelinating diseases, such as multiple sclerosis (126200). He had subacute onset of right-sided hemiparesis and dysmetria, right-sided extensor plantar responses, and aphasia. Brain MRI showed multiple bilateral concentric ring-like structures in the centrum semiovale and the corona radiata on T2 imaging. CSF analysis showed leukocytes and erythrocytes with absent oligoclonal bands. Plasmapheresis exchanges resulted in significant improvement. One year later, his neurologic examination was essentially normal. Chitnis and Hollmann (2012) raised questions about the role of the NOTCH3 mutation in this patient's presentation, which may shed light on disease pathogenesis of both CADASIL and Balo concentric sclerosis. Hypotheses included the idea that Balo may result from mutations predisposing to hypoxic tissue injury, that CADASIL can present as Balo, and that vascular risk factors such as a NOTCH3 mutation may influence the presentation of a primary demyelinating disorder. It was of note that the patient responded well to plasmapheresis, which suggested a demyelinating disorder.

CADASIL1 Patients with Biallelic NOTCH3 Cysteine-Involving Variants

In a 54-year-old man, born of consanguineous Finnish parents, with CADASIL, Tuominen et al. (2001) identified a homozygous R133C mutation in the NOTCH3 gene (600276.0008). He first had a mild stroke at 28 years of age, and a subsequent stroke at age 36. CT scan showed periventricular and internal capsular white matter hypodensities. At age 39, he had left-sided hemiparesis with aphasia and dysarthria. His motor and sensory disturbances were aggravated at age 47 years, associated with accentuated white matter changes. Cognitive decline diagnosed as dementia was apparent at 48 years, and the patient had to retire. Each of his 2 sons was heterozygous for the mutation. Both sons had migraine with aura (at ages 28 and 19 years, respectively) and minor white matter abnormalities. The 28-year-old had an acute episode of facial paresis, visual disturbance, and dysarthria that may have represented a stroke (brain imaging was not performed after this episode). Functional studies of the variant were not performed. A clinical review of 9 unrelated Finnish individuals who were heterozygous for the R133C variant showed that they had a later age at onset (late forties to early fifties), and overall less severe symptoms compared to the individual who was homozygous for the mutation. However, 2 heterozygous patients had a disease course similar or even more severe (in 1) compared to the homozygous patient. Skin biopsy of the homozygous patient showed greater granular osmiophilic deposition compared to 1 heterozygous patient. Tuominen et al. (2001) concluded that the phenotype of the homozygous patient was within the clinical spectrum of CADASIL, although at the severe end compared to most of the heterozygous patients. The findings indicated that CADASIL1 appears to follow the classic definition of an autosomal dominant disease, in which the phenotypes of heterozygous and homozygous patients are indistinguishable (Zlotogora, 1997).

In a 65-year-old Dutch woman with mild symptoms of CADASIL, Liem et al. (2008) identified a homozygous mutation in the NOTCH3 gene (R578C; 600276.0024). Her brother, who was heterozygous for the mutation, had a similar phenotype, although his white matter lesions were not as severe as those of his homozygous sister. Functional studies of the variant were not performed. The authors suggested that the most likely pathogenic mechanism is a toxic gain-of-function effect rather than a dominant-negative effect, which would require the presence of a normal allele for the disease phenotype to occur.

Ragno et al. (2013) reported a homozygous G528C mutation in the NOTCH3 gene in a 54-year-old woman with CADASIL who was born of consanguineous Italian parents. Her first symptoms were migraine headaches at age 38. At age 39, she had acute encephalopathy, with delirium, headache, fever, right hemiparesis, aphasia, right homonymous hemianopia, and seizures. She had a full recovery with treatment, but later had similar less severe episodes. However, the authors stated that these episodes may have been related to other unknown genetic factors. She later had mild memory difficulties with visuospatial defects and constructional apraxia. Brain imaging showed partially confluent T2-weighted hyperintensities in the subcortical white matter, centrum semiovale, external capsule, basal ganglia, and brainstem. Subcortical lacunar lesions were also found. Skin sample showed extracellular deposits of granular osmiophilic material near indentations of vascular smooth muscle cells. Capillaries showed subocclusion of the capillary lumen and thickening and multilayering of the basal membrane. Six additional family members spanning 2 generations carried the G528C mutation in the heterozygous state. Overall, the phenotype was mild in this family, with younger mutation carriers having minimal, if any, symptoms. None of the mutation carriers had evidence of stroke, although there was a family history of stroke in older deceased relatives. The clinical course, brain imaging findings, and neuropsychologic examination of the homozygous patients was similar to that of her 6 heterozygous relatives and 6 additional unrelated individuals with CADASIL1 who were heterozygous for the same mutation. Ragno et al. (2013) concluded that CASASIL1 conforms to the classic definition of autosomal dominant diseases, in which homozygous and heterozygous mutation carriers are phenotypically indistinguishable.

Soong et al. (2013) reported 3 Taiwanese sisters with CADASIL1 associated with a missense variant in the NOTCH3 gene introducing a cysteine residue (R544C; 600276.0023). The proband and 1 sister were homozygous for the variant, whereas the other sister was heterozygous for the variant. All 3 presented in adulthood (range 58 to 67 years) with variable neurologic abnormalities, including hemiparesis, memory impairment, temporal lobe epilepsy (in 1), and dysarthria. Brain imaging showed diffuse white matter abnormalities and lacunar infarcts. The proband, who was homozygous for the variant, and the sister who was heterozygous for the variant had relatively mild symptoms, whereas the other sister who was homozygous for the variant had a more severe phenotype, including dementia by age 64, marked white matter abnormalities, and multiple lacunar infarcts in the corona radiata and basal ganglia. The authors stated that R544C is common among East Asians, and may account for up to one-half of Chinese CADASIL1 patients in Taiwan.

Mukai et al. (2018) identified a homozygous R544C mutation in a Japanese man, born of consanguineous parents, with a mild form of CADASIL. He presented at age 63 years with sudden weakness of the left arm. He had a history of asymptomatic cerebral infarctions since his mid-forties. Brain MRI showed a few punctiform deep white matter lesions in the temporal lobe, external capsules, and centrum semiovale. Skin biopsy showed granular osmiophilic material (GOM) deposition, consistent with the diagnosis. Mukai et al. (2018) stated that 70% of Taiwanese CADASIL patients have the R544C variant, and that the allele frequency of R544C in East Asia is 0.0036 (31 of 8,574 alleles) in ExAC, compared to 1 in 111,042 alleles in other populations. This suggests that the variant may show reduced penetrance.

He et al. (2020) reported 2 brothers from mainland China who presented with ischemic cerebral episodes at 47 and 50 years of age. Features included hemiparesis, muscle weakness, gait difficulties and ataxia, brisk tendon reflexes, and cognitive impairment, which was worse in the older brother. Brain imaging in both patients showed diffuse white matter hyperintensities and lacunar infarcts. Skin biopsy of the older brother showed GOM deposits between irregularly shaped vascular smooth muscle cells and the basement membrane. Direct sequencing of the NOTCH3 gene identified a homozygous R587C mutation in the NOTCH3 gene in both patients. Their father had a history of ischemic stroke and died at age 50, and the mother died at age 69 of heart disease; no genetic material was available from the parents. Functional studies of the variant were not performed. The phenotype was comparable to that of patients with heterozygous missense cysteine-involving variants in the NOTCH3 gene.

Ragno et al. (2022) identified a homozygous C1315Y variant in the NOTCH3 gene in a 71-year-old Italian woman, born of consanguineous parents, who presented with mild memory deficits, mood disorders, and difficulties with abstract logical thinking. Brain imaging showed multifocal leukoencephalopathy and cortical atrophy. She did not have a history of stroke episodes, although there was a history of stroke and heart disease on both sides of the family. Functional studies of the variant were not performed. In contrast, the authors noted that Valenti et al. (2011) had identified a heterozygous C1315Y variant in the NOTCH3 gene in 2 brothers with a severe CADASIL1 phenotype, although without stroke. One had progressive parkinsonism, behavioral disturbances, cognitive impairment, and loss of autonomy; the other had progressive gait disturbances, action tremor, and bradykinesia.

Iruzubieta et al. (2024) reported 24 patients from 17 unrelated families with CADASIL who carried biallelic missense cysteine-involving variants in the NOTCH3 gene. Seven unrelated individuals (P19-P25, from families F11-F17) were newly reported, and 17 patients (P34-P50) from 9 families (F23-F31) had previously been reported. Fourteen distinct variants were identified, but only 2 (R133C, 600276.0008 and C183S) were located in EGFR domains 1-6, which have been associated with a more severe phenotype. Nine cases, including 7 members of a consanguineous family from India reported by Abou Al-Shaar et al. (2016), carried the R1231C variant (600276.0026). Iruzubieta et al. (2024) noted that the R1231C variant has conflicting evidence regarding its pathogenicity due to a relatively high population frequency: 0.489% in South Asians, 0.347% in Middle Easterners, and 3 homozygous carriers in gnomAD (v4.0.0). Among the 9 who were homozygous for the R1231C variant, 3 younger patients in 1 family were asymptomatic at the last examination (ages 22 to 31 years). In the 6 others (age range 35 to 59 years), 3 had only migraine with or without aura, whereas the 3 others had a more severe phenotype manifest as dementia, nocturnal blindness, and stroke (in 2 from the family) and cognitive impairment (in 1 unrelated patient). All 7 individuals in this group who were studied showed periventricular and deep white matter hyperintensities. The 15 patients with biallelic cysteine-involving variants who did not carry the R1231C variant had symptom onset at a mean age of 43 years (range 13-64 years). Nine (60%) presented with stroke, 4 (27%) with migraine, and 1 (with a homozygous R1242C variant) was asymptomatic at age 47 years. All patients had normal neurodevelopment; over half (57%) showed cognitive decline, mostly dementia (6 of 14, 43%). Some patients had spasticity or ataxia; seizures were rare (only 1 patient). Granular osmiophilic material was found in skin biopsies from all 5 of the 5 patients tested. Brain imaging, when available, showed confluent deep subcortical white matter lesions with perivascular extension (sunburst appearance), and lesions involving the anterior temporal lobe, basal ganglia with extension to the external capsule, and brainstem. Periventricular leukomalacia-like abnormalities were less common, and abnormalities of the corpus callosum and cerebellum were rare. Family members who had heterozygous variants commonly presented with CADASIL, although the manifestations were highly variable and some heterozygous relatives were asymptomatic. There was intrafamilial variability regarding disease severity. The volume of white matter hyperintensities did not differ significantly between biallelic and heterozygous carriers of cysteine-involving variants. The findings suggested reduced penetrance and variable expressivity of disease manifestations.

Radiologic Findings

Skehan et al. (1995) studied the MRI appearance in 10 individuals in one large Irish autosomal dominant family and found 2 major types of abnormalities. The most striking were large confluent patches of high-signal change on T2- and proton density-weighted images present throughout the white matter, especially in the anterior part of the temporal lobes and the periventricular portion of the occipital lobes. Additionally, they detected small linear and punctate lacunes present not only in the periventricular white matter but also in the brainstem, basal ganglia, thalamus, external capsule, and corpus callosum.

Among 6 individuals under the age of 35 years who carried a mutation in the NOTCH3 gene, Lesnik Oberstein et al. (2003) found an increase in white matter hyperintensities on brain MRI compared to controls. The lesions showed a characteristic pattern in the anterior temporal lobes, the frontal lobes, and the periventricular caps. Although there was no physical or cognitive impairment in the 6 mutation carriers, migraine with aura was more common than in the controls.

Van den Boom et al. (2003) reported MRI findings in 40 CADASIL patients ranging in age from 21 to 59 years. All 5 patients younger than 30 years of age were clinically asymptomatic. All patients, including those who were asymptomatic, demonstrated hyperintense lesions on T2-weighted MRI. In patients aged 20 to 30 years, supratentorial hyperintense lesions were generally found in the frontal and anterior temporal lobe. About 20% of younger patients also developed subcortical lacunar lesions. After age 30 years, patients developed hyperintense lesions and lacunar infarcts in infratentorial structures, the basal ganglia, and the thalamus, as well as in periventricular regions. In addition to progression of the other lesions, patients over 40 years developed microbleeds, which were usually smaller than 5 mm. Lacunar infarcts were demonstrated in the brainstem in older patients. In general, there was a clear progression of lesions with age.

Using serial brain imaging in 76 patients with CADASIL over 2 years, Peters et al. (2006) identified brain atrophy as an important aspect of the disease process and established significant correlations with disability and global cognitive performance. The mean annualized rate of brain volume loss was 0.56%, which is 2 times higher than that of healthy age-matched subjects. Age, male sex, and increased systolic blood pressure were the main risk factors for lower brain volume.

By brain MRI of 147 patients with CADASIL, Viswanathan et al. (2007) observed a correlation between T1-weighted hypointense lacunar lesions and global cognitive dysfunction. In contrast, T2-weighted hyperintense lesions, representing subcortical white matter lesions, and cerebral microhemorrhages had no independent influence on cognitive function. Disability was associated with age, volume of lacunar lesions, cerebral microhemorrhages, and systolic blood pressure, but not with white matter hyperintensities. The findings implicated lacunar lesions as having an important clinical impact on patients with CADASIL.

The transmission pattern of CADASIL1 in the family reported by Saiki et al. (2006) was consistent with autosomal dominant inheritance.

Tuominen et al. (2001), Soong et al. (2013), Ragno et al. (2013), Iruzubieta et al. (2024) and others reported patients with typical features of CADASIL1 associated with homozygous or compound heterozygous missense variants in the NOTCH3 gene, most of which result in the gain or loss of a cysteine residue. Although the inheritance pattern of individuals with biallelic missense variants is consistent with autosomal recessive inheritance and many of these families are consanguineous, family members carrying the same variants in heterozygosity have a similar phenotype. CADASIL1 thus appears to follow the classic definition of an autosomal dominant disease, in which the phenotypes of heterozygous and homozygous patients are indistinguishable (Zlotogora, 1997). Phenotypic variability of CADASIL1 may be due to incomplete penetrance and additional genetic or nongenetic factors.

Through analysis of genetic linkage in 2 unrelated French families, including a family reported by Mas et al. (1992), Tournier-Lasserve et al. (1993) mapped the disease locus (CASIL) to 19q12. St Clair et al. (1995) used polymorphic DNA markers spanning the 19q12 region in linkage studies in a large Scottish pedigree with neuropathologically confirmed hereditary multiinfarct dementia; linkage was excluded. Ragno et al. (1995) reported an Italian kindred in which at least 16 subjects had either symptomatic or asymptomatic MRI evidence of a small vessel leukoencephalopathy. Linkage analysis with a marker for D19S226 at theta = 0.05 gave a maximum lod score of 3.660. Neuropathologic examination of 1 subject from this kindred demonstrated widespread vasculopathy of the perforating arterials, characterized by deposition of eosinophilic-congophilic material that did not immunostain with antibodies against prion protein, beta amyloid (104760), cystatin C (604312), transthyretin (176300), or HSP70 (140550).

To the original 2 large French families in which linkage of CADASIL to a 12-cM interval on chromosome 19 was demonstrated, Ducros et al. (1996) added 13 more families, including a total of 199 potentially informative meioses, and did genotyping with 8 polymorphic markers located between flanking markers D19S221 and D19S215 identified in the earlier study. All families were linked to chromosome 19. The highest combined lod score (maximum lod = 37.24 at theta = 0.01) was obtained with marker D19S841. This narrowed the mapping to a 2-cM interval on 19p13.1. The data strongly supported genetic homogeneity of this condition and established the value of its clinical and neuroimaging diagnostic criteria. Strong evidence of linkage to 19p was also found by Sabbadini et al. (1995) in an Italian CADASIL pedigree. Ducros et al. (1996) suggested that the negative results of St Clair et al. (1995) cannot be taken as proof of genetic heterogeneity since the scoring of pedigree members for linkage analysis was not established on the basis of MRI for many family members, leading to a high risk of misclassification and therefore false recombinants. Ducros et al. (1996) pointed out that paroxysmal cerebellar ataxia (108500) and familial hemiplegic migraine (141500) map to the same region, 19p13.

Dichgans et al. (1996) identified a crossover in a clinically affected family member which helped to refine the localization of the CADASIL locus to an 8-cM interval bracketed by D19S226 and D19S222. From the previous location of the gene involved in familial hemiplegic migraine, it was concluded that these disorders are probably not allelic.

Joutel et al. (1996) characterized the human NOTCH3 gene, which they mapped to the CADASIL critical region. Furthermore, they identified heterozygous mutations in the NOTCH3 gene (e.g., 600276.0001) in CADASIL patients that caused serious disruption of NOTCH3, suggesting that mutations in this gene are the cause of the disorder.

Filley et al. (1999) reported a 62-year-old man who had a slowly progressive 25-year history of personality change, psychosis, mood disorder, and dementia. He showed minimal motor impairment, as well as a deficit in sustained attention, slowed information processing, impaired learning with intact recognition, a mild visuospatial deficit, and frontal lobe dysfunction. MRI of the brain revealed extensive leukoencephalopathy. Right frontal brain biopsy showed ill-defined white matter pallor. Granular osmiophilic material adjacent to vascular smooth muscle cells on electron microscopy of a skin biopsy and an arg169-to-cys mutation (R169C; 600276.0002) in the EGF domain of the NOTCH3 gene established the diagnosis of CADASIL. The authors concluded that the dementia that occurs in CADASIL closely resembles that which may occur in other white matter disorders.

Arboleda-Velasquez et al. (2002) reported a Colombian kindred with CADASIL characterized by early-onset stroke (median age, 31 years), migraine with aura, and confluent MRI hyperintensities. They identified a heterozygous missense mutation in the NOTCH3 gene (C455R; 600276.0006). The mutation abolishes the fourth cysteine residue at EGF-like repeat 11 and may affect the interaction of the NOTCH3 receptor with its ligands. Despite the early onset of stroke, all patients had relatively well-preserved cognitive and functional status more than 2 decades after onset.

In affected members of an English family with CADASIL (Stevens et al., 1977), Low et al. (2007) identified a heterozygous missense mutation in the NOTCH3 gene (R141C; 600276.0018). The cerebral microvasculature of affected individuals showed intense accumulation of NOTCH3 N-terminal fragments.

Liem et al. (2008) identified a homozygous R578C mutation in the NOTCH3 gene (600276.0024) in a 65-year-old Dutch woman with mild symptoms of CADASIL. Her brother, who was heterozygous for the mutation, had a similar phenotype, although his white matter lesions were not as severe as those in his homozygous sister. Functional studies of the variant were not performed. The authors suggested that the most likely pathogenic mechanism is a toxic gain-of-function effect rather than a dominant-negative effect, which would require the presence of a normal allele for the disease phenotype to occur.

In 6 individuals spanning 2 generations of a family with CADASIL1, Ragno et al. (2013) identified a heterozygous missense mutation in the NOTCH3 gene (G528C; 600276.0025). One additional family member with a similar phenotype was homozygous for the mutation. Functional studies of the variant were not performed. The phenotype in the family member who was homozygous for the variant was similar to that of her heterozygous family members, as well as 6 unrelated individuals who carried the same heterozygous variant.

Soong et al. (2013) reported 3 Taiwanese sisters with CADASIL1 associated with a cysteine-involving missense variant in the NOTCH3 gene (R544C; 600276.0023). The proband and 1 sister were homozygous for the variant, whereas the other sister was heterozygous for the variant. Functional studies of the variant were not performed. The authors stated that R544C is common among East Asians, and may account for up to half of Chinese CADASIL1 patients in Taiwan. Mukai et al. (2018) identified a homozygous R544C mutation in a Japanese man, born of consanguineous parents, with a mild form of CADASIL. Mukai et al. (2018) stated that 70% of Taiwanese CADASIL patients have the R544C variant, and that the allele frequency of R544C in East Asia is 0.0036 (31 of 8,574 alleles) in ExAC, compared to 1 in 111,042 alleles in other populations. This suggests that the variant may show reduced penetrance.

Rutten et al. (2020) investigated exome and genome sequencing datasets of the UK Biobank (50,000 individuals) and cohorts of cognitively healthy elderly (751 individuals) to identify cysteine-altering mutations in the NOTCH3 gene in the general population. They identified 108 individuals (2.2 in 1000; average age, 64.9 years), of whom 75% had a NOTCH3 mutation that had previously been reported in patients with CADASIL. In 103 individuals, the cysteine-altering mutations were located in the epidermal growth factor-like repeat (EGFr) domains 7 through 3.4 Three individuals had cysteine-altering mutations in EGFr domains 1 through 6 and were not studied further. Neuroimaging data in the 103 individuals showed that they had more white matter hyperintensity lesions compared to controls, but fewer white matter hyperintensity lesions compared to patients with CADASIL. About one-half of the unaffected individuals had no neuroimaging abnormalities up to 70 years of age, and no increase in stroke was found. Rutten et al. (2020) concluded that CADASIL constitutes the severe and rare end of NOTCH3-associated small vessel disease, and that most individuals with cysteine-altering NOTCH3 mutations have milder and later-onset disease.

Iruzubieta et al. (2024) reported 24 patients from 17 unrelated families with CADASIL who carried biallelic cysteine-involving missense variants in the NOTCH3 gene. Seven unrelated individuals (P19-P25, from families F11-F17) were newly reported, and 17 patients (P34-P50) from 9 families (F23-F31) had previously been reported. Fourteen distinct variants were identified, but only 2 (R133C, 600276.0008 and C183S) were located in EGFR domains 1-6, which had been associated with a more severe phenotype. Nine cases, including 7 members of a consanguineous family from India reported by Abou Al-Shaar et al. (2016), carried the R1231C variant (600276.0020). This variant has conflicting evidence regarding its pathogenicity due to a relatively high population frequency: 0.489% in South Asians, 0.347% in Middle Easterners, and 3 homozygous carriers in gnomAD (v4.0.0). Functional studies of the variants were not performed.

Heterozygous mutations affecting EGF-like repeats in the N-terminal extracellular domain cause CADASIL1. Most of these mutations are missense variants that result in gain or loss of a cysteine residue (cysteine-involving variants), which are hypothesized to cause protein misfolding with secondary accumulation of granular osmiophilic material (GOM) surrounding vascular smooth muscle cells. This hypothesis suggests a toxic gain-of-function effect. Of note, biallelic missense cysteine-involving variants have also been identified in patients with CADASIL1 who usually have a similar phenotype to those with heterozygous variants, although some patients with biallelic variants and a slightly more severe phenotype have been reported. These findings are consistent with the classic definition of autosomal dominance, in which the phenotype of patients with heterozygous and homozygous (or compound heterozygous) mutations is indistinguishable. Within CADASIL1, NOTCH3 variants affecting EGF repeats (EGFr) 1-6 are associated with a more severe phenotype compared to variants affecting EGF repeats 7-34. Among 664 CADASIL1 patients, Rutten et al. (2019) found that those with a pathogenic variant in EGFr 1-6 had a 12-year earlier onset of stroke, lower overall survival, and increased amounts of hyperintense white matter lesions on brain imaging compared to those with a pathogenic variant in EGFr 7-34. Moreover, NOTCH3 variants affecting EGFr 7-34 were more commonly found in the general population. There is both intrafamilial and interfamilial phenotypic variability among CADASIL1 patients with the same mutation. Phenotypic variability of CADASIL1 may be due to incomplete penetrance and additional genetic or nongenetic factors (Zlotogora, 1997; Tuominen et al., 2001; Soong et al., 2013; Ragno et al., 2013; Iruzubieta et al., 2024; Garg et al., 2025).

Scheid et al. (2008) reported a German family in which 3 individuals had a relatively mild variant of CADASIL. The index patient had episodic headache, vertigo, paresthesias, weakness, and cognitive decline in her forties. She also had sensorineural hearing loss and arterial hypertension. Brain MRI showed widespread white matter lesions. Two affected relatives at ages 71 and 63 years, respectively, had very mild neurologic signs, including nystagmus and hearing loss, associated with variable severity of white matter lesions. An additional unrelated patient had clinical disease apparent in her seventies. All patients had the same cysteine-sparing mutation in the NOTCH3 gene (A1020P; 600276.0010), which the authors postulated may have resulted in the milder phenotype of later symptom onset and later onset of MRI changes. Scheid et al. (2008) also suggested that sensorineural hearing loss may be an additional manifestation of the disorder.

From a clinical and genetic study in 2 unrelated families, Rutten et al. (2013) provided evidence that heterozygous loss-of-function NOTCH3 mutations do not cause CADASIL. In the first family, a 55-year-old man with polyneuropathy, migraine with aura, and ischemic strokes between ages 50 and 52 was found to carry a heterozygous truncating variant in the NOTCH3 gene (R103X). Brain MRI showed old large vessel infarctions, but no white matter changes consistent with CADASIL. Skin biopsy was negative for NOTCH3 staining, but there was normal structure of the vessel wall and no electron microscopic deposits characteristic of the disorder. The patient's 50-year-old brother also carried the NOTCH3 variant, but was asymptomatic with a normal brain MRI; family history was negative for stroke and dementia. In a second family, a patient with classic MRI findings of CADASIL was compound heterozygous for a tyr710-to-cys (Y710C) mutation in the NOTCH3 gene and an intragenic frameshift deletion. The Y710C mutation was inherited from his possibly affected mother who had transient functional deficit of the arm at age 40 years without available brain imaging, and the deletion was inherited from his unaffected father whose skin biopsy was negative for CADASIL. Most CADASIL-associated NOTCH3 mutations alter conserved cysteine residues and are postulated to cause a toxic neomorphic effect. Rutten et al. (2013) concluded that hypomorphic NOTCH3 mutations do not cause CADASIL, which has important implications for diagnostic interpretation.

Gravesteijn et al. (2020) identified a heterozygous G498C (600276.0019) mutation in the NOTCH3 gene in 5 individuals from 1 family with mild CADASIL. Studies in patient fibroblasts showed that the mutation resulted in highly efficient exon 9 skipping. The phenotype of the family members included only minimal levels of NOTCH3 protein aggregation in skin vasculature, suggesting that the mutant NOTCH3 does not aggregate. The 63-year-old index patient had confluent white matter hyperintensities on brain MRI with no lacunae and a history of headaches, vertigo, and tinnitus. She had a normal neuropsychologic examination. All 3 of her affected sibs, aged 63 to 71 years, had confluent white matter hyperintensities on brain MRI. None of the sibs had lacunar strokes or vascular cognitive decline, and all lived independently. An affected nephew of the index patient had a few focal white matter hyperintensities on brain MRI.

In skin biopsies from 25 CADASIL1 patients, Gravesteijn et al. (2022) found that those with cysteine-involving NOTCH3 mutations in EGFr domains 1-6 had higher levels of granuloosmiophilic material (GOM) deposition and increased amounts of vascular NOTCH3 aggregation compared to patients with cysteine-involving NOTCH3 mutations in EGFr domains 7-34. Almost half of patients with an EGFr 7-34 variant had no granular NOTCH3 immunostaining, whereas all patients with an EGFr 1-6 variant had granular NOTCH3 immunostaining. Similarly, most patients with EGFr 7-34 variants had no GOM deposits at all, whereas all but 1 patient with EGFr 1-6 had GOM. These findings indicated that the absence of GOM in skin biopsies does not exclude a CADASIL1 diagnosis. A similar trend was observed in brain vasculature from 7 patients. In the EGFr 7-34 group, NOTCH3 aggregation levels were associated with lacunae count and white matter hyperintensity volume, but not with neurologic disability.

In a study of 27 Chinese CADASIL1 patients, Li et al. (2025) found increased global cerebral atrophy and reduced brain volume compared to controls. CADASIL1 patients also had enlarged perivascular space in the brain compared to controls, possibly indicating impaired glymphatic flow, and the size of enlarged perivascular spaces was positively associated with global cerebral atrophy. Mutant mice homozygous for a Notch3 R170C variant (corresponding to the human R169C mutation, 600276.0002) showed deposition of granular osmiophilic material and accumulation of NOTCH3 extracellular domain aggregates in brain blood vessels. Glymphatic influx and efflux was impaired in both homozygous and heterozygous mutant mice. Astrocytes from R170C mutant mice showed decreased transcription of AQP4 (600308), decreased AQP4 protein expression in astrocytic endfeet, and downregulation of the RUNX1 (151385)-CMYB (MYB; 189990)-AQP4 signaling pathway compared to controls. Brain tissue from mutant mice showed increased markers of senescence, neuronal death, and severe white matter injury, suggestive of advanced aging. AAV-mediated expression of AQP4 in astrocytes of mutant mice lessened the expression of senescent markers and improved glymphatic activity. The authors hypothesized that mutant R170C Notch3 causes downregulation of AQP4 expression in astrocyte endfeet, which impairs glymphatic function and promotes senescence of brain cells.

Mykkanen et al. (2004) performed haplotype analysis in 60 patients from 18 Finnish CADASIL families with an arg133-to-cys mutation in the NOTCH3 gene (R133C; 600276.0008). Using 10 microsatellite markers, the authors found a similar haplotype linked to the mutation in all 18 pedigrees, indicating a single common ancestor for all of the Finnish R133C families. Age analysis of the founder mutation placed the introduction of the mutation in the late 1600s or early 1700s.

Schroder et al. (1995) demonstrated pathologic findings on sural nerve biopsy in individuals from a family with 4 affected members in 3 successive generations. Light microscopic abnormalities were very mild. However, by electron microscopy, they were able to demonstrate characteristic electron dense, extracellular granular deposits in close association with smooth muscle cells and to a lesser degree with pericytes and endothelial cells. They found focal pinocytotic vesicles at the site of close contact between the extracellular deposit and the surface membrane of the smooth muscle cell, suggesting exocytosis of abnormal material. The authors stated that this was the first demonstration that the diagnosis of CADASIL could be verified by sural nerve biopsy.

Joutel et al. (2001) established whether immunostaining skin biopsy samples with a monoclonal antibody specific for NOTCH3 could form the basis of a reliable and easy diagnostic test. They compared the sensitivity and specificity of this method in 2 groups of patients suspected of having CADASIL with complete scanning of mutation-causing exons of NOTCH3 (in a retrospective series of 39 patients) and with limited scanning of 4 exons that are mutation hotspots (prospective series of 42 patients). In the retrospective series, skin biopsy was positive in 21 (96%) of the 22 CADASIL patients examined and negative in all others; in the prospective series, 7 of the 42 patients had a positive skin biopsy whereas only 4 had a mutation detected by limited NOTCH3 scanning. Their immunostaining technique, based on the abnormal accumulation of NOTCH3 within small vessels, was judged to be highly sensitive (96%) and specific (100%) for the diagnosis of CADASIL.

In a study in Britain, Markus et al. (2002) found 15 different point mutations in the NOTCH3 gene in 48 families, 73% of which were in exon 4, 8% in exon 3, and 6% in each of exons 5 and 6. They suggested that on the basis of this spectrum the suggested protocol is to screen exon 4 and proceed to mutational screening of exons 3, 5, and 6 where indicated. The presence of granular osmiophilic material on skin biopsy is diagnostic but can be negative. Skin biopsy, performed in 18 cases, had a sensitivity of 45% and specificity of 100%. Anterior temporal pole involvement on MRI was considered a useful diagnostic marker.

Peters et al. (2005) identified 54 distinct mutations in the NOTCH3 gene in 120 (96%) of 125 patients with biopsy-proven CADASIL. Of the mutations, 58.3% were located in exon 4, and 85.8% were in exons 2 through 6. In 5 (4%) patients, no mutation was identified, indicating false negative results. Peters et al. (2005) suggested that cases with a high index of clinical suspicion should be investigated by skin biopsy if the result of genetic testing is negative.

In a retrospective study of 131 Finnish, Swedish, and French CADASIL patients, Tikka et al. (2009) found 100% concordance between the presence of granular osmiophilic material in skin biopsies and presence of pathogenic mutations in the NOTCH3 gene. The findings suggested that adequate skin biopsies, which must include the border zone between the deep dermis and upper subcutis that contains small arterial vessels, which contain the deposits, are a cost-effective guide for determining who should be further evaluated by molecular diagnosis. Deposits were absent in skin biopsies from 26 controls without NOTCH3 mutations.

Sonninen and Savontaus (1987) reported a family in which 16 patients had adult-onset multiinfarct dementia associated with occlusive cerebrovascular infarcts in the white matter, which was also generally reduced. The disorder was characterized by relapsing strokes with neuropsychiatric symptoms, affected relatively young adults of both sexes, and was transmitted in an autosomal dominant pattern. This may be the same disorder as that called familial subcortical dementia with arteriopathic leukoencephalopathy by Davous and Fallet-Bianco (1991).