CADASIL

General Information (adopted from Orphanet):

Synonyms, Signs: CADASIL
DEMENTIA, HEREDITARY MULTI-INFARCT TYPE
CASIL
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
Hereditary multi-infarct dementia
Number of Symptoms 104
OrphanetNr: 136
OMIM Id: 125310
ICD-10: F01.1
I67.8
UMLs:
MeSH: D046589
MedDRA: 10065551
Snomed: 390936003

Prevalence, inheritance and age of onset:

Prevalence: < 1.98 of 100 000 - PMID: 15834040 [IBIS]
Inheritance: Monogenic
Autosomal dominant
- PMID: 15834040 [IBIS]
Age of onset:

Disease classification (adopted from Orphanet):

Parent Diseases: Cerebrovascular dementia
 -Rare neurologic disease
Genetic central nervous system and retinal vascular disease
 -Rare genetic disease
Genetic cerebrovascular dementia
 -Rare genetic disease
Nervous system anomaly with eye involvement
 -Rare eye disease
 -Rare genetic disease
Rare central nervous system and retinal vascular disease
 -Rare neurologic disease

Comment:

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small artery disease leading to disability and dementia. The linkage studies in several families enabled the identification of the mutated gene as NOTCH3 on chromosome 19. The disease is not limited to Caucasian families although the disorder was initially recognized in European pedigrees. CADASIL has been reported in more than 500 families worldwide. The disease is characterized by 5 main symptoms: migraine with aura, subcortical ischemic events, mood disturbances, apathy, and cognitive impairment. The mean age at onset of symptoms is 45 years and the duration of the disease varies between 10 and 40 years. The mean age at death is about 65 years, but it varies from 30 to 80 years within the affected pedigrees (PMID:21045164).

Symptom Information: Sort by abundance 

1
 (HPO:0000020) Urinary incontinence 20301673 IBIS 75 / 7739
2
 (HPO:0010628) Facial palsy Frequent [Orphanet] typical [HPO] 25834748 IBIS 146 / 7739
3
 (HPO:0008046) Abnormality of the retinal vasculature Very frequent [Orphanet] 15313839 IBIS 41 / 7739
4
 (HPO:0001138) Optic neuropathy 16193254 IBIS 12 / 7739
5
 (HPO:0000618) Blindness 23635925 IBIS 124 / 7739
6
 (HPO:0000649) Abnormality of visual evoked potentials 15096408 IBIS 34 / 7739
7
 (HPO:0000505) Visual impairment Frequent [Orphanet] 16193254 IBIS 297 / 7739
8
 (HPO:0000572) Visual loss 23635925 IBIS 272 / 7739
9
 (HPO:0007763) Retinal telangiectasia Very frequent [Orphanet] 23635925 IBIS 6 / 7739
10
 (HPO:0007634) Nonarteritic anterior ischemic optic neuropathy 15096408 IBIS 2 / 7739
11
 (HPO:0000587) Abnormality of the optic nerve 15313839 IBIS 5 / 7739
12
 (HPO:0000512) Abnormal electroretinogram 15313839 IBIS 61 / 7739
13
 (HPO:0100576) Amaurosis fugax Very frequent [Orphanet] 14687018 IBIS 13 / 7739
14
 (HPO:0000365) Hearing impairment Occasional [Orphanet] 15829071 IBIS 539 / 7739
15
 (HPO:0002445) Tetraplegia 8418535 IBIS 26 / 7739
16
 (HPO:0002067) Bradykinesia 9541301 IBIS 62 / 7739
17
 (HPO:0100543) Cognitive impairment 20301673 IBIS 230 / 7739
18
 (HPO:0002071) Abnormality of extrapyramidal motor function Occasional [Orphanet] 18258841 IBIS 76 / 7739
19
 (HPO:0002076) Migraine Very frequent [Orphanet] 21409506 IBIS 41 / 7739
20
 (HPO:0002015) Dysphagia 16864835 IBIS 301 / 7739
21
 (HPO:0007359) Focal seizures Occasional [IBIS] 21045164 IBIS 27 / 7739
22
 (HPO:0002357) Dysphasia Very frequent [Orphanet] 16796821 IBIS 33 / 7739
23
 (HPO:0000708) Behavioral abnormality Very frequent [Orphanet] 20301673 IBIS 212 / 7739
24
 (HPO:0002167) Neurological speech impairment Very frequent [Orphanet] 16717212 IBIS 308 / 7739
25
 (HPO:0000716) Depression Occasional [IBIS] Very frequent [Orphanet] 20% (n=45) 7564728 IBIS 99 / 7739
26
 (HPO:0002315) Headache Very frequent [Orphanet] 19207299 IBIS 175 / 7739
27
 (HPO:0002354) Memory impairment Frequent [Orphanet] 20301673 IBIS 63 / 7739
28
 (HPO:0001347) Hyperreflexia 9541301 IBIS 363 / 7739
29
 (HPO:0002133) Status epilepticus Occasional [Orphanet] 20301673 IBIS 59 / 7739
30
 (HPO:0003477) Peripheral axonal neuropathy Occasional [Orphanet] occasional [HPO] 15827866 IBIS 62 / 7739
31
 (HPO:0001270) Motor delay 20301673 IBIS 322 / 7739
32
 (HPO:0000726) Dementia Very frequent [IBIS] 21045164 IBIS 131 / 7739
33
 (HPO:0002353) EEG abnormality Frequent [Orphanet] 25870789 IBIS 188 / 7739
34
 (HPO:0007108) Demyelinating peripheral neuropathy 15827866 IBIS 8 / 7739
35
 (HPO:0002301) Hemiplegia Very frequent [Orphanet] hallmark [HPO] 15798438 IBIS 42 / 7739
36
 (HPO:0002329) Drowsiness Very frequent [Orphanet] 12531961 IBIS 19 / 7739
37
 (HPO:0000739) Anxiety Very frequent [Orphanet] 23355563 IBIS 67 / 7739
38
 (HPO:0001310) Dysmetria 22218279 IBIS 76 / 7739
39
 (HPO:0002077) Migraine with aura Frequent [IBIS] 21045164 IBIS 14 / 7739
40
 (HPO:0001269) Hemiparesis Very frequent [Orphanet] hallmark [HPO] 20301673 IBIS 51 / 7739
41
 (HPO:0006824) Cranial nerve paralysis Frequent [Orphanet] 17726918 IBIS 81 / 7739
42
 (HPO:0001288) Gait disturbance Frequent [Orphanet] 20301673 IBIS 318 / 7739
43
 (HPO:0007123) Subcortical dementia 23308019 IBIS 1 / 7739
44
 (HPO:0001257) Spasticity Frequent [Orphanet] 11458185 IBIS 251 / 7739
45
 (HPO:0001300) Parkinsonism 19542611 IBIS 75 / 7739
46
 (HPO:0007024) Pseudobulbar paralysis 25834748 IBIS 7 / 7739
47
 (HPO:0002197) Generalized seizures Occasional [IBIS] 21045164 IBIS 30 / 7739
48
 (HPO:0007178) Motor polyneuropathy Occasional [Orphanet] occasional [HPO] 19488673 IBIS 31 / 7739
49
 (HPO:0000741) Apathy Very frequent [Orphanet] 20301673 IBIS 42 / 7739
50
 (HPO:0001289) Confusion Very frequent [Orphanet] 20123231 IBIS 36 / 7739
51
 (HPO:0000737) Irritability Very frequent [Orphanet] 15819734 IBIS 93 / 7739
52
 (HPO:0001259) Coma Very frequent [Orphanet] 12531961 IBIS 65 / 7739
53
 (HPO:0001268) Mental deterioration Very frequent [Orphanet] hallmark [HPO] 16421111 IBIS 88 / 7739
54
 (HPO:0002361) Psychomotor deterioration Very frequent [Orphanet] hallmark [HPO] 23355563 IBIS 26 / 7739
55
 (HPO:0001575) Mood changes Occasional [IBIS] 20% (n=45) 7564728 IBIS 7 / 7739
56
 (HPO:0000709) Psychosis 10371078 IBIS 61 / 7739
57
 (HPO:0001260) Dysarthria 16864835 IBIS 329 / 7739
58
 (HPO:0004372) Reduced consciousness/confusion Very frequent [Orphanet] 11810186 IBIS 73 / 7739
59
 (HPO:0004374) Hemiplegia/hemiparesis Very frequent [Orphanet] 20301673 IBIS 158 / 7739
60
 (HPO:0002381) Aphasia Very frequent [Orphanet] 19369672 IBIS 27 / 7739
61
 (HPO:0002300) Mutism Very frequent [Orphanet] 20464302 IBIS 28 / 7739
62
 (HPO:0002078) Truncal ataxia 9541301 IBIS 41 / 7739
63
 (HPO:0000951) Abnormality of the skin 10463351 IBIS 147 / 7739
64
 (HPO:0001933) Subcutaneous hemorrhage Occasional [Orphanet] 15727650 IBIS 50 / 7739
65
 (HPO:0002326) Transient ischemic attack Frequent [Orphanet] 9818928 IBIS 13 / 7739
66
 (HPO:0002619) Varicose veins Occasional [Orphanet] 16864835 IBIS 11 / 7739
67
 (HPO:0005293) Venous insufficiency Occasional [Orphanet] 16864835 IBIS 27 / 7739
68
 (HPO:0001297) Stroke Frequent [Orphanet] 17726918 IBIS 44 / 7739
69
 (HPO:0002140) Ischemic stroke Frequent [Orphanet] 20301673 IBIS 70 / 7739
70
 (HPO:0001342) Cerebral hemorrhage Occasional [Orphanet] occasional [HPO] 24344756 IBIS 24 / 7739
71
 (HPO:0002637) Cerebral ischemia Frequent [Orphanet] 21345538 IBIS 17 / 7739
72
 (HPO:0002621) Atherosclerosis Occasional [Orphanet] 21178349 IBIS 33 / 7739
73
 (HPO:0002170) Intracranial hemorrhage Occasional [Orphanet] 17135568 IBIS 40 / 7739
74
 (HPO:0000822) Hypertension Occasional [Orphanet] 25109394 IBIS 224 / 7739
75
 (HPO:0001945) Fever Very frequent [Orphanet] 12531961 IBIS 218 / 7739
76
 (HPO:0004370) Abnormality of temperature regulation Very frequent [Orphanet] 12531961 IBIS 58 / 7739
77
 (HPO:0003657) Granular osmiophilic deposits (GROD) in cells 20301673 IBIS 3 / 7739
78
 (HPO:0001943) Hypoglycemia Occasional [Orphanet] 12791811 IBIS 131 / 7739
79
 (HPO:0011947) Respiratory tract infection Occasional [Orphanet] occasional [HPO] 15364702 IBIS 28 / 7739
80
 (OMIM) Patients 30-40 years old have hyperintense lesions in periventricular areas, the external capsule, basal ganglia, thalamus, and brainstem 14593195 IBIS 1 / 7739
81
 (MedDRA:10072731) White matter lesion 8418535 IBIS 7 / 7739
82
 (MedDRA:10063750) Life expectancy shortened Occasional [Orphanet] 15364702 IBIS 4 / 7739
83
 (OMIM) Patients 20-30 years old have hyperintense lesions on T2-weighted MRI in the frontal and anterior temporal lobes 14593195 IBIS 1 / 7739
84
 (OMIM) Narrowing of retinal vessels 15313839 IBIS 3 / 7739
85
 (MedDRA:10008398) Change in sustained attention 10371078 IBIS 1 / 7739
86
 (OMIM) MRI shows T2-weighted signals in the basal ganglia 7564728 IBIS 4 / 7739
87
 (OMIM) Biopsy shows granular osmiophilic material of variable electron density adjacent to basal membrane of vascular smooth muscle cell 17620550 IBIS 1 / 7739
88
 (HPO:0002352) Leukoencephalopathy 20301673 IBIS 32 / 7739
89
 (MedDRA:10072809) Arterial wall hypertrophy 8418535 IBIS 1 / 7739
90
 (HPO:0012444) Brain atrophy 16717211 IBIS 24 / 7739
91
 (HPO:0006799) Basal ganglia cysts 9541301 IBIS 6 / 7739
92
 (HPO:0007162) Diffuse demyelination of the cerebral white matter 8418535 IBIS 3 / 7739
93
 (OMIM) Hyaline thickening of cerebral arteries 9541301 IBIS 7 / 7739
94
 (OMIM) Affected arteries have electron-dense granular material close to vascular smooth muscle cell membranes 7732783 IBIS 1 / 7739
95
 (HPO:0007236) Recurrent subcortical infarcts 20301673 IBIS 2 / 7739
96
 (MedDRA:10027939) Mood alterations with manic symptoms 21045164 IBIS 1 / 7739
97
 (MedDRA:10019476) Hemiplegic migraine 8418535 IBIS 2 / 7739
98
 (HPO:0007305) CNS demyelination 9541301 IBIS 21 / 7739
99
 (HPO:0007204) Diffuse white matter abnormalities 20301673 IBIS 2 / 7739
100
 (OMIM) Vasculopathy of the small arteries penetrating the white matter 8418535 IBIS 1 / 7739
101
 (OMIM) Patients older than 50 years have hyperintensities, lacunar infarcts, and microbleeds 17620550 IBIS 1 / 7739
102
 (HPO:0002120) Cerebral cortical atrophy Frequent [Orphanet] 16643314 IBIS 187 / 7739
103
 (MedDRA:10051078) Lacunar infarction 14593195 IBIS 1 / 7739
104
 (HPO:0100308) Cerebral cortical hemiatrophy Frequent [Orphanet] 22000857 IBIS 7 / 7739

Associated genes:

NOTCH3;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant 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 ...
Diagnosis OMIM 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 ...
Clinical Description OMIM Hereditary multi-infarct dementia in multiple members of families in a pattern consistent with autosomal dominant inheritance was reported by Sourander and Walinder (1977) and Sonninen and Savontaus (1987). The disorder is characterized by relapsing strokes with neuropsychiatric symptoms ...
Genotype-Phenotype Correlations OMIM 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 ...
Molecular genetics OMIM Joutel et al. (1996) characterized the human NOTCH3 gene, which they mapped to the CADASIL critical region. Furthermore, they identified mutations of the NOTCH3 gene (e.g., 600276.0001) in CADASIL patients that caused serious disruption of NOTCH3, suggesting that ...
Population genetics OMIM 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 ...