SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
CADASIL is an autosomally dominantly inherited multi-infarct dementia caused by mutations in the Notch3 gene in chromosome 19. In this report we present the first patient in the world literature with CADASIL and schizophrenia and discuss the co-occurrence of these conditions in the light of the literature.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently described neurovascular disease affecting young to middle age individuals. The disease is caused by mutations in the Notch3 gene located in the short arm of chromosome 19. Clinically, the disease is characterized by migrainous headaches (with or without aura), mood disturbances, focal neurologic deficits, transient ischemic attacks, strokes, and dementia. Pathologically, the disease is characterized by a stereotypic degeneration of the arterial walls (especially in the intracranial compartments) with deposition in the media of a nonatheromatous, nonamyloidotic substance that under the electron microscope (EM) appears as a granular osmiophilic material (GOM), pathognomonic for the disease. The nature of the GOM is undetermined and the pathogenesis remains to be elucidated. A review of current literature in English language is presented on the clinical, radiologic, pathologic, and genetic features of CADASIL.
The clinical and radiological overlap between multiple sclerosis and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; MIM 125310) raises the possibility of diagnostic confusion and suggests that pleiotropic effects of the Notch3 gene might include influencing susceptibility to multiple sclerosis. To investigate these possibilities three microsatellites markers closely flanking the Notch 3 gene in 745 simplex families with multiple sclerosis were genotyped and exon 3 and exon 4 of the gene were directly sequenced in a subset of the index members from these families (n=93). No evidence for association was found in any of the three markers and none of the commoner mutations causing CADASIL were found in the sequenced patients.
The main clinical features of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) are stroke, dementia, and migraine. A reversible acute encephalopathy was the principal presentation in six of 70 patients in a British prevalence study. The episodes lasted seven to 14 days, presenting with fever, acute confusion, coma, and fits; there was full recovery but in two cases identical episodes recurred some years later. All patients had a previous history of migraine with aura and were originally misdiagnosed as viral encephalitis. CADASIL should be considered in acute unexplained encephalopathies. MRI white matter changes, previous migraine with aura, and a family history of stroke and dementia may be useful pointers to the diagnosis.
Mutations in Notch3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an inherited small vessel disease leading to subcortical strokes and vascular dementia. The phenotypic presentation is variable but remarkable for a high frequency of migraine with aura. Magnetic resonance images show a microangiopathic pattern of lesions. Prominent involvement of the temporopolar white matter and involvement of the temporopolar arcuate fibers are conspicuous findings seen in many patients. The underlying angiopathy is characterized by a unique type of ultrastructural basal lamina deposits and by degeneration of vascular smooth muscle cells which are the major source of Notch3 expression. In line with these findings there is evidence for a functional impairment of vascular smooth muscle cells. CADASIL has opened a new perspective in studying basic mechanisms of vessel wall degeneration and ischemic tissue damage related to small vessel disease.
The Notch3 gene has been recently identified as a causative gene for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). To investigate the genetic contribution of Notch mutations in familial cases with vascular leukoencephalopathy, we screened 13 patients from 11 unrelated families, which were selected on the basis of magnetic resonance imaging findings and positive family history. We identified three different missense mutations in 5 patients from 4 families. Two (Arg90Cys and Arg133Cys) are the same as previously reported in Caucasian patients, the other (Cys174Phe) is a novel mutation causing a loss of a cysteine in epidermal-growth-factor-like repeats of Notch3. These data indicate that the CADASIL Notch3 mutations were found in approximately 35% of familial cases with leukoencephalopathy, suggesting genetic heterogeneity of the disease.
BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disorder typified by early onset lacunar strokes, subcortical dementia, psychiatric disturbances, and migraine. Mutations in the Notch3 gene are responsible. Atypical phenotypes have been recognized, and the disease is probably underdiagnosed in the wider stroke population. Therefore, we determined the yield of screening for Notch3 mutations in lacunar stroke with or without leukoaraiosis. METHODS: Two hundred eighteen consecutive patients were studied. All had brain and carotid imaging. Polymerase chain reaction-single-stranded conformational polymorphism analysis was used to screen exons 3, 4, 5, and 6 of the Notch3 gene for mutations and polymorphisms. RESULTS: A single mutation in exon 4 (C697T) was identified in a young patient, giving an overall carrier frequency of 0.05% (95% CI, 0.0 to 2.0). For patients with onset of lacunar stroke at < or =65 years and leukoaraiosis, the yield was 2.0% (95% CI, 0.4 to 10.9). CONCLUSIONS: Notch3 mutations are rare in patients with typical strokes due to cerebral small-vessel disease. In the absence of classic features suggestive of CADASIL, screening for Notch3 mutations has a low yield.
BACKGROUND AND PURPOSE: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) causes repeated ischemic attacks leading to subcortical vascular dementia. The aim of this study was to characterize cognitive function in subjects with a C475T (R133C) mutation in the Notch3 gene, leading to CADASIL. METHODS: Prestroke (n=13) and poststroke (n=13) mutation carriers and mutation carriers with dementia (n=8) were compared with healthy noncarriers from the same families using a comprehensive set of neuropsychological tests. RESULTS: Changes in working memory and executive function were observed in the very early phase of the disease before transient ischemic attack (TIA) or stroke. Later, in the poststroke phase, the cognitive impairment concerned also mental speed and visuospatial ability. Finally, the subjects with dementia had multiple cognitive deficits, which engaged even verbal functions, verbal episodic memory, and motor speed. The 2 mutation carrier groups without dementia and the controls could be reliably distinguished using 3 tests that assessed working memory/attention, executive function, and mental speed. Episodic memory was relatively well-preserved late in the disease. CONCLUSIONS: A deterioration of working memory and executive function was already observed in the prestroke phase, which means that cognitive decline may start insidiously before the first onset of symptomatic ischemic episodes.
CADASIL is an autosomal dominant non-atherosclerotic vasculopathy that frequently presents as recurrent subcortical strokes, or vascular dementia in middle age. Some patients may have prominent mental symptoms or migraine. Widespread white matter demyelination and subcortical lacunar infarcts are demonstrated by magnetic resonance imaging. Demonstration of granular osmophilic material in arteries in skin biopsies is a useful diagnostic tool. CADASIL has been linked to mutation in the Notch 3 gene locus on chromosome 19. Genetic testing is available for clinical diagnosis.
The authors carried out genetic analyses and visual electrophysiologic evaluations in six asymptomatic sons and daughters of patients with symptomatic cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Three subjects showed Notch3 Cys146Tyr missense mutation and a dysfunction of the outer, middle, and innermost retinal layers, with normal neural conduction in postretinal visual pathways, whereas in the remaining subjects without genetic mutations, no electrophysiologic abnormalities were found. An early vascular retinal impairment in CADASIL may precede the onset of clinical manifestations.
The authors obtained MR and magnetization transfer (MT) imaging of the cervical cord from 25 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). They found no conventional MR abnormalities, but a reduced peak height of the MT ratio (MTR) histogram. This suggests a reduced amount of "truly" normal cord tissue in CADASIL. A significant correlation was found between the extent of brain lesions and cord MTR, suggesting wallerian degeneration as the substrate of the cord MTR changes.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the notch3 epidermal growth factor-like repeats. A Colombian kindred carries a novel C455R mutation located in the predicted ligand-binding domain. Stroke occurred in the patients at an unusually early age (median age: 31 years) in comparison to the more frequent onset in the fourth decade of life in other CADASIL populations, including a second Colombian kindred with an R1031C mutation.
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited autosomal dominant condition characterized by migraine, recurrent stroke, and dementia. It results from mutations in the notch3 gene but mutations may occur at multiple sites making molecular diagnosis time consuming. It has been suggested that the presence of granular osmiophilic material (GOM) on skin biopsy and involvement of the anterior temporal lobe and external capsule on MRI may help in diagnosis. METHODS: The authors identified 83 potential index cases from the British population and screened exons 2 to 23 of notch3. MRI scans were scored using a modified Scheltens scale. Skin biopsy was performed in a subgroup. RESULTS: Fifteen different point mutations were identified in 48 families, 73% of which were in exon 4, 8% in exon 3, and 6% in each of exons 5 and 6. Moderate or severe involvement of the anterior temporal pole on MRI had a sensitivity of 89% and specificity of 86% for diagnosis of CADASIL, whereas external capsule involvement had a high sensitivity of 93% but a low specificity of 45%. Skin biopsy, performed in 18 cases, had a sensitivity of 45% and specificity of 100%. CONCLUSIONS: The spectrum of mutations in this study can be used to plan appropriate screening protocols; a suggested protocol is to screen exon 4, and proceed to exons 3, 5, and 6 where indicated. GOM on skin biopsy is diagnostic but can be negative. Anterior temporal pole involvement on MRI is a useful diagnostic marker.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare hereditary stroke disease. In the present study, a Japanese CADASIL family was first reported with missense mutation of Arg141Cys of Notch3 and a unique lesion of corpus callosum. Upon neuropsychological examination, our case 1 showed only right-handed constructional apraxia associated with corpus callosum lesion. No other callosal disconnection signs were present. Sagittal T2 weighted image of case 1 showed multiple small lesions along with the pericallosal branches from the truncus to the posterior part of the splenium in the corpus callosum. Although detailed mapping of the corpus callosum for functional fractionation in humans remains incomplete, the constructional apraxia on the right may be related to callosal dysfunction from the truncus to the posterior part of the splenium in the corpus callosum.
OBJECTIVE: The cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by the recurrence of subcortical infarcts leading to dementia. It is known the genetic and neuroimaging findings, but there are few studies about its histopathology. Our objective had been to study the pathological findings in this arteriopathy. SUBJECTS AND METHODS: We studied two families spreading over four generations. We performed a detailed clinical history, laboratory investigations, neuroimaging study and genetic analysis. Two brain biopsies and one autopsy were done in patients from the two families. RESULTS: Eight affected members, with autosomal dominant inheritance. Age at onset was between 40 and 50 years. This was characterized clinically by recurrent ischemic attacks, headache and subcortical dementia without vascular risk factors. Histopathological findings showed an arteriopathy characterized by a slightly basophilic small arterial granular degeneration of the medial sheath associated with the presence of ballooned smooth muscle cells with clear cytoplasm. CONCLUSION: The histopathological findings of CADASIL show a characteristic arteriopathy that allow a better understanding of its pathogenesis and could contribute for its diagnosis.
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a diffuse disease of small arteries, predominating in the brain. It starts during mid-adulthood and is characterized by recurrent ischaemic events (transient or permanent), attacks of migraine with aura, severe mood disorders, subcortical dementia and at MRI white periventricular leukoencephalopathy. CADASIL is an autosomal dominant disease. The gene Notch3 on which the mutation was detected is located on chromosome 19. There is so far no specific treatment and death occurs after a mean of twenty years.
We here report a 42-year-old woman diagnosed cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) by age, family history, neurological findings, and neuro imagings. Magnetic resonance imaging well demonstrated the multiple lesions in the cerebrum including the brain stem, which was characteristic findings in CADASIL.
Atypical phenotypes of CADASIL and corresponding anatomical data in two cases are described in 6 members of 2 new French families. In the first family, 4 cases in the same kindred were probably affected, two of them with a predominant psychiatric presentation, two others with dementia and a pseudo-bulbar syndrome of progressive evolution. No history of migraine or ischemic event were documented in any. In the propositus, the diagnosis was documented by skin biopsy, Notch 3 gene mutation and autopsy after the patient had died when 67 years old, 8 years after onset. Brain examination showed a widespread leukoencephalopathy with subcortical infarcts. Characteristic granular lesions of the small arteries of the brain and other organs were observed. In the second family, two cases are reported. One patient died when 63 years old after a subacute evolution mimicking intracranial hypertension. The anatomical diagnosis was retrospectively proven typical of CADASIL with Notch 3 immunostaining of arterial smooth muscle cells. The other case had a progressive evolution over 20 years of limb paresthesia with a mild spasticity diagnosed as a progressive form of multiple sclerosis. It was followed by a pseudo-bulbar syndrome and a mild subcortical dementia without acute ischemic attack. The diagnosis was confirmed by skin biopsy and mutation of the Notch 3 gene. This report illustrates