Spectrum of Mutations in Biopsy-Proven CADASIL

Peters, Nils; Opherk, Christian; Bergmann, T.; Castro, Mirna; Herzog, Jürgen; Dichgans, Martin

doi:10.1001/archneur.62.7.1091

Cited by 138 publications

(30 citation statements)

References 14 publications

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“…191 Most of these are missense mutations altering the number of cysteine residues expressed in an extracellular receptor domain. 192 Though Notch3 is widely expressed in the body and plays an important role in development, CADASIL only affects the nervous system clinically, for unknown reasons. While the defective receptors usually do not interfere with phenotypic signaling, they have been shown to accumulate in the basal lamina of the small arteries.…”

Section: Genetic Risk Factors For Strokementioning

confidence: 99%

Stroke Risk Factors, Genetics, and Prevention

Boehme

Esenwa

Elkind

2017

Circulation Research

1,318

895

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Stroke is a heterogeneous syndrome, and determining risk factors and treatment depends on the specific pathogenesis of stroke. Risk factors for stroke can be categorized as modifiable and nonmodifiable. Age, sex, and race/ethnicity are nonmodifiable risk factors for both ischemic and hemorrhagic stroke, while hypertension, smoking, diet, and physical inactivity are among some of the more commonly reported modifiable risk factors. More recently described risk factors and triggers of stroke include inflammatory disorders, infection, pollution, and cardiac atrial disorders independent of atrial fibrillation. Single-gene disorders may cause rare, hereditary disorders for which stroke is a primary manifestation. Recent research also suggests that common and rare genetic polymorphisms can influence risk of more common causes of stroke, due to both other risk factors and specific stroke mechanisms, such as atrial fibrillation. Genetic factors, particularly those with environmental interactions, may be more modifiable than previously recognized. Stroke prevention has generally focused on modifiable risk factors. Lifestyle and behavioral modification, such as dietary changes or smoking cessation, not only reduces stroke risk, but also reduces the risk of other cardiovascular diseases. Other prevention strategies include identifying and treating medical conditions, such as hypertension and diabetes, that increase stroke risk. Recent research into risk factors and genetics of stroke has not only identified those at risk for stroke but also identified ways to target at-risk populations for stroke prevention.

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Section: Genetic Risk Factors For Strokementioning

confidence: 99%

Stroke Risk Factors, Genetics, and Prevention

Boehme

Esenwa

Elkind

2017

Circulation Research

1,318

895

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“…28 The stereotyped mis-sense mutations 2 or deletions 29 responsible for CADASIL are within epidermal-growth-factor-like (EGF-like) repeats and only located in the extracellular domain of the NOTCH3 protein. 30-32 All mutations responsible for the disease lead to an uneven number of cystein residues.…”

Section: Pathophysiologymentioning

confidence: 99%

Neuropsychiatric Symptoms of CADASIL

Chabriat

Reyes

2013

Neuropsychiatric Symptoms of Neurological Disease

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL) is an inherited small-artery disease of mid-adulthood caused by mutations of the NOTCH3 gene. The disease is responsible for widespread white-matter Iesions associated with lacunar infarctions in varinus subcortical areas. The disease is responsible for migraine with aura and ischemic strokes, and is associated with various degrees of cognitive impairment and with mood disturbances. CADASIL is considered as a unique model to investigate what is known as "subcortical ischemic vascular dementia. "Recent data suggest that the number of lacunar infarctions and severity of cerebral atrophy are the main magnetic resonance imaging markers associated with cognitive and motor disabilities in this disorder. Mood disturbances are reported in 10% to 20% of patients, most often in association with cognitive alterations. Their exact origin remains unknown; the presence of ischemic lesions within the basal ganglia or the frontal white matter may promote the occurrence of these symptoms. Further studies are needed to better understand the relationships between cerebral lesions and both cognitive and psychiatric symptoms in this small-vessel disease of the brain.

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“…Resulting from mutations in the Notch3 gene on chromosome 19q12, CADASIL is associated with progressive degeneration of smooth muscle cells and the accumulation of granular osmiophilic deposits in the vascular basal lamina of small arteries (44). This disorder may be diagnosed by skin biopsy or by genetic testing (45). Patients experience migraine headaches, seizures, and progressive SIVD.…”

Section: B Cadasilmentioning

confidence: 99%

Subcortical Ischemic Vascular Dementia

Chui

2007

Neurologic Clinics

136

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Subcortical ischemic vascular dementia (SIVD) has been proposed as a subtype of vascular cognitive impairment (VCI). The syndrome is defined clinically by cognitive impairment and evidence of subcortical vascular brain injury, including lacunar infarcts and deep white matter changes. SIVD has been traditionally recognized as lacunar state, strategic infarct dementia, and Binswanger syndrome, but these clinical syndromes represent the tip of the iceberg. Proton density magnetic resonance (MRI) often discloses "silent" hyperintensities in 20-40% of community dwelling elderly. Efforts to relate MRI-measured lacunes and white matter changes to cognitive impairment have not been straightforward. The hidden possibility that concomitant Alzheimer disease pathology contributes significantly to cognitive impairment increases with age. Nonetheless, new knowledge is being gained from longitudinal MRI and systematic neuropathological studies. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL), a rare genetic disorder, provides an opportunity to study pure SIVD in the absence of AD. Dysexecutive syndrome characterized by slowing of mental processing speed, decreased working memory, and impairment of abstract reasoning are associated with lacunes and deep white matter changes. But data related to sensitivity and specificity which would support dysexecutive syndrome as diagnostic criteria are limited. Hypertension, by far the leading risk factor for sporadic SIVD, is eminently treatable. High priority must be given to reducing vascular risk profiles.

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Spectrum of Mutations in Biopsy-Proven CADASIL

Cited by 138 publications

References 14 publications

Stroke Risk Factors, Genetics, and Prevention

Stroke Risk Factors, Genetics, and Prevention

Neuropsychiatric Symptoms of CADASIL

Subcortical Ischemic Vascular Dementia

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