CADASIL
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What is CADASIL?
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, usually called CADASIL, is an inherited form of stroke and other impairments. This condition affects small blood vessels, mainly in the brain. An abnormality in the muscle cells surrounding these blood vessels (vascular smooth muscle cells) gradually destroys the blood vessel cells. The resulting blood vessel damage can lead to migraines, emotional and mental disorders, stroke-like episodes, dementia, and other impairments of normal brain function. Patients with CADASIL are also at increased risk of heart attack (myocardial infarction) because of damaged blood vessels in the heart. Most patients with CADASIL do not have the common risk factors for stroke and heart attack, such as high blood pressure and high cholesterol, although in some cases these features may also be present.
How common is CADASIL?
The prevalence of CADASIL is unknown. A Scottish study suggested the prevalence of CADASIL in that population was about 2 in every 100,000 adults. Worldwide, approximately 400 families have been described with this disorder.
What genes are related to CADASIL?
Mutations in the NOTCH3 gene cause CADASIL.
The NOTCH3 gene makes a protein called the Notch3 receptor protein, which plays a role in the development, function and maintenance of vascular smooth muscle cells. Mutations in the NOTCH3 gene lead to an abnormal version of the Notch3 protein that builds up in vascular smooth muscle cells. Accumulation of the abnormal Notch3 protein is thought to cause the degeneration of these muscle cells, leading to the loss of function of blood vessels in the brain and heart.
How do people inherit CADASIL?
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene is sufficient to cause the disorder.
In most cases, an affected person has one parent with the condition.
A few rare cases of patients with new mutations in the NOTCH3 gene have been identified.
Source: National Institutes of Health
New findings from National Institute of Mental Health in the area of bipolar disorder therapy published
2009 MAY 18 - (NewsRx.com) -- Research findings, 'Valproate activates the Notch3/c-FLIP signaling cascade: a strategy to attenuate white matter hyperintensities in bipolar disorder in late life,' are discussed in a new report. "Increased prevalence of deep white matter hyperintensities (DWMHs) has been consistently observed in patients with geriatric depression and bipolar disorder. DMWHs are associated with chronicity, disability, and poor quality of life," scientists in the United States report. "They are thought to be ischemic in their etiology and may be related to the underlying pathophysiology of mood disorders in the elderly. Notably, these lesions strikingly resemble radiological findings related to the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy (CADASIL) syndrome. CADASIL arises from mutations in Notch3, resulting in impaired signaling via cellular Fas-associated death domain-like interleukin-1-beta-converting enzyme-inhibitory protein (c-FLIP) through an extracellular signal-regulated kinase (ERK)-dependent pathway. These signaling abnormalities have been postulated to underlie the progressive degeneration of vascular smooth muscle cells (VSMC). This study investigates the possibility that the anticonvulsant valproate (VPA), which robustly activates the ERK mitogen-activated protein kinase (MAPK) cascade, may exert cytoprotective effects on VSMC through the Notch3/c-FLIP pathway. Human VSMC were treated with therapeutic concentrations of VPA subchronically. c-FLIP was knocked down via small interfering ribonucleic acid transfection. Cell survival, apoptosis, and protein levels were measured. VPA increased c-FLIP levels dose-and time-dependently and promoted VSMC survival in response to Fas ligand-induced apoptosis in VSMC. The anti-apoptotic effect of VPA was abolished by c-FLIP knockdown. VPA also produced similar in vivo effects in rat brain. These results raise the intriguing possibility that VPA may be a novel therapeutic agent for the treatment of CADASIL and related disorders," wrote P. Yuan and colleagues, National Institute of Mental Health. The researchers concluded: "They also suggest that VPA might decrease the liability of patients with late-life mood disorders to develop DWMHs." Yuan and colleagues published their study in Bipolar Disorders (Valproate activates the Notch3/c-FLIP signaling cascade: a strategy to attenuate white matter hyperintensities in bipolar disorder in late life' Bipolar Disorders, 2009;11(3):256-69). For more information, contact P. Yuan, National Institutes of Health, Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Bethesda, MD 20892 USA.. Publisher contact information for the journal Bipolar Disorders is: Blackwell Publishing Inc., 350 Main St., Malden, MA 02148, USA. Keywords: United States, Bethesda, Bipolar Disorder Therapy, Bipolar Disorder, Depression, Enzyme Research, Enzymology, Kinase, Manic-Depressive Illness, Mental Health, Physiology, Psychiatry, Quality of Life, Therapy, Treatment. This article was prepared by Biotech Business Week editors from staff and other reports. Copyright 2009, Biotech Business Week via NewsRx.com.
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