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   CADASIL: The Most Common Hereditary Subcortical Vascular Dementia   
      
   Hannu Kalimo; Qing Miao; Saara Tikka; Kati Mykkänen; Maija Junna; Susanna   
   Roine; Matti Viitanen; Minna Pöyhönen; Marc Baumann | Disclosures   
   Future Neurology. 2008;3(6):683-704.    
       
   ABSTRACT AND INTRODUCTION   
   Abstract   
      
   Cerebral autosomal dominant arteriopathy with subcortical infarct and   
   leukoencephalopathy (CADASIL) is the most common hereditary subcortical   
   vascular dementia. It is caused by the defective NOTCH3 gene, which encodes a   
   transmembrane receptor; over 170    
   different mutations are known. The main clinical features are migraine with   
   aura (often atypical or isolated), strokes, cognitive decline/dementia and   
   psychiatric symptoms. Executive and organizing cognitive functions are   
   impaired first, memory is    
   affected late. Typical MRI findings are T2 weighted hyperintensities in   
   temporopolar white matter and the capsula externa. Smooth muscle cells in   
   small arteries throughout the body degenerate and vessel walls become   
   fibrotic. In the brain, this results    
   in circulatory disturbances and lacunar infarcts, mainly in cerebral white   
   matter and deep gray matter. The exact pathogenesis is still open: a   
   dominant-negative toxic effect is suggested, possibly related to Notch3   
   misfolding. Diagnosis is reached    
   either by identifying a pathogenic NOTCH3 mutation or by electron microscopic   
   demonstration of granular osmiophilic material in a (skin) biopsy. Only   
   symptomatic treatment is available at present.   
      
   Introduction   
      
   Cerebral autosomal dominant arteriopathy with subcortical infarct and   
   leukoencephalopathy (CADASIL) is the most common hereditary vascular dementia.   
   The disease is caused by more than 170 different stereotypic mutations in the   
   NOTCH3 gene encoding a 280    
   kDa transmembrane receptor [1, Suppl. table in 2]. The mutations lead to   
   progressive vascular smooth muscle cell (VSMC) degeneration, thickening and   
   fibrosis of the vessel walls and accumulation of the Notch3 extracellular   
   domain (N3ECD) on the VSMCs.    
   The four most common characteristic clinical symptoms of CADASIL are migraine   
   with aura, recurrent ischemic attacks, cognitive decline and psychiatric   
   symptoms. Only symptomatic therapy is available and thus, as a progressive   
   disease, CADASIL leads to    
   severe dementia and finally to death, commonly within 20-25 years after   
   symptoms have occurred.   
      
       
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   http://www.medscape.com/viewarticle/583073   
      
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