From: mjs23x@gmail.com   
      
   CADASIL: Is it a Rare Disease? ➡ may not be rare ➡ Migraine headaches,   
   vision issues, and psychiatric problems can all occur, typically beginning in   
   a person’s 30s. Multiple successive strokes eventually lead to dementia by   
   age 65.   
      
   *****   
      
      
   CADASIL: Is it a Rare Disease?   
   James Radke, PhD   
   Published Online: Friday, Dec 16, 2016   
    24  729  20 Reddit3     
   A new study in the Annals of Clinical and Translational Neurology suggests   
   that the rare disease CADASIL (cerebral autosomal dominant arteriopathy with   
   subcortical infarcts and leukoencephalopathy) may not be rare.   
       
   The study examined the genetic mutations believed to be responsible for the   
   symptoms of CADASIL and found that those mutations were present in 3.4 / 1000   
   people.  A prevalence that is 100 times higher than currently believed   
   prevlance for CADASIL (2 –    
   5 / 100,000).   
   About CADASIL   
      
   CADASIL is a disease that affects the small blood vessels in the brain’s   
   white matter. Thickening of blood vessel walls blocks the blood flow to the   
   brain, leading to the symptoms of the condition. Migraine headaches, vision   
   issues, and psychiatric    
   problems can all occur, typically beginning in a person’s 30s. Multiple   
   successive strokes eventually lead to dementia by age 65.   
       
   CADASIL is caused by a mutation in the NOTCH3 gene that leads to inflammation   
   and thickening of the blood vessels.   
       
   In most cases, CADASIL is not diagnosed until a person has had an ischemic   
   stroke or other vascular event.    
       
   Currently there are no treatments for CADASIL but patients can receive   
   symptomatic treatment for migraines and other symptoms that are common in   
   patients.    
   Study Results   
      
   The mutations investigated by Rutten et al were distinct mutations along the   
   NOTCH3 gene that affect cysteine. More specifically, over 98% of CADASIL   
   patients have a distinctive missense mutation in one of NOTCH3 exons 2–24,   
   that leads to the gain or    
   loss of a cysteine residue in one of the 34 epidermal growth factor-like   
   repeat (EGFr) domains of the NOTCH3 protein.   
       
   These EGFr cysteine altering NOTCH3 mutations were assessed in the general   
   populations using the Exome Aggregation Consortium (ExAC) database that   
   contains exome data of 60,706 unrelated individuals. NOTCH3 mutations present   
   in ExAC were compared to    
   those reported in the Dutch CADASIL registry and the international CADASIL   
   literature.   
       
   And the study found 206 EGFr cysteine altering NOTCH3 mutations in ExAC, with   
   a total prevalence of 3.4/1000.   
       
   The authors discuss many hypotheses to explain the large difference in   
   prevalence rates found but conclude that “the most likely explanation for   
   the observed high mutation frequency in ExAC is a much higher prevalence than   
   recognized to date of a very    
   mild, late-onset NOTCH3 mutation-associated cerebral small vessel disease,   
   which may remain undiagnosed into old age.”   
       
   In the open source article, the authors illustrate the significant   
   pathophysiologic diversity that can exist in the CADASIL population in the   
   following set of MRIs.   
       
       
       
       
   Brain MRI of elderly asymptomatic and paucisymptomatic individuals with a   
   NOTCH3 mutation compared to MRI in classical cerebral autosomal dominant   
   arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).   
   (A–C) Brain MRI images of a    
   classical CADASIL phenotype in the 6th decade. (A–B) FLAIR images showing   
   extensive confluent symmetric white matter hyperintensities and multiple   
   lacunar infarcts (arrows indicate random samples). (C) T2*-weighted MRI   
   showing multiple microbleeds (   
   open arrows indicate random samples). (D–F) Brain MRI images of a female,   
   diagnosed with CADASIL after predictive DNA testing at 78 years of age, with   
   only very mild clinical symptoms. (D, E) FLAIR images showing symmetric white   
   matter hyperintensities,   
    but no lacunar infarcts. (F) T2*- weighted MRI showing some small microbleeds   
   (open arrows). (G-I) Dual echo images of a female who was still clinically   
   asymptomatic at 73 years of age. MRI images were made at 58 years of age,   
   showing very mild    
   symmetric white matter hyperintensities, no lacunar infarcts and no   
   microbleeds.    
       
   Reference   
      
   Rutten JW, Dauwerse HG, Gravesteijn G, et al. Archetypal NOTCH3 mutations   
   frequent in public exome: implications for CADASIL. Ann Clin Trans Neurol.   
   2016;3:844-853. doi:10.1002/acn3.344   
       
       
       
       
       
      
      
   http://www.raredr.com/news/cadasil-rare-disease   
      
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