Rare Disease Report

CADASIL: Is it a Rare Disease?

DECEMBER 16, 2016
James Radke, PhD
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).


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. 


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

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