Is it MS or CADASIL? The distinctions affect the diagnosis.

CADASIL or “cerebral autosomal dominant arteriopathy and subcortical infarct leukoencephalopathy” is likely not something you hear about every day. It is indeed a rare diagnosis and in the course of my career I have seen only two cases of this condition. BUT…a recent article regarding the possibility that some cases of CADSASIL may be mistaken for multiple sclerosis (MS) gives us reason enough to discuss the differences and the importance of obtaining a proper diagnosis in any illness. 

What is CADASIL?
 
A genetic disorder, CADASIL is the most common form of hereditary stroke affecting the small blood vessels in the brain. It is caused by a mutation in a specific gene or, from a scientific perspective, “by a cysteine-altering mutation in epidermal growth factor-like repeat (EGFr) domain of the NOTCH3 gene located on chromosome 19q12.1
 
The core features of CADASIL are:
-Migraine with aura
-Recurrent strokes
-Dementia
-Psychiatric issues.
 
A CADASIL diagnosis can be difficult as the disease prevalence is extremely low for severe cases, estimated at roughly 5 per 100,000 individuals although it is thought that the disease is likely under-diagnosed. Men represent only a slightly higher percentage of cases than women and there is no other known demographic or geographic association.2
 
According to NORD (National Organization for Rare Disorders) “the CADASIL diagnosis can only be confirmed by DNA testing of blood samples for characteristic mutations in the NOTCH3 gene or by identifying granular osmiophilic material (GOM) inclusions on a skin biopsy.”
 
The NOTCH3 gene.
 
The NOTCH3 gene provides instructions for making a protein with one end (the intracellular end) that remains inside the cell, a middle (transmembrane) section that spans the cell membrane, and another end (the extracellular end) that projects from the outer surface of the cell. The manufactured protein plays a key role in the function and survival of vascular smooth muscle cells and is essential for the maintenance of blood vessels - including those that supply blood to the brain.
 
More than 270 mutations in the NOTCH3 gene have been found to cause CADASIL; most of these mutations change just a single protein building block (amino acid) in the NOTCH3 protein that affects the gene’s function in vascular smooth muscle cells. This disruption can thereby lead to the self-destruction (apoptosis) of the cells and result in the recurrent strokes and other symptoms associated with CADASIL.3
 
MS vs. CADASIL – understanding the differences.
 
There are signs and symptoms that overlap in both diseases and it is now thought there may be involvement of (systemic) autoimmune mechanisms in some patients with CADASIL. Cases can look very, very similar and both can have a relapsing remitting pattern and progression over time. But without DNA testing for the NOTCH3 gene mutation, a diagnosis using clinical observations and magnetic resonance imaging (MRI) alone is not sufficient.
 
While CADASIL is an inherited disorder, scientists have cautioned that the lack of familial history cannot rule out this diagnosis as it’s entirely possible it was not appropriately diagnosed in other family members. The case report additionally notes that “involvement of autoimmune mechanisms in CADASIL and the role of NOTCH3 mutations in provoking an autoimmune process should be further investigated.”4
 
It’s important to note that treatments for MS are not applicable for treating CADASIL – the two disorders may look similar, but are different in why they occur as well as how they affect the brain. But as we always recommend with any disease, addressing modifiable risk factors such as dietary choices, exposure to toxins, stress management, and other lifestyle influences is critical to reducing inflammation and ideally improving patient outcomes.  
 
If you have questions or would like more information about integrative medicine in any aspect of neurology care, please don’t hesitate to reach out and let us know. We are here for you!
 
In health and hope,
Dr. Suzanne Gazda 
 
References:
 
1 Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. (1996) 383:707–10. doi: 10.1038/383707a0
 
2 Cramer, J., White, M.L. “Cerebral Autosomal Dominant Arteriopathy (CADASIL).” August 2020. https://www.ncbi.nlm.nih.gov/books/NBK470293/
 
3 Medline Plus: NOTCH3gene
https://medlineplus.gov/genetics/gene/notch3/
 
4 Khan, A., Abedi, V., Li, J., Malik, M.T., Esch, M., Zand, R. CADASIL vs. Multiple Sclerosis: Is It Misdiagnosis or Concomitant? A Case Series. Frontiers in Neurology. Vol. 11 (2020). P 865.
ISSN=1664-2295. 
https://www.frontiersin.org/article/10.3389/fneur.2020.00860                
DOI: 10.3389/fneur.2020.00860
 
Additional reading:
 
https://medlineplus.gov/genetics/condition/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy/#frequency
 
Mayo Clinic
https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/57461