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Cited by 2Multiple Sclerosis Research StudiesCerebrovascular and genetic disordersGenomics and Rare Diseases

Uncovering genetic mimics in multiple sclerosis: A single-center clinical exome sequencing study

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Mandler, Julia M., Härtl, Johanna, Cordts, Isabell, Sturm, Marc, Hedderich, Dennis M., Bafligil, Cemsel, Baki, Enayatullah, Becker, Benedikt +5 more·2024·Multiple Sclerosis Journal - Experimental, Translational and Clinical
DOI 10.1177/20552173241263491PMC PMC11273569
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Abstract

Background: Multiple sclerosis (MS) shares clinical/radiological features with several monogenic diseases that can mimic MS. Objective: We aimed to determine if exome sequencing can identify monogenic diseases in patients diagnosed with MS according to the McDonald criteria thus uncovering them as being misdiagnosed. Methods: We performed whole exome sequencing in a cohort of 278 patients with MS, clinically or radiologically isolated syndrome without cerebrospinal fluid-specific oligoclonal bands (CSF-OCBs) (n = 228), a positive family history of MS (n = 44), or both (n = 6), thereby focusing on individuals potentially more likely to have underlying monogenic conditions mimicking MS. We prioritized 495 genes associated with monogenic diseases sharing features with MS. Results: A disease-causing variant in NOTCH3 was identified in one patient without CSF-OCBs, no spinal lesions, with non-response to immunotherapy, and a family history of dementia, thereby converting the diagnosis to cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Moreover, 18 patients (6.5% of total) carried variants of unclear significance. Conclusion: Monogenic diseases being misdiagnosed as MS seem rare in patients diagnosed with MS according to the McDonald criteria, even in CSF-OCB negative cases. The detected pathogenic NOTCH3 variant emphasizes CADASIL as a rare differential diagnosis and highlights the relevance of genetic testing in selected MS cases with atypical presentations.

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  • Diagnostic confusion between CADASIL and MS stems from overlapping clinical and radiologic features such as migraine, transient neurologic symptoms, and widespread white matter lesions on MRI, which, when combined with an absent or unrecognized stroke history, can push clinicians toward an MS diagnosis.

    “The diagnostic confusion stems from overlapping clinical and radiologic features such as migraine, transient neurologic symptoms, and widespread white matter lesions on MRI, which, when combined with an absent or unrecognized stroke history, can push clinicians toward an MS diagnosis.2,3”

    From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [3]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • MS-directed treatments incurred financial costs and avoidable risks.

    “While no significant clinical or radiologic progression was observed during the typically short interval between misdiagnosis and diagnostic correction, 45.5% of misdiagnosed patients received MS-directed treatments for a median of 10 months, incurring financial costs and avoidable risks.2,3”

    From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [3]

    The Discussion says that identifying a genetic MS mimic can prevent unnecessary immunomodulatory treatment and its potentially harmful side effects, supporting the avoidable-risks point. Our copy does not state that these treatments incurred financial costs; its mention of reimbursement regulations concerns genetic testing, not treatment costs. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • A subsequent CADASIL diagnosis is often made after progressive ischemic events, characteristic white matter changes, or as clear family history emerges.

    “A subsequent CADASIL diagnosis is often made after progressive ischemic events, characteristic white matter changes, or as clear family history emerges.2-5”

    From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [3]

    The Results section describes one patient whose CADASIL diagnosis followed evolving CADASIL-typical MRI changes and a reevaluation of family history; the Discussion says the diagnosis was corrected from MS to CADASIL. The paper does not establish that this sequence occurs often, or that progressive ischemic events generally prompt the later diagnosis. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • CADASIL can be misdiagnosed as multiple sclerosis.

    “Despite these characteristic features, CADASIL can be misdiagnosed as multiple sclerosis (MS).2-4”

    From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [3]

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Research works printed but not linked: 35

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Authors
Mandler, J. M., Härtl, J., Cordts, I., Sturm, M., Hedderich, D. M., Bafligil, C., Baki, E., Becker, B., Machetanz, G., Haack, T. B., Berthele, A., Hemmer, B., & Deschauer, M.
Affiliations
  • TUM Klinikum (DE)
  • University of Tübingen (DE)
Corresponding author
Deschauer, Marcus
ORCID
Venue
Multiple Sclerosis Journal - Experimental, Translational and Clinical
Publisher
SAGE Publications
Published
2024-07
Volume
10
Issue
3
Pages
20552173241263491-20552173241263491
ISSN
2055-2173 (ISSN-L)
DOI
10.1177/20552173241263491
PMC
PMC11273569
OpenAlex
W4400995901
Cited by
2
References
39
Citations by year
2026: 2
FWCI
0.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Multiple Sclerosis Journal - Experimental Translational and Clinical (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by-nc)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • mediaTUM (Technical University of Munich) (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (EXC 2145 SyNergy - ID 390857198)
  • European Union's Horizon 2020 Research Innovation Program (grant MultipleMS, EU RIA 733161)
  • Clinicians scientist`s program of the Technical University of Munich
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
multiple sclerosis, monogenic disorders, differential diagnosis, misdiagnosis, clinical exome sequencing, CADASIL, clinically isolated syndrome, family history of dementia, atypical presentation

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