Genetic diseases misdiagnosed as multiple sclerosis: Observational study and review of literature
Abstract
Background Adult-onset neurogenetic diseases (NGDs) with white matter abnormalities are rare and often misdiagnosed as Multiple Sclerosis (MS) due to overlapping clinical and radiological features. Misdiagnosis can lead to unnecessary immunosuppressive treatments and delayed genetic counseling. This study combines a retrospective multicenter analysis with a systematic review of the literature to assess the characteristics of patients with NGDs misdiagnosed as MS (Mis-MS) or with coexisting MS (NGD-MS), with the goal of improving diagnostic accuracy. Methods The retrospective study was conducted across seven tertiary MS centers in Europe and North America. Patients with confirmed NGDs initially misdiagnosed as MS or with coexisting MS were included. Clinical, radiological, and genetic data were analyzed. Brain MRIs were evaluated for MS-consistent and atypical features using standardized criteria. A systematic literature review of NGDs mimicking MS was also performed. Results The retrospective study included 46 patients (37 Mis-MS, 9 NGD-MS). Common NGDs in Mis-MS were Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) (22 %), Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (8 %), and Adult-onset Alexander Disease (AOAD) (5 %). NGD-MS cases were primarily mitochondrial disorders (67 %). The median diagnostic delay for NGDs was nine years. Despite 80 % of Mis-MS patients showing atypical MRI features, 41 % met MS dissemination in space and 20 % dissemination in time criteria. CSF oligoclonal bands were absent in 92 % of Mis-MS patients but present in 83 % of NGD-MS patients. Literature review identified 81 Mis- MS and 22 NGD-MS cases, with Fabry disease and CADASIL most frequently involved. Discussion Diagnosing NGDs that mimic MS is challenging. CADASIL, ALSP, and AOAD were the most commonly misdiagnosed neurogenetic diseases as MS. Vasculopathies like CADASIL are challenging to differentiate from MS due to similar clinical and imaging features, including remitting course and gadolinium enhancement. Recognizing atypical MRI patterns and integrating clinical and genetic evaluations can improve diagnostic accuracy and patient care by preventing unnecessary MS treatment and enabling timely genetic counseling.
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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 [2]
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 [2]
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 [2]
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 [2]
In a retrospective study across 7 MS tertiary centers, CSF oligoclonal bands were absent in 100% of patients with CADASIL misdiagnosed as MS, but present in 83% of those with confirmed codiagnosis of neurogenetic disease and MS.
“In a retrospective study conducted across 7 MS tertiary centers, CSF oligoclonal bands were absent in 100% of patients with CADASIL misdiagnosed as MS, but present in 83% of those with confirmed codiagnosis of neurogenetic disease and MS.2”
From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [2]
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- Authors
- Mandia, D., Shor, N., Carlson, A. K., Obusez, E., Cohen, J. A., Fenu, S., Salsano, E., La Piana, R., Durães, J., Faustino, P., Deschamps, R., Bensa, C., de Pemille, C. V., Maillart, E., Papeix, C., Macaron, G., & Nadjar, Y.
- Affiliations
- Pitié-Salpêtrière Hospital (FR)
- Cleveland Clinic (US)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Unidade Local de Saúde de Coimbra (PT)
- Hôpital Rothschild (FR)
- Corresponding author
- Nadjar, Yann
- ORCID
- Venue
- Multiple Sclerosis and Related Disorders
- Publisher
- Elsevier BV
- Published
- 2025-07
- Volume
- 99
- Pages
- 106439
- ISSN
- 2211-0348 (ISSN-L)
- OpenAlex
- W4409342705
- Cited by
- 9
- References
- 32
- Citations by year
- 2026: 8 · 2025: 1
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Multiple Sclerosis and Related Disorders (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Takeda Pharmaceuticals U.S.A.
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Health Sciences › Medicine › Family Practice › Clinical Reasoning and Diagnostic Skills
- Keywords
- multiple sclerosis misdiagnosis, adult-onset leukoencephalopathy, CADASIL, ALSP, adult-onset Alexander disease, mitochondrial disease, Fabry disease, white matter abnormalities, dissemination in space, dissemination in time, delayed diagnosis, genetic counseling
- MeSH terms
- Adult, Diagnostic Errors, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Retrospective Studies, Genetic Diseases, Inborn, Young Adult
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