Uncovering genetic mimics in multiple sclerosis

Mandler, Julia M.; Härtl, Johanna; Cordts, Isabell; Sturm, Marc ; Hedderich, Dennis M.; Bafligil, Cemsel; Baki, Enayatullah; Becker, Benedikt; Machetanz, Gerrit; Haack, Tobias B. ; Berthele, Achim; Hemmer, Bernhard und Deschauer, Marcus (2024): Uncovering genetic mimics in multiple sclerosis. A single-center clinical exome sequencing study. In: Multiple Sclerosis Journal - Experimental, Translational and Clinical, Bd. 10, Nr. 3

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2055-2173
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198