Genetic diseases misdiagnosed as multiple sclerosis: Observational study and review of literature

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.

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.

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.

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.