To characterize leukodystrophy red flags for consideration of genetic testing in suspected MS patients.

Many adult-onset neurological disorders are inaccurately diagnosed as MS or other adult-onset leukodystrophies due to overlapping clinical/radiographic findings. Nearly 20–30% of patients who receive an initial diagnosis of MS have been misdiagnosed and ~40% of adult-onset genetic leukodystrophies, a family of monogenic white matter disorders with radiological and clinical findings, are often misdiagnosed as progressive forms of MS.

Misdiagnosis of adult-onset leukodystrophies may be avoidable through identification of clinical or radiological findings suggestive of alternative diagnoses, and/or genetic testing for leukodystrophy-associated genes. While criteria exists to identify MS or high likelihood of MS once other diagnoses have been deemed unlikely, detailed characterization and awareness of ‘red flags’ to prompt consideration of alternate diagnoses and genetic testing in MS clinics are lacking.

A systematic literature review (PubMed, 1980–2024) to identify published case studies of adult-onset leukodystrophies with clinical presentations mimicking MS was conducted. Eligible publications were manually screened to identify those with clinical symptoms and brain imaging findings which may differentiate leukodystrophies from MS.

Adult-onset leukodystrophies are frequently misdiagnosed as MS due to overlapping clinical and radiological presentations. Several of the following red flags should prompt genetic testing for leukodystrophies: family history of neurological disorders, white matter abnormalities atypical of MS, and early-onset cognitive impairment with behavioral or motor dysfunction. Low cost or no cost genetic testing programs may expedite access to testing as needed.