Adult-Onset Leukodystrophies Mimicking Multiple Sclerosis

Genetic white matter disorders may be difficult to distinguish from multiple sclerosis (MS). This article reviews the clinical and radiologic features of leukodystrophies in adults and how to differentiate them from MS.

The rapid implementation of next-generation sequencing techniques in clinical practice has led to an increasing number of adult patients diagnosed with leukodystrophies, often with expanded clinical and radiologic phenotypes that include features mimicking MS. Advances in neuroimaging tools allow for the identification of radiologic features that distinguish between genetic and acquired white matter disorders.

Although individually rare, adult-onset leukodystrophies represent a non-negligible diagnostic challenge to clinicians assessing patients for MS. Patients with adult-onset leukodystrophies often present with multifocal white matter involvement that may mimic MS lesions. Their variable clinical presentation, often characterized by progressive spasticity, ataxia, and cognitive decline, can overlap with that of primary progressive MS, further adding to the diagnostic challenge of correctly identifying these rare disorders. The impact on patients is considerable and extends from potential exposure to inappropriate immunomodulatory treatments to missing timely genetic counseling and targeted leukodystrophy-specific therapies. Thus, it is crucial to know clinical and radiologic red flags for adult-onset leukodystrophies that can assist the differential diagnosis.