When Multiple Sclerosis Overlaps with Neuromuscular Disorders: Clinical Associations, Shared Mechanisms, and Diagnostic Challenges

Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disorder of the central nervous system, traditionally considered distinct from neuromuscular diseases, which primarily affect the peripheral nervous system, neuromuscular junction, or skeletal muscle. Growing clinical and experimental evidence, however, indicates that certain neuromuscular disorders may coexist with MS or shared overlapping pathophysiological, immunological, and metabolic mechanisms. This narrative review summarizes reported associations between MS and neuromuscular diseases, with particular focus on well-characterized overlaps such as Leber hereditary optic neuropathy (LHON)-associated MS (Harding’s disease), combined central and peripheral demyelination (CCPD), and myasthenia gravis (MG) co-occurring with MS. Additional associations with Charcot–Marie–Tooth disease, mitochondrial disorders with MS-like phenotypes, inherited and autoimmune myopathies, and rare syndromes such as Guillain–Barré syndrome are also discussed. This review highlights proposed mechanisms potentially linking these conditions, including immune dysregulation, T- and B-cell-mediated autoimmunity, antibody-driven demyelination, mitochondrial dysfunction, impaired neuromuscular transmission, and molecular mimicry. Limitations of the current literature are acknowledged, particularly the predominance of case reports for rare associations and the frequent lack of systematic screening for coexisting disorders. By integrating evidence from case series, cohort studies, and mechanistic research, this review provides a comprehensive overview of the biological and clinical intersections between MS and neuromuscular diseases. Enhanced understanding of these overlaps may improve diagnostic accuracy, guide individualized management strategies, and inform future research on shared neuroimmunological and neurodegenerative pathways.