Fatigue in Charcot–Marie–Tooth Disease: Beyond Muscle Weakness Toward a Multidimensional Patient-Centred Model

Abstract Background Fatigue is among the most prevalent and functionally significant symptoms in Charcot–Marie–Tooth disease (CMT), the most common inherited peripheral neuropathy. Despite its substantial impact on participation and quality of life, fatigue in CMT remains incompletely understood and is often inadequately captured by traditional clinical measures of strength and nerve conduction. Emerging evidence suggests that fatigue may arise through interactions among peripheral neuromuscular, central, biomechanical, psychological, sleep-related, and metabolic mechanisms that extend well beyond the conventional model of muscle weakness.2 Methods A narrative review was conducted by searching PubMed and Google Scholar through May 2026. Search terms included combinations of: Charcot–Marie–Tooth disease, fatigue, peripheral neuropathy, neuromuscular disease, exercise, sleep, rehabilitation, central fatigue, and quality of life. Peer-reviewed studies published in English were included. No formal systematic review protocol, PRISMA methodology, or risk-of-bias assessment was applied. Results The reviewed literature identified seven principal contributing domains for fatigue in CMT: (1) dissociation between experienced and physiological fatigue; (2) potential central nervous system contributions through elevated cognitive and attentional demand; (3) biomechanical compensation and energetic inefficiency arising from distal weakness; (4) bidirectional relationships with psychological distress; (5) sleep dysfunction; (6) physical deconditioning; and (7) preliminary evidence of metabolic and mitochondrial dysfunction in specific subtypes. Quantitative anchors from the largest study to date (n = 251) include abnormal fatigue in 36% of patients (MFIS > 38), poor sleep quality in 56%, and abnormal daytime somnolence in 23%. Evidence for targeted fatigue interventions remains limited, and most available studies are small and cross-sectional. Conclusions Fatigue in CMT is best understood as a multidimensional phenomenon arising from the cumulative burden of chronic neuropathic disease across biological, psychological, and social domains. The available evidence does not support any single explanatory mechanism for fatigue in CMT. Future research should prioritise longitudinal designs, standardised assessment tools, CMT subtype-specific analyses, and greater integration of patient-reported outcomes. The relative contributions of individual mechanisms remain uncertain and require further investigation. Keywords: Charcot–Marie–Tooth disease; fatigue; peripheral neuropathy; rehabilitation; sleep; quality of life; patient-centred care; disability; neuromuscular disease; fatigue mechanisms