Investigating the role of serum NfL, FGF21, NCAM1 and GDF15 as disease biomarkers for Charcot-Marie-Tooth type 2A

Charcot–Marie–Tooth disease type 2A (CMT2A) is the most common axonal form of inherited peripheral neuropathy, caused by mutations in the mitofusin 2 (MFN2) gene that impair mitochondrial fusion and axonal transport, ultimately leading to progressive neurodegeneration. The identification of accessible molecular biomarkers may improve diagnostic accuracy, enable patient stratification, and support the development and monitoring of emerging therapies. We investigated serum levels of neurofilament light chain (NfL), neural cell adhesion molecule 1 (NCAM1), growth differentiation factor 15 (GDF15), and fibroblast growth factor 21 (FGF21) in CMT2A patients (n = 15), healthy controls (n = 10), and neurological disease controls (n = 16; amyotrophic lateral sclerosis ALS, n = 10, spinal muscular atrophy type 3 SMA3, n = 6), evaluating their utility as diagnostic and monitoring biomarkers. In parallel, serum NfL levels were assessed in transgenic Thy1-MFN2*R94Q mice, a validated preclinical model of CMT2A. Serum NfL levels were significantly elevated in CMT2A patients compared to healthy controls, a finding corroborated in transgenic mice. Notably, NfL levels in CMT2A patients were higher than in SMA3 but lower than in ALS patients, supporting the ability of this biomarker to discriminate between clinically overlapping neuromuscular conditions. Higher NfL levels were associated with younger age, earlier disease onset, and shorter disease duration, suggesting a role as a marker of early disease burden. However, no significant correlation was observed with clinical severity scores or electrophysiological measures. Serum FGF21 levels were also significantly elevated in CMT2A patients compared to controls, whereas NCAM1 and GDF15 levels did not differ significantly between groups. These findings support the role of serum NfL as a translational biomarker of axonal damage in CMT2A, capable of distinguishing affected individuals from both healthy and neurological disease controls. The concomitant elevation of FGF21 further underscores the contribution of mitochondrial dysfunction to CMT2A pathophysiology. Together, these results highlight the potential of serum biomarkers to refine diagnostic workflows and facilitate therapeutic development and future clinical trials for CMT2A.