CMT2A: blood-based biomarkers identified to monitor peripheral nerve damage

A blood-measurable biomarker capable of detecting peripheral nerve damage in Charcot-Marie-Tooth disease type 2A (CMT2A): this is the main discovery of a study just published in Scientific Reports, conducted by researchers from the “Centro Dino Ferrari” of the University of Milan and the Policlinico di Milano, in collaboration with the IRCCS E. Medea of Bosisio Parini (Lecco). For the first time, a study systematically evaluates serum biomarkers in a cohort of patients affected by CMT2A, a rare hereditary peripheral neuropathy caused by mutations in the Mitofusin2 (MFN2) gene.

CMT2A is a rare neuromuscular disease that causes a progressive degeneration of nerve fibers, with muscle weakness, loss of sensitivity, and walking difficulties. To date, there is no approved therapy, and until this study, there was a lack of objective tools to measure disease progression or evaluate the efficacy of new treatments.

The research, coordinated by Prof. Stefania Paola Corti and Dr. Elena Abati of the Neural Stem Cell Laboratory at the “Centro Dino Ferrari,” measured four candidate molecules in the blood of 15 patients affected by CMT2A, 10 healthy controls, and 16 patients affected by other neuromuscular diseases (Amyotrophic Lateral Sclerosis – ALS and Spinal Muscular Atrophy – SMA type 3). The same biomarkers were evaluated in a transgenic animal model of CMT2A, i.e., genetically modified to reproduce the human disease.

“Neurofilament light chain (NfL) was found to be elevated in the blood of patients with CMT2A compared to healthy controls, and this finding was also confirmed in the affected animals,” explains Dr. Elena Abati, first author of the study. “The NfL levels in CMT2A patients were intermediate between those observed in patients affected by ALS and SMA3: this suggests that the biomarker may help distinguish CMT2A from clinically similar conditions with a simple blood draw.”

The study identified a second promising biomarker: FGF21 (Fibroblast Growth Factor 21), a protein that increases when cells are subjected to mitochondrial stress—that is, an alteration in the functioning of mitochondria, the cell’s “energy plants.” This biomarker was also significantly elevated in patients with CMT2A. The data is consistent with the mechanism underlying the disease: CMT2A is, in fact, caused by mutations in the MFN2 gene, which is fundamental for the proper functioning of mitochondria. Alterations of this gene compromise the fusion and transport of mitochondria within nerve cells, contributing to the progressive peripheral nerve damage typical of the disease.

“Having validated blood biomarkers means being able to objectively measure the effect of new therapies—including the gene therapy approaches we are developing—without resorting to invasive procedures,” emphasizes Dr. Federica Rizzo, co-author of the study. “This study is a fundamental step toward more effective and accessible clinical trials for patients with CMT2A.”

The study also describes three new variants of the MFN2 gene (p.Ile88Val, p.Lys243Met, p.Leu733Pro) never before reported in literature, further expanding the knowledge of the genetic heterogeneity of CMT2A.

The research was made possible thanks to the central financial support of the Associazione Progetto Mitofusina 2 onlus, whose support was decisive in carrying forward this line of research. A fundamental contribution also came from the patients affiliated with ACMT-Rete (the Italian association for CMT), who participated in the study on a voluntary basis and after providing written informed consent, donating biological samples essential for the validation of the biomarkers.