NEFL, encoding the neurofilament light chain protein, is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. It is crucial for maintaining axonal structure and function [1,3].

Pathogenic variants in NEFL cause demyelinating, axonal and intermediate forms of Charcot-Marie-Tooth disease (CMT) with varying severity [3]. In Taiwanese CMT patients, certain NEFL mutations were identified, and some patients had additional central nervous system (CNS) involvement [4]. In two Italian families, a NEFL mutation (p.P440L) was associated with a mild, childhood-onset CMT phenotype, along with some new findings like cardiological and urinary dysfunctions [5]. Also, in esophageal squamous carcinoma cells, NEFL overexpression promotes invasion and migration via the EGFR/AKT/S6 pathway [2]. Moreover, serum NEFL levels are increased in children and adolescents with bipolar disorder and schizophrenia, indicating possible neuronal damage [6].

In conclusion, NEFL is essential for axonal integrity. Studies on NEFL-related diseases, such as CMT, esophageal squamous carcinoma, bipolar disorder, and schizophrenia, through patient-based genetic analysis, have enhanced our understanding of the role of NEFL in these disease conditions, providing insights into potential disease mechanisms and possible therapeutic targets.