NEFL – Charcot-Marie-Tooth disease type 2

Charcot‐Marie‐Tooth disease type 2 (CMT2) is an autosomal dominant axonal neuropathy characterized by distal muscle weakness and sensory loss. Mutations in the neurofilament light chain gene (NEFL) (HGNC:7739) have been implicated in CMT2E, a subtype of CMT2, and represent a significant cause of CMT2 in multiple populations. Genetic screening and functional studies support NEFL as a moderate‐strength CMT2 gene–disease association with evidence from unrelated probands, familial segregation, and concordant in vitro and in vivo models.

Clinical Validity

The association of NEFL with CMT2 falls into the ClinGen “Moderate” category based on six unrelated probands in a Han Chinese CMT2 cohort (16.7% of 36) (PMID:22206013) and an additional family with a Pro22Ser mutation in CMT2E (PMID:18758688). Segregation in multiplex families and replication in independent cohorts, combined with functional concordance, support a moderate clinical validity.

Genetic Evidence

Inheritance is autosomal dominant. In a Taiwanese cohort, NEFL mutations were identified in six of 36 unrelated CMT2 patients (16.7%) (PMID:22206013). Three distinct missense variants were reported: c.22C>G (p.Pro8Ala), c.23C>G (p.Pro8Arg), and c.1186G>A (p.Glu396Lys). Familial segregation of c.23C>G (p.Pro8Arg) was observed in one kindred, confirming co‐segregation with disease.

Functional Evidence

Cell culture assays of NEFL mutants demonstrate defective intermediate filament assembly and axonal transport, with dominant‐negative effects on wild‐type neurofilaments (PMID:15282209; PMID:15857389). A NeflE397K mouse model recapitulates early and chronic axonal neuropathy with reduced sciatic nerve axon area and electrophysiological deficits consistent with human CMT2E (PMID:39975190; PMID:40413792).

Conflicting Evidence

The I214M substitution (c.639C>G (p.Ile213Met)) in NEFL does not segregate with CMT and shows only mild assembly changes in vitro, suggesting a benign polymorphism or modifier role (PMID:16930284).

Integrated Conclusion

NEFL harbors recurrent missense mutations that cluster in the head and tail domains, disrupting filament assembly and axonal transport. The frequency of NEFL mutations in diverse CMT2 cohorts and the replication of neuropathic phenotypes in cellular and mouse models establish a moderate level of evidence for NEFL in CMT2. Additional large segregation studies would further strengthen the association.

Key Take-home: NEFL mutation screening should be included in the diagnostic workup for CMT2, particularly in patients negative for MFN2 and other common CMT2 genes.

References

• PloS one • 2011 • The mutational spectrum in a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese in Taiwan. PMID:22206013
• Journal of human genetics • 2008 • NEFL Pro22Arg mutation in Charcot-Marie-Tooth disease type 1. PMID:18758688
• Human molecular genetics • 2004 • Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models. PMID:15282209
• Journal of neurochemistry • 2005 • Mutations in the neurofilament light gene linked to Charcot-Marie-Tooth disease cause defects in transport. PMID:15857389
• bioRxiv • 2025 • Novel neurofilament light (Nefl) E397K mouse models of Charcot-Marie-Tooth type 2E (CMT2E) present early and chronic axonal neuropathy. PMID:39975190
• Human molecular genetics • 2025 • The NeflE397K mouse model demonstrates muscle pathology and motor function deficits consistent with CMT2E. PMID:40413792
• Journal of the peripheral nervous system : JPNS • 2006 • Is a novel I214M substitution in the NEFL gene a cause of Charcot-Marie-Tooth disease? Functional analysis using cell culture models. PMID:16930284

Evidence Based Scoring (AI generated)