NEFL – Charcot-Marie-Tooth Disease

Neurofilament light polypeptide (NEFL) pathogenic variants underlie autosomal dominant Charcot-Marie-Tooth disease (CMT), including demyelinating (CMT1F), axonal (CMT2E), and intermediate forms. Over 174 CMT patients from unrelated families harboring 34 distinct NEFL variants demonstrate the gene’s critical role in peripheral nerve integrity (PMID:38578900). The core clinical features encompass progressive sensorimotor neuropathy with distal muscle weakness, pes cavus deformity, and reduced nerve conduction velocities.

1. Clinical Validity

ClinGen classification: Strong
Rationale: Association supported by 174 patients with 34 pathogenic NEFL variants across multiple families, including eight de novo occurrences, and consistent pathogenicity from functional and animal model studies (PMID:38578900).

2. Genetic Evidence

Inheritance mode: Autosomal dominant
Segregation: Eight de novo events in unrelated kindreds
Case series: At least 174 probands with NEFL variants documented across demyelinating, axonal, and intermediate CMT (PMID:38578900).
Variant spectrum: Predominantly missense substitutions (e.g., c.64C>T (p.Pro22Ser) in CMT with mixed axonal and demyelinating neuropathy) (PMID:19286384). Recurrent Pro8 and Pro22 hot-spot mutations and founder effects observed.

3. Functional Evidence

Mechanism: Dominant-negative disruption of neurofilament assembly and axonal transport.
Key assays: Cell culture models show mutant NEFL filaments aggregate and impair transport of wild-type neurofilaments and mitochondria (PMID:15282209; PMID:15857389). Mouse NEFL^E397K models recapitulate axonal neuropathy with early CMAP reduction and axonal degeneration (PMID:39975190).

4. Conflicting Evidence

Some variants (e.g., I214M) show minimal impact on filament assembly in vitro, suggesting potential benign or modifier roles rather than primary pathogenicity (PMID:16930284).

5. Integration and Clinical Utility

NEFL mutations exhibit a broad phenotypic spectrum owing to position-specific effects on filament assembly. Genetic testing for NEFL should be considered in CMT patients with intermediate or demyelinating features, particularly when ulnar MNCV is 25–45 m/s or CNS signs co-occur. Functional assays and animal models corroborate the pathogenicity of key NEFL variants, underscoring the gene’s diagnostic and therapeutic relevance.

Key Take-home: NEFL pathogenic variants cause dominantly inherited CMT with diverse neuropathic phenotypes; their detection informs precise diagnosis, prognosis, and emerging targeted interventions.

References

• Journal of neuromuscular diseases • 2024 • Novel Genetic and Biochemical Insights into the Spectrum of NEFL-Associated Phenotypes PMID:38578900
• Journal of clinical neuroscience • 2009 • The neurofilament light chain gene (NEFL) mutation Pro22Ser can be associated with mixed axonal and demyelinating neuropathy PMID:19286384
• 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

Evidence Based Scoring (AI generated)