To describe Anti-Neurofascin 140 (NF140) antibody-mediated autoimmune nodopathy (AN) and distinguish its pathophysiology from other neuropathies.

NF140-AN is not well-described. NF140 is an embryonic pioneer protein that brings voltage-gated sodium channels together during development and repair. In adults, NF140 is re-expressed after injury, and can be attacked at Nodes of Ranvier (NoR) through molecular mimicry, often after an infection.

A comprehensive literature review of all eleven relevant articles was performed focusing on molecular biology of NF140 re-expression, pathophysiology of pseudo-conduction block and sodium channel dispersion, clinical phenotype, and emerging therapeutic approaches.

NF140 antibodies are mostly IgG3 or IgG4 that attack extracellular domain in NoR rather than myelin as in chronic inflammatory demyelinating polyneuropathy (CIDP), combined central and peripheral demyelination (CCPD), or multiple sclerosis. The conduction failure from disruption of sodium channels and ankyrin-G is initially reversible, but can become irreversible if not properly treated. Infections such as C. jejuni can trigger NF140 antibody formation through molecular mimicry. Clinically, NF140-AN is associated with sensory ataxia, high-frequency action tremor, and severe quadriparesis. Compared to CIDP, distal weakness is often more prominent. If there is NF-140 re-expression in the brain, the central nervous system can be affected as well. IgG3-mediated NF140-AN is complement-activating, inflammatory, acute, and often mistaken for GBS. IgG4 mediated NF140-AN is complement-independent, non-inflammatory, chronic, gradual, yet aggressive and refractory to IVIG. FcRN inhibitors such as Efgartigimod and B-cell depleting agents like Rituximab have demonstrated promising results.

NF140-AN is distinct from most autoimmune conditions as it attacks NoR rather than myelin. NF140-AN should be considered in patients presenting with high-frequency action tremor and sensory ataxia that is refractory to IVIG. Determining whether NF140-AN is IgG3 or IgG4 mediated can help prognosticate speed of clinical progression. Future studies should compare efficacy of different immunomodulatory treatments in IgG3 vs. IgG4 mediated NF140-AN.