Severe neuropathies with predominant affection of motor fibers can mimic lower motor neuron disease (LMND) phenotypes such as in motor predominant chronic inflammatory demyelinating polyradiculoneuropathy and bulbar anti-IgLON5 disease. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to provide treatment options to patients.

Consecutive patients’ sera (n=2266, referred for antineuronal antibody testing, collected over one year) were tested for IgG reactivity against nervous system tissues. A novel binding pattern on murine teased fibers was further investigated by target identification using immunoprecipitation coupled to mass-spectrometry. Target specificity of these autoantibodies was validated in cell-based assays, neutralization assays, and knock-out models. A retrospective study cohort consisting of healthy controls (n=50), disease controls (n=50 amyotrophic lateral sclerosis, n=50 multiple sclerosis), and patients with neuropathies and similar IgG reactivity on teased fibers (n=27) were screened for presence of anti-septin multimer autoantibodies. Histopathological analysis of skin and sural nerve in one seropositive patient was performed, and antibody binding was characterized in vitro. Immunotherapy was initiated, with clinical and serological follow-up over three years.

Two patients initially diagnosed with LMND showed a novel pattern on peripheral nerves, binding to Schmidt-Lanterman incisures (SLIs), paranodes, and abaxonal myelin. Target identification revealed septin multimers as autoantibody epitopes. In living myelinated dorsal root ganglia cells, binding of autoreactive IgGs was evident primarily at SLIs (“incisuropathy”), and septin multimer IgGs initiated complement deposition on cell-based assays. Sural nerve and skin biopsies showed inflammation, myelin predominant pathology, and morphological alterations of SLIs. Immunotherapy in one patient led to stabilization, while the other untreated patient deceased two years after symptom onset.

Our data suggest that septin multimer autoimmunity can occur in severe motor predominant neuropathies, initially mimicking lower motor neuron disease. Screening for anti-septin multimer IgGs with consequent immunotherapy initiation in seropositive cases should be considered in LMND.