Brain. 2026 Jun 8:awag183. doi: 10.1093/brain/awag183. Online ahead of print.
ABSTRACT
Severe neuropathies with predominant involvement of motor fibers can resemble lower motor neuron disease (LMND) phenotypes. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to provide treatment options to patients. We investigated a novel autoantibody binding pattern observed on murine teased sciatic nerve fibers. Target antigens were identified using immunoprecipitation combined with 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 different neuropathies (chronic inflammatory demyelinating polyradiculopathy n=86, Guillain-Barré syndrome n=37, multifocal motor neuropathy n=18, diabetic neuropathy n=30, other inflammatory neuropathies n=10), amyotrophic lateral sclerosis (n=50), multiple sclerosis (n=50), and healthy controls (n=50) was negative for septin multimer autoantibodies. Histopathological analysis of skin and sural nerve including electron microscopy was performed in one seropositive patient, and autoantibody binding was characterized in vitro. Extensive immunotherapy was initiated in one patient, with clinical and serological follow-up over four years. Among 3,543 total samples tested, three patients (two male, one female) - diagnosed with the LMND variant of amyotrophic lateral sclerosis (ages 65, 72, and 79, respectively) - showed a novel and distinct autoantibody binding pattern of indirect immunofluorescence staining on peripheral nerves, targeting Schmidt-Lanterman incisures (SLIs), paranodes, and the abaxonal myelin. Target identification and validation revealed septin multimers as autoantibody epitopes. Despite the primarily intracellular location of septins, autoantibody binding was evident in living myelinated dorsal root ganglia, primarily at SLIs ("incisuropathy"). Septin multimer autoantibodies further initiated complement deposition on fixed and permeabilized cell-based assays. Sural nerve and skin biopsies showed inflammation, myelin and axonal pathology. Extensive immunotherapy in one patient was followed by disease stabilization over three years. The other two patients died of rapid disease progression: One of them received no immunotherapy while the other had ineffective treatments with single administrations of IVIG and rituximab. Our data suggest that septin multimer autoimmunity occurs in severe motor predominant neuropathies which can clinically resemble a neurodegenerative LMND. Screening for septin multimer autoantibodies should be considered in patients presenting with this phenotype. Follow-up studies need to determine the direct pathogenicity of septin multimer autoantibodies, their potential as a biomarker of an autoimmune syndrome, and responses to immunotherapy in larger cohorts.
PMID:42252093 | DOI:10.1093/brain/awag183