Muscle Regeneration Failure May Lead to Clinical Features of Myopathy in Anti-IgLON5 Disease

BACKGROUND AND OBJECTIVES: Anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease is a novel and potentially treatable entity. Therefore, it is important to recognize all clinical symptoms and diagnostic clues. We specifically investigated neuromuscular signs and symptoms and muscle biopsy pathology, providing a link between IgLON5 and clinical features of myopathy. METHODS: All patients diagnosed with anti-IgLON5 disease in the Netherlands between 2016 and 2023 were included. Serum and CSF samples were tested with immunohistochemistry on rat brain and in-house cell-based assay using live cells. Biopsies of the vastus lateralis muscle were performed in patients with neuromuscular signs and symptoms and analyzed in Vienna together with 3 biopsies of non-Dutch patients sent to Vienna for second opinion. RESULTS: Twenty patients with anti-IgLON5 disease were included (10 male, 50%). The median age at onset was 61.5 years (range 45-85), and the median time from onset to diagnosis was 30 months (range 3-280). Neuromuscular symptoms were present in over half of the patients (11/20), including proximal limb weakness (n = 11), axial weakness (n = 1), muscle atrophy (n = 6), and fasciculations (n = 5). All 12 muscle biopsies (9 from the Dutch cohort, 3 external) showed mild myopathic alterations, 2 additionally presented target fibers and fiber type grouping (compatible with neurogenic myopathy), and 3 patients showed immune cell infiltration. We found a strong upregulation of IgLON5 expression in muscle fibers in all patients and also in different muscle disease controls, while immunoreactivity in healthy control muscle was faint/absent. DISCUSSION: Our data support that IgLON5 might play a role in muscle regeneration, which might result in proximal myopathy as a prominent clinical feature in anti-IgLON5 disease. This finding broadens the clinical phenotype of anti-IgLON5 disease and can be an important clue for earlier diagnosis and start of immunotherapy.