New knowledge on anti-IgLON5 disease

Abstract

Purpose of review: Anti-IgLON5 disease is characterized by a distinctive sleep disorder, associated with a heterogeneous spectrum of neurological symptoms. Initial autopsies showed a novel neuronal tauopathy predominantly located in the tegmentum of the brainstem. Recently, new diagnostic red flags, biomarkers predictors of response to immunotherapy, and novel insights into the autoimmune pathogenesis of the disease have been reported.

Recent findings: Patients with diagnosis of neurodegenerative dementia, progressive supranuclear palsy (PSP) or with motor-neuron disease (MND)-like syndrome have been reported to have IgLON5 antibodies, which are the hallmark of anti-IgLON5 disease. Second, low levels of neurofilament light chain in serum and cerebrospinal fluid of patients at disease onset could be a predictor of immunotherapy response. Recent neuropathological studies indicate that the neuronal tau deposits occur late in the course of the disease. Moreover, IgLON5 antibodies induce cytoskeletal changes in cultured hippocampal neurons suggesting that the tauopathy could be secondary of the IgLON5 antibody effects.

Summary: Anti-IgLON5 disease can mimic and should be considered in atypical presentations of MND, neurodegenerative dementia and PSP. Neurofilament light chain levels seem promising biomarker for disease prognosis. Finally, the neuropathological and in vitro experimental studies strengthen the autoimmune hypothesis of the disease.

Box 1

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FIGURE 1

Graphical representation of clinical symptoms observed in anti-IgLON5 disease in combination with subtypes and possible mimics. In grey circles, IgLON5 mimics disorders and diseases that can resemble anti-IgLON5 disease. MSA, multiple system atrophy; OSAS, obstructive sleep apnoea syndrome; PSP, progressive supranuclear palsy; RBD, REM sleep behaviour disorder. Dark grey rectangles: Subtypes. Original figure.

FIGURE 2

Cellular inflammation in anti-IgLON5 disease. Cellular inflammation was mild to moderate and mainly composed of perivascular and parenchymal CD3 (a) and CD8 positive T cells (b) and few perivascular CD79a positive B cells/plasma cells (c). Parenchymal CD8 T cells were granzyme B positive and granules showed a polarization towards neurons (d; arrows). In addition, neurons showed an upregulation of MHC class I in the reticular formation and olivary nuclei (e, rectangle enlarged in f). Marked microglia activation was found in the HLA-DR staining in tegmentum of medulla oblongata and nucleus olivaris (g), including formation of microglial nodules (h; rectangle in g enlarged in h). Images are depicted from patient 1. Scale bars: 50 μm. Adapted from [6^▪].