Anti-IgLON5 Autoantibodies Tauopathy

1. ANTI-IGLON5 DISEASE
Ade Wijaya, MD – April 2023

2. Introduction
 Rare autoimmune neurological disorder
 Autoantibodies against the IgLON5 protein
 Tau deposits mainly involving the
hypothalamus and brainstem tegmentum
Zhang YZ, Ni Y, Gao YN, Shen DD, He L, Yin D, Meng HY, Zhou QM, Hu J, Chen S. Anti-IgLON5 disease: a novel topic beyond neuroimmunology. Neural Regeneration Research. 2023 May
Gelpi E, Höftberger R, Graus F, Ling H, Holton JL, Dawson T, Popovic M, Pretnar-Oblak J, Högl B, Schmutzhard E, Poewe W, Ricken G, Santamaria J, Dalmau J, Budka H, Revesz T, Kovacs GG
(2016) Neuropathological criteria of anti-IgLON5-related tauopathy Acta Neuropathol 132 531 543
Sabater L, Gaig C, Gelpi E, Bataller L, Lewerenz J, Torres-Vega E, Contreras A, Giometto B, Compta Y, Embid C, Vilaseca I, Iranzo A, Santamaría J, Dalmau J, Graus F (2014) A novel non-rapid-
eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study
Lancet Neurol 13 575 586

3. The Structure and Function of
IgLON5
 IgLON5 is a cell adhesion molecule belonging to
the IgLON family
 Characterized by an N-terminal signal peptide,
three Ig-like domains, and a
glycosylphosphatidylinositol (GPI) anchor
 In humans, IgLON5 proteins are mainly expressed
in the brain and testis
 In the brain, the highest IgLON5 protein levels are
found in the cerebellum
 IgLON5 transcripts are distributed in a wide
variety of tissues, but particularly in the brain,
retina, and testis
Vanaveski T, Singh K, Narvik J, Eskla KL, Visnapuu T, Heinla I, Jayaram M, Innos J, Lilleväli K, Philips MA, Vasar E (2017) Promoter-specific expression and genomic structure of IgLON family
genes in mouse Front Neurosci 11 38

4. The Structure and Function of
IgLON5
 Comprises five members:
- Opioid binding protein/cell adhesion molecule
(OPCML)
- Neurotrimin (NTM)
- Limbic system associated membrane protein
(LSAMP)
- Neural growth regulator 1 (NEGR1)
- IgLON family member 5 (IgLON5)
Zhang YZ, Ni Y, Gao YN, Shen DD, He L, Yin D, Meng HY, Zhou QM, Hu J, Chen S. Anti-IgLON5 disease: a novel topic beyond neuroimmunology. Neural Regeneration Research. 2023 May

5. The Structure and Function of
IgLON5
Functions:
- Regulates the adhesion and differentiation of
myoblasts and promotes myogenesis and
regeneration
- Central nervous systems development and
regulation
- Involved in tumor inhibition, depression, and
obesity
Karis K, Eskla KL, Kaare M, Täht K, Tuusov J, Visnapuu T, Innos J, Jayaram M, Timmusk T, Weickert CS, Väli M, Vasar E, Philips MA (2018) Altered expression profile of IgLON family of neural cell
adhesion molecules in the dorsolateral prefrontal cortex of schizophrenic patients Front Mol Neurosci 11 8
Lim JH, Beg MMA, Ahmad K, Shaikh S, Ahmad SS, Chun HJ, Choi D, Lee WJ, Jin JO, Kim J, Jan AT, Lee EJ, Choi I (2021) IgLON5 regulates the adhesion and differentiation of
myoblasts Cells 10 417

6. The Structure and Function of
IgLON5
Venkannagari H, Kasper JM, Misra A, Rush SA, Fan S, Lee H, Sun H, Seshadrinathan S, Machius M, Hommel JD, Rudenko G (2020) Highly conserved molecular features in IgLONs contrast their
distinct structural and biological outcomes J Mol Biol 432 5287 5303

7. Pathophysiology
Zhang YZ, Ni Y, Gao YN, Shen DD, He L, Yin D, Meng HY, Zhou QM, Hu J, Chen S. Anti-
IgLON5 disease: a novel topic beyond neuroimmunology. Neural Regeneration Research.
2023 May 1;18(5):1017-22

8. Clinical Features (Main)
Sleep
disorders
Bulbar
syndrome
Gait
instability
Cognitive
impairment
Madetko N, Marzec W, Kowalska A, Przewodowska D, Alster P, Koziorowski D (2022) Anti-IgLON5 disease - The current state of knowledge and further perspectives Front Immunol 13 852215
Often associated with other
autoimmune diseases
¾ cases chronic form; ¼
cases acute-subacute
Zhang YZ, Ni Y, Gao YN, Shen DD, He L, Yin D, Meng HY, Zhou QM, Hu J, Chen S. Anti-IgLON5 disease: a novel topic beyond neuroimmunology. Neural Regeneration Research. 2023 May
1;18(5):1017-22

9. Clinical Features (Additional)
 Dysautonomia
 Oculomotor abnormalities
 Neuropsychiatric symptoms
 Movement disorders
 Cerebellar dysfunction (intention tremors,
nystagmus)
 Peripheral neuropathy
 Motor neuron disease
 Epilepsy
 Headache
 Influenza-like illnesses
Gaig C, Compta Y, Heidbreder A, Marti MJ, Titulaer MJ, Crijnen Y, Högl B, Lewerenz J, Erro ME, Garcia-Monco JC, Nigro P, Tambasco N, Patalong-Ogiewa M, Erdler M,
Macher S, Berger-Sieczkowski E, Höftberger R, Geis C, Hutterer M, Milán-Tomás A, et al. (2021) Frequency and characterization of movement disorders in anti-IgLON5
disease Neurology 97 e1367 1381
Grüter T, Möllers FE, Tietz A, Dargvainiene J, Melzer N, Heidbreder A, Strippel C, Kraft A, Höftberger R, Schöberl F, Thaler FS, Wickel J, Chung HY, Seifert F, Tschernatsch M, Nagel M,
Lewerenz J, Jarius S, Wildemann BC, de Azevedo L, et al. (2022) Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease Brain: awac090
Zhang YZ, Ni Y, Gao YN, Shen DD, He L, Yin D, Meng HY, Zhou QM, Hu J, Chen S. Anti-IgLON5 disease: a novel topic beyond neuroimmunology. Neural Regeneration Research. 2023 May
1;18(5):1017-22

10. Diagnosis
 Clinical + detection of IgLON5 antibodies in
serum and/or CSF
 Other tests:
- Signs of inflammation in the CSF or on MRI
- HLA genotyping may represent a means of
identifying susceptible patients. (HLA-
DRB1*10:01 and HLA-DQB1*05:01 alleles)
Zhang YZ, Ni Y, Gao YN, Shen DD, He L, Yin D, Meng HY, Zhou QM, Hu J, Chen S. Anti-IgLON5 disease: a novel topic beyond neuroimmunology. Neural Regeneration Research. 2023 May

11. Neuroimaging
 MRI:
- Brain atrophy, T2 hyperintensity, white matter
changes
- “High-convexity tight sulci” (defined as the
compression of sulci at the vertex, enlarged
CSF spaces in the Sylvian fissure, and
ventriculomegaly
- Mainly involving the hippocampus, brainstem,
white matter, cerebellum, and cortex
Zhang YZ, Ni Y, Gao YN, Shen DD, He L, Yin D, Meng HY, Zhou QM, Hu J, Chen S. Anti-IgLON5 disease: a novel topic beyond neuroimmunology. Neural Regeneration Research. 2023 May

12. Neuroimaging
 SPECT:
- Hyperperfusion was also seen in the high-
convexity area on single-photon emission
computed tomography and arterial spin labeling-
MRI, which may reflect the increased gray matter
density of the convexity
- Using dopamine transporter radioligands showed
decreased ligand uptake mostly in the striatum
 F-FDG PET:
- hypermetabolism in the basal ganglia, cerebellum,
brainstem, and left temporal lobe
Zhang YZ, Ni Y, Gao YN, Shen DD, He L, Yin D, Meng HY, Zhou QM, Hu J, Chen S. Anti-IgLON5 disease: a novel topic beyond neuroimmunology. Neural Regeneration Research. 2023 May

13. Neuropathological Findings

14. Treatment
 Longterm Immunotherapy:
- First line: Steroids, intravenous
immunoglobulin, and plasmapheresis
- Second line: Rituximab, cyclophosphamide,
azathioprine, and mycophenolate mofetil
Zhang YZ, Ni Y, Gao YN, Shen DD, He L, Yin D, Meng HY, Zhou QM, Hu J, Chen S. Anti-IgLON5 disease: a novel topic beyond neuroimmunology. Neural Regeneration Research. 2023 May

15. Prognosis
 Poor prognosis
 High mortality
 Causes of death:
• Laryngeal spasm
• Respiratory failure
• Central hypoventilation
• Aspiration pneumonia
• Cardiac complications
Zhang YZ, Ni Y, Gao YN, Shen DD, He L, Yin D, Meng HY, Zhou QM, Hu J, Chen S. Anti-IgLON5 disease: a novel topic beyond neuroimmunology. Neural Regeneration Research. 2023 May

16. Summary
 Rare autoimmune neurological disorder
 Tau depositions mainly at hypothalamus and
brainstem tegmentum
 Main clinical features: sleep disorders, bulbar
dysfunctions, cognitive impairment, gait
instability
 Diagnosis: clinical + autoantibodies against the
IgLON5 protein
 Poor prognosis and high mortality

17. THANK YOU