Autoimmune Septin-5 Disease Presenting as Spinocerebellar Ataxia and Nystagmus

Martín, Alejandro Herrero-San; Cuadrado, Carla Amarante; Arbizu, Maialen Gonzalez; Rábano-Suárez, Pablo; Ostos, Fernando; Naranjo, Laura; Sabater, Lidia; Hernandez, Eugenia Martinez; Garcia, R. Ruiz; Alfocea, Daniel Toledo

doi:10.1212/wnl.0000000000012240

Cited by 6 publications

(12 citation statements)

References 2 publications

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“…We report novel forms of immune therapy‐responsive autoimmune disorders targeting neuronal septins whereby clinical presentations are distinct depending on the IgG profile. Patients with septin‐5 autoimmunity (with or without septin‐7‐IgG co‐existing) had ataxia with prominent hyperkinetic eye movement disorders 1,2 In keeping with this, septin‐5 expression is particularly abundant in the cerebellum and basal ganglia, and most especially enriched in the oculomotor control‐relevant cerebellar dentate nuclei 1,10 . CNS phenotypes were more diverse among patients who were septin‐7‐IgG positive.…”

Section: Discussionsupporting

confidence: 85%

“…W e previously reported septin-5-immunoglobulin-G (IgG) autoantibody as an autoimmune central nervous system (CNS) disease biomarker in 4 patients with ataxia, an association confirmed by others. 1,2 We have since determined an additional form of septin neurological autoimmunity for which septin-7 is the principal target. The clinical spectrum of neuronal septin autoimmunity requires elucidation.…”

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confidence: 99%

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Septin‐5 and ‐7‐IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics

Hinson

Honorat

Grund

et al. 2022

Annals of Neurology

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Background and Objectives: We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects. Methods: Septin-IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform. Results: Septin-IgGs were identified in 23 patients. All 8 patients with septin-5-IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co-existing septin-7-IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin-7 autoimmunity, without septin-5-IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre-and post-synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation. Interpretation: Septin-IgGs are predictive of distinct treatment-responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin-specific pathophysiology.

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Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 99%

Septin‐5 and ‐7‐IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics

Hinson

Honorat

Grund

et al. 2022

Annals of Neurology

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“…Previously, autoantibodies against another neuron-specific septin, septin-5, have been reported in patients with cerebellar ataxia, which was associated with eye movement disorders in most of them. However, no associated tumor was found in any of the published cases associated with anti-septin-5 autoantibodies [ 3 – 5 ].…”

Section: Discussionmentioning

confidence: 99%

“…Eight out of ten anti-septin-5 or -7 patients with immunotherapy data available improved after treatment. [ 3 – 5 ]. In the present study, only transient improvement (patient 1 and 2) or stabilization of symptoms but no improvement (patient 3) was observed in the anti-septin-3-positive patients.…”

Section: Discussionmentioning

confidence: 99%

“…Septin proteins as target antigens in neurological autoimmune diseases were first described in patients with cerebellar ataxia and anti-septin-5 autoantibodies [ 3 , 4 ]. Recently, anti-septin-7 autoantibodies were identified in patients with encephalopathy and myelopathy [ 5 ], suggesting that autoantibodies targeting different septins may be associated with distinct neurological phenotypes.…”

Section: Introductionmentioning

confidence: 99%

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Septin-3 autoimmunity in patients with paraneoplastic cerebellar ataxia

Miske

Scharf

Borowski³

et al. 2023

J Neuroinflammation

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Background Septins are cytoskeletal proteins with filament forming capabilities, which have multiple roles during cell division, cellular polarization, morphogenesis, and membrane trafficking. Autoantibodies against septin-5 are associated with non-paraneoplastic cerebellar ataxia, and autoantibodies against septin-7 with encephalopathy with prominent neuropsychiatric features. Here, we report on newly identified autoantibodies against septin-3 in patients with paraneoplastic cerebellar ataxia. We also propose a strategy for anti-septin autoantibody determination. Methods Sera from three patients producing similar immunofluorescence staining patterns on cerebellar and hippocampal sections were subjected to immunoprecipitation followed by mass spectrometry. The identified candidate antigens, all of which were septins, were expressed recombinantly in HEK293 cells either individually, as complexes, or combinations missing individual septins, for use in recombinant cell-based indirect immunofluorescence assays (RC-IIFA). Specificity for septin-3 was further confirmed by tissue IIFA neutralization experiments. Finally, tumor tissue sections were analyzed immunohistochemically for septin-3 expression. Results Immunoprecipitation with rat cerebellum lysate revealed septin-3, -5, -6, -7, and -11 as candidate target antigens. Sera of all three patients reacted with recombinant cells co-expressing septin-3/5/6/7/11, while none of 149 healthy control sera was similarly reactive. In RC-IIFAs the patient sera recognized only cells expressing septin-3, individually and in complexes. Incubation of patient sera with five different septin combinations, each missing one of the five septins, confirmed the autoantibodies’ specificity for septin-3. The tissue IIFA reactivity of patient serum was abolished by pre-incubation with HEK293 cell lysates overexpressing the septin-3/5/6/7/11 complex or septin-3 alone, but not with HEK293 cell lysates overexpressing septin-5 as control. All three patients had cancers (2 × melanoma, 1 × small cell lung cancer), presented with progressive cerebellar syndromes, and responded poorly to immunotherapy. Expression of septin-3 was demonstrated in resected tumor tissue available from one patient. Conclusions Septin-3 is a novel autoantibody target in patients with paraneoplastic cerebellar syndromes. Based on our findings, RC-IIFA with HEK293 cells expressing the septin-3/5/6/7/11 complex may serve as a screening tool to investigate anti-septin autoantibodies in serological samples with a characteristic staining pattern on neuronal tissue sections. Autoantibodies against individual septins can then be confirmed by RC-IIFA expressing single septins.

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