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

Abstract

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.

Septin-3 autoimmunity in patients with paraneoplastic cerebellar ataxia

“…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 ].…”

“…Most recently, we and others identified antibodies against septin-7, which is ubiquitously expressed throughout the body. The clinical phenotypes of septin-7 IgG-positive patients were more diverse [ 5 ]. The majority developed encephalopathy, partially accompanied by neuropsychiatric symptoms.…”

“…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.…”

“…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.…”

Paraneoplastic Neurologic Disorders

“…More rapid and slowly progressive forms have also been described [47]. For this phenotype, a diverse range of antibodies (paraneoplastic and non-paraneoplastic) could be considered, starting with those more common with higher cancer risk (such as PCA-1 [ovarian and breast adenocarcinoma associated], PCA-Tr and metabotropic glutamate receptor [mGluR]-1, which are both lymphoma associated), while research-based testing could be considered for the less common and infrequently cancer-associated analytes (such as inositol triphosphate receptor [ITPR]-1 and septin-7 antibodies) [25,[48][49][50][51]. Distinct clinical features may aid in the diagnosis of certain ataxias such as loss of taste sensation in mGluR1 ataxia and episodic ataxia which can arise in the context of contactinassociated protein-like 2 (CASPR2) autoimmunity (sometimes accompanying thymoma) [52,53].…”