Autoimmune septin-5 cerebellar ataxia

Abstract

ObjectiveTo report a form of autoimmune cerebellar ataxia in which antibodies target septin-5, a guanosine triphosphate (GTP)-binding neural protein involved in neurotransmitter exocytosis.MethodsArchived sera and CSF specimens with unclassified synaptic antibodies were re-evaluated by tissue-based indirect immunofluorescence assay. Autoantigens were identified by Western blot and mass spectrometry. Recombinant protein assays (Western blot, cell based, and protein screening array) confirmed antigen specificity.ResultsSerum and CSF from 6 patients produced identical synaptic immunoglobulin G (IgG) staining patterns of synaptic regions (neuropil) of the mouse cerebrum and cerebellum. The molecular layer of the cerebellum and the thalamus demonstrated stronger immunoreactivity than the midbrain, hippocampus, cortex, and basal ganglia. The antigen revealed by mass spectrometry analysis of immunoprecipitated cerebellar proteins and confirmed by recombinant protein assays was septin-5. All 4 patients with records available had subacute onset of cerebellar ataxia with prominent eye movement symptoms (oscillopsia or vertigo). None had cancer detected. Improvements occurred after immunotherapies (2) or spontaneously (1). One patient died.ConclusionSeptin-5 IgG represents a biomarker for a potentially fatal but treatable autoimmune ataxia.

Neurochondrin neurological autoimmunity

“…4,5 Neurochondrin autoimmunity was previously described in 3 adult patients with cerebellar degeneration and in a child with chorea. 6,7 All but 1 of the 7 patients with clinical information available in our report had predominance of rhombencephalitis (cerebellar and brainstem localization). Myelopathy and acute psychosis (accompanying ataxia) and neuropathy (without other features) were each encountered in single patients.…”

Autoimmune Vestibulocerebellar Syndromes

“…Although one patient recovered spontaneously, one patient had a robust response to conventional rescue immunotherapy (plasma exchange, corticosteroids, IVIg), and one patient had transient improvement, with death following 6 months later. 156,157 Metabotropic Glutamate Receptor 1 Antibody mGLuR1 antibody is a biomarker of autoimmune cerebellar syndrome and has been classically reported in association with Hodgkin's lymphoma, although it has been reported in non-cancer-associated settings as well. The median age for symptom onset is 58 years (range: 33-81 years).…”

Further reducing terra incognita on the map of synaptic autoimmunity

“…Third, the predominance of cerebellar ataxia deserves further investigations, given that septin-5 is expressed throughout the brain 10 and that human immunoglobulin G binds to most parts of the cerebellum and cerebrum. 2 It seems possible that heteromeric proteins with other septin family members might play a role here. 3 …”

“…Over the past few years, neurology has witnessed an unprecedented discovery of new clinical entities related to autoantibodies targeting natively expressed neuronal proteins, often at the synapse. 1 In this issue of Neurology® : Neuroimmunology and Neuroinflammation, Honorat et al 2 report that they successfully dug for yet another disease. Starting with the observation in 6 patients of a specific, previously unknown antibody reaction with murine brain sections, the authors identified septin-5 as the underlying target of serum and CSF antibodies.…”