Contactin-associated protein-2 antibodies in non-paraneoplastic cerebellar ataxia

Becker, Esther B. E.; Zuliani, Luigi; Pettingill, Rosemary; Lang, Bethan; Waters, Patrick; Dulneva, Anna; Sobott, Frank; Wardle, Mark; Graus, Francesc; Bataller, Luís; Robertson, Neil; Vincent, Angela

doi:10.1136/jnnp-2011-301506

Cited by 108 publications

(75 citation statements)

References 17 publications

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“…The relative proportions of patients with LGI1 and CASPR2 antibodies and those who remain without a known cell-surface antigenic target (Neuroglial cell-surface antibody [NGSAb] unknown) are depicted in the gradient bars. Movement disorders include ataxia, chorea, and parkinsonism 44,93,94. A number of patients, especially those with cramp fasciculation syndrome–neuromyotonia (CFS-NMT; high frequency discharges shown) and epilepsy (excluding faciobrachial dystonic seizures [FBDS]) currently have no defined antigenic target (NGSAb unknown), although their sera precipitate VGKC complexes in the radioimmunoassay.…”

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confidence: 99%

Cell‐surface central nervous system autoantibodies: Clinical relevance and emerging paradigms

Irani

Gelfand

Al-Diwani

et al. 2014

Annals of Neurology

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167

149

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The recent discovery of several potentially pathogenic autoantibodies has helped identify patients with clinically distinctive central nervous system diseases that appear to benefit from immunotherapy. The associated autoantibodies are directed against the extracellular domains of cell-surface–expressed neuronal or glial proteins such as LGI1, N-methyl-D-aspartate receptor, and aquaporin-4. The original descriptions of the associated clinical syndromes were phenotypically well circumscribed. However, as availability of antibody testing has increased, the range of associated patient phenotypes and demographics has expanded. This in turn has led to the recognition of more immunotherapy-responsive syndromes in patients presenting with cognitive and behavioral problems, seizures, movement disorders, psychiatric features, and demyelinating disease. Although antibody detection remains diagnostically important, clinical recognition of these distinctive syndromes should ensure early and appropriate immunotherapy administration. We review the emerging paradigm of cell-surface–directed antibody–mediated neurological diseases, describe how the associated disease spectrums have broadened since the original descriptions, discuss some of the methodological issues regarding techniques for antibody detection and emphasize considerations surrounding immunotherapy administration. As these disorders continue to reach mainstream neurology and even psychiatry, more cell-surface–directed antibodies will be discovered, and their possible relevance to other more common disease presentations should become more clearly defined.

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confidence: 99%

Cell‐surface central nervous system autoantibodies: Clinical relevance and emerging paradigms

Irani

Gelfand

Al-Diwani

et al. 2014

Annals of Neurology

Self Cite

167

149

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“…They thus add another important disease entity to the spectrum of immune-mediated cerebellar ataxias. 37,38 …”

Section: Discussionmentioning

confidence: 99%

Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration

Miske

Groß

Scharf

et al. 2017

Neurol Neuroimmunol Neuroinflamm

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Objective: To report on a novel neuronal target antigen in 3 patients with autoimmune cerebellar degeneration.Methods: Three patients with subacute to chronic cerebellar ataxia and controls underwent detailed clinical and neuropsychological assessment together with quantitative high-resolution structural MRI. Sera and CSF were subjected to comprehensive autoantibody screening by indirect immunofluorescence assay (IFA) and immunoblot. Immunoprecipitation with lysates of hippocampus and cerebellum combined with mass spectrometric analysis was used to identify the autoantigen, which was verified by recombinant expression in HEK293 cells and use in several immunoassays. Multiparameter flow cytometry was performed on peripheral blood and CSF, and peripheral blood was subjected to T-cell receptor spectratyping.Results: Patients presented with a subacute to chronic cerebellar and brainstem syndrome. MRI was consistent with cortical and cerebellar gray matter atrophy associated with subsequent neuroaxonal degeneration. IFA screening revealed strong immunoglobulin G1 reactivity in sera and CSF with hippocampal and cerebellar molecular and granular layers, but not with a panel of 30 recombinantly expressed established neural autoantigens. Neurochondrin was subsequently identified as the target antigen, verified by IFA and immunoblot with HEK293 cells expressing human neurochondrin as well as the ability of recombinant neurochondrin to neutralize the autoantibodies' tissue reaction. Immune phenotyping revealed intrathecal accumulation and activation of B and T cells during the acute but not chronic phase of the disease. T-cell receptor spectratyping suggested an antigen-specific T-cell response accompanying the formation of antineurochondrin autoantibodies. No such neurochondrin reactivity was found in control cohorts of various neural autoantibody-associated neurologic syndromes, relapsing-remitting multiple sclerosis, cerebellar type of multiple system atrophy, hereditary cerebellar ataxias, other neurologic disorders, or healthy donors. Conclusion:Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration.Neurol Neuroimmunol Neuroinflamm 2017;4:e307; doi: 10.1212/NXI.0000000000000307 GLOSSARY AD 5 axial diffusivity; AI 5 antibody indices; DTI 5 diffusion tensor imaging; FA 5 fractional anisotropy; IFA 5 immunofluorescent assay; IgG 5 immunoglobulin G; IVIg 5 IV immunoglobulin; mGluR 5 metabotropic glutamate receptor; MSA-c 5 cerebellar type of multiple system atrophy; PB 5 peripheral blood; RD 5 radial diffusivity; RRMS 5 relapsing-remitting multiple sclerosis; SARA 5 Scale for the Assessment and Rating of Ataxia; TCR 5 T-cell receptor.Autoantibodies against neuronal constituents are associated with several severe immune-mediated CNS disorders. These disorders may predominantly affect gray matter structures of different brain regions such as the archicortex of the limbic system, neocortex, and basal ganglia, as well as cerebellar cortex and brainstem.

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“…In a following study, LGI1 was identified as the real antigen in VGKC positive patients by CBA. CASPR2 which forms part of the scaffold required to anchor the VGKC [142] was also described as an antigen [93,143].…”

Section: Autoimmune Encephalitismentioning

confidence: 99%

Autoantibodies in Neuropsychiatric Disorders

et al. 2016

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Abstract:Little is known about the etiology of neuropsychiatric disorders. The identification of autoantibodies targeting the N-methyl-D-aspartate receptor (NMDA-R), which causes neurological and psychiatric symptoms, has reinvigorated the hypothesis that other patient subgroups may also suffer from an underlying autoimmune condition. In recent years, a wide range of neuropsychiatric diseases and autoantibodies targeting ion-channels or neuronal receptors including NMDA-R, voltage gated potassium channel complex (VGKC complex), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R), γ-aminobutyric acid receptor (GABA-R) and dopamine receptor (DR) were studied and conflicting reports have been published regarding the seroprevalence of these autoantibodies. A clear causative role of autoantibodies on psychiatric symptoms has as yet only been shown for the NMDA-R. Several other autoantibodies have been related to the presence of certain symptoms and antibody effector mechanisms have been proposed. However, extensive clinical studies with large multicenter efforts to standardize diagnostic procedures for autoimmune etiology and animal studies are needed to confirm the pathogenicity of these autoantibodies. In this review, we discuss the current knowledge of neuronal autoantibodies in the major neuropsychiatric disorders: psychotic, major depression, autism spectrum, obsessive-compulsive and attention-deficit/hyperactivity disorders.

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Contactin-associated protein-2 antibodies in non-paraneoplastic cerebellar ataxia

Cited by 108 publications

References 17 publications

Cell‐surface central nervous system autoantibodies: Clinical relevance and emerging paradigms

Cell‐surface central nervous system autoantibodies: Clinical relevance and emerging paradigms

Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration

Autoantibodies in Neuropsychiatric Disorders

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