Intrathecal injection of P/Q type voltage-gated calcium channel antibodies from paraneoplastic cerebellar degeneration cause ataxia in mice

Martín‐García, Elena; Mannara, Francesco; Gutiérrez‐Cuesta, Javier; Sabater, Lidia; Dalmau, Josep; Maldonado, Rafaël; Graus, Francesc

doi:10.1016/j.jneuroim.2013.05.003

Cited by 47 publications

(37 citation statements)

References 31 publications

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“…[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Responses to treatment are variable. In contrast to PCA-1 and other neuronal nuclear and cytoplasmic (NNC) antibodies, IgG antibodies that target plasma membrane proteins (PMPs) (eg, voltagegated calcium channels) might be directly pathogenic, 15,[22][23][24] and the accompanying neurologic disorders may be treatable. 25 Herein, we report our treatment and outcome experience for adult patients with autoimmune cerebellar ataxia undergoing evaluation at the Mayo Clinic, Rochester, Minnesota, and include analyses of factors predicting outcomes in those patients.…”

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confidence: 99%

Responses to and Outcomes of Treatment of Autoimmune Cerebellar Ataxia in Adults

et al. 2015

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confidence: 99%

Responses to and Outcomes of Treatment of Autoimmune Cerebellar Ataxia in Adults

et al. 2015

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“…Indirect experimental arguments were provided by a study using a polyclonal antibody generated against a major epitope in the P/Q‐type VGCCs that inhibited VGCC function in neuronal and recombinant VGCCs, altered cerebellar synaptic transmission, and conferred the phenotype of cerebellar ataxia (Liao et al ., ). More importantly, passive immunization of mice with antibodies from VGCC‐Ab cerebellar ataxia patients induced acute ataxia in mice, demonstrating the pathogenic potential of VGCC‐Abs (Martín‐García et al ., ). Questions remain concerning the variability of the clinical manifestations associated with VGCC‐Abs between patients.…”

Section: Cerebellitis Associated With Antibodies Directed Against Thementioning

confidence: 99%

Neuronal central nervous system syndromes probably mediated by autoantibodies

Chefdeville

Honnorat

Hampe

et al. 2016

Eur J of Neuroscience

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In the last few years, a rapidly growing number of autoantibodies targeting neuronal cell-surface antigens have been identified in patients presenting with neurological symptoms. Targeted antigens include ionotropic receptors such as N-methyl-D-aspartate receptor or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, metabotropic receptors such as mGluR1 and mGluR5, and other synaptic proteins, some of them belonging to the voltage-gated potassium channel complex. Importantly, the cell-surface location of these antigens makes them vulnerable to direct antibody-mediated modulation. Some of these autoantibodies, generally targeting ionotropic channels or their partner proteins, define clinical syndromes resembling models of pharmacological or genetic disruption of the corresponding antigen, suggesting a direct pathogenic role of the associated autoantibodies. Moreover, the associated neurological symptoms are usually immunotherapy-responsive, further arguing for a pathogenic effect of the antibodies. Some studies have shown that some patients’ antibodies may have structural and functional in vitro effects on the targeted antigens. Definite proof of the pathogenicity of these autoantibodies has been obtained for just a few through passive transfer experiments in animal models. In this review we present existing and converging evidence suggesting a pathogenic role of some autoantibodies directed against neuronal cell-surface antigens observed in patients with central nervous system disorders. We describe the main clinical symptoms characterizing the patients and discuss conflicting arguments regarding the pathogenicity of these antibodies.

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“…This presumes that PCD patients have a distinct subtype of VGCC antibodies, reacting to an epitope repertoire of the VGCC expressed on the Purkinje cells in the cerebellum [18]. Symptoms of LEMS usually precede tumor detection.…”

Section: Tumor Associationmentioning

confidence: 99%

“…MJ Titulaer is supported by grants from the Netherlands Organisation for Scientific Research (NOW, Veni-incentive), the Dutch Epilepsy Foundations (NEF, project[14][15][16][17][18][19], an ErasmusMC fellowship and a clinical research fellowship by the Dutch Cancer Society (KWF, number 2009-4451). MJ Titulaer received a travel grant for lecturing in India from Sun Pharma, India.…”

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Treatment options for Lambert–Eaton myasthenic syndrome

Sonderen

Wirtz

Verschuuren

et al. 2014

Expert Opinion on Orphan Drugs

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Introduction: Lambert--Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction. Antibody-mediated functional loss of voltage-gated calcium channels (VGCCs) on the presynaptic surface results in reduced neurotransmitter release. Muscle weakness starts in the proximal limbs and is accompanied by autonomic failure and areflexia. About 50 --60% of the patients have small-cell lung cancer (SCLC), with antibodies produced in reaction to VGCC on tumor cells. In non-tumor LEMS, an autoimmune reaction causes antibody production. Knowledge of the pathophysiology of antibody production in SCLC-LEMS and non-tumor LEMS and a detailed understanding of the neuromuscular junction and its dysfunction in LEMS is needed for drug development. Areas covered: This review gives an overview of the clinical symptoms, diagnosis and pathophysiology of LEMS. Current treatment options and results of recent research on newly developed symptomatic treatment are described. Expert opinion: Extensive search for SCLC is needed in LEMS patients. Appropriate tumor treatment should be started in SCLC-LEMS. In both SCLC-LEMS and non-tumor LEMS, symptomatic treatment consists of 3,4-diaminopyridine. If insufficient, pyridostigmine can be added, although a small trial failed to prove its benefit in LEMS and it is probably only efficient in a subset of patients. In moderate-to-severe disease, immunosuppressive treatment with prednisolone and azathioprine should be started. Research on drugs in LEMS is complicated by the infrequency of the disorder. Future developments are mainly expected in the field of symptomatic treatment. Possibly, further studies on immunosuppression in myasthenia gravis will be meaningful for the therapeutic strategy in LEMS as well.

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Intrathecal injection of P/Q type voltage-gated calcium channel antibodies from paraneoplastic cerebellar degeneration cause ataxia in mice

Cited by 47 publications

References 31 publications

Responses to and Outcomes of Treatment of Autoimmune Cerebellar Ataxia in Adults

Responses to and Outcomes of Treatment of Autoimmune Cerebellar Ataxia in Adults

Neuronal central nervous system syndromes probably mediated by autoantibodies

Treatment options for Lambert–Eaton myasthenic syndrome

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