Reduction of P/Q‐type calcium channels in the postmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert‐Eaton myasthenic syndrome

Abstract

The aim of this study was to clarify whether autoimmunity against P/Q-type voltage-gated calcium channels (VGCCs) in the cerebellum was associated with the pathogenesis of paraneoplastic cerebellar degeneration (PCD) with Lambert-Eaton myasthenic syndrome (LEMS). We used human autopsy cerebellar tissues from three PCD-LEMS patients and six other disease patients including one with LEMS as the controls. We compared cerebellar P/Q-type VGCC in these patients and controls for the amount and ratio of autoantibody-channel complex using an 125I-omega-conotoxin MVIIC-binding assay with Scatchard analysis, and their distribution using autoradiography. The quantity of cerebellar P/Q-type VGCC measured by Scatchard analysis were reduced in PCD-LEMS patients (63.0 +/- 7.0 fmol/mg, n = 3), compared with the controls (297.8 +/- 38.9 fmol/mg, n = 6). The ratio of autoantibody-VGCC complexes to total P/Q-type VGCCs measured by immunoprecipitation assay were increased in PCD-LEMS patients. We analysed cerebellar specimens by autoradiography using (125)I-omega-conotoxin MVIIC, which specifically binds to P/Q-type VGCCs. In PCD-LEMS cerebellum, the toxin binding sites of P/Q-type VGCCs were markedly reduced compared with controls, especially in the molecular layer, which is the richest area of P/Q-type VGCCs in the normal cerebellum. This suggests that P/Q-type VGCCs of the cerebellar molecular layer is the immunological target in developing PCD-LEMS.

Transient subacute cerebellar ataxia in a patient with Lambert-Eaton myasthenic syndrome after intracranial aneurysm surgery

“…In previous reports of subacute CA-LEMS, subacute CA has shown little efficacy to various treatments 1,2,4,6 . PCA without LEMS is also considered unlikely to have a fully effective treatment in general 8 .…”

Anti-Ca 2+ channel antibody attenuates Ca 2+ currents and mimics cerebellar ataxia in vivo

“…PCA patients have a high titer of anti-VGCC antibody (14)(15)(16)(17) and undergo a selective loss of P/Q-type VGCC-containing cerebellar neurons (2,18). Sera from LEMS patients, known to contain anti-VGCC antibodies, reduce P/Q-type VGCC surface expression in cerebellar granule and Purkinje neurons (19), consistent with an overlap of clinical syndromes between LEMS and PCA and, possibly, of pathogenic mechanism.…”

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

“…Despite P/Q-type VGCC-ab with a particular epitope repertoire may be relevant in the pathogenesis of PCD, it remains unclear why the ataxia does not usually respond to the immunotherapy and the mechanism of the Purkinje cell loss found in postmortem studies (Blumenfeld et al, 1991;Fukuda et al, 2003;Goldstein et al, 1994). A similar situation occurs in patients with glutamic acid decarboxylase (GAD)-ab.…”