Pathogenic Autoantibodies in the Lambert‐Eaton Myasthenic Syndrome

Abstract

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission in which antibodies are directed against voltage-gated calcium channels (VGCCs). We studied the action of LEMS immunoglobulin G (IgG) on cloned human VGCCs stably transfected into human embryonic kidney cells (HEK293). All LEMS IgGs tested bound to the surface of the P/Q-type VGCC cell line and caused a significant reduction in whole-cell calcium currents in these cells. By contrast, only 2 out of 6 IgGs bound extracellularly to the N-type VGCC cell line, and none of the LEMS IgGs tested was able to reduce whole-cell calcium currents in these cells. We used this apparent specificity of LEMS IgG for the P/Q-type VGCC to investigate the action of these IgGs on model systems where a number of different VGCC populations exist in equilibrium. LEMS IgG caused a significant downregulation in the omega-agatoxin IVA-sensitive P/Q-type VGCCs of cultured rat cerebellar neurons, but this was accompanied by a concomitant rise in the "resistant" R-type VGCCs. By using the passive transfer model of LEMS, similar results were observed at the mouse neuromuscular junction, where a significant reduction in P/Q-type VGCCs was paralleled by an increase in L- and R-type VGCCs. These results demonstrate an unexpected plasticity in the expression of VGCCs in mammalian neurons and may represent a mechanism by which the pathogenic effects of LEMS IgG are reduced.

The Lambert-Eaton Myasthenic Syndrome

“…Some patients also have antibodies to L-type VGCC (Johnston et al 1994). Anti-P/ Q-type VGCC antibodies were detectable in 1-4 % of patients with SCLC and no neurological symptoms Lang et al 1998) Also, 24 % of patients with SCLC and paraneoplastic cerebellar degeneration had anti-P/Q-type VGCC antibodies, half of whom had no manifestations of LEMS (Mason et al 1997). In clinical practice, only P/Q-type VGCC antibodies are important in the diagnostic phase, and not the more rare N-type of L-type VGCC antibodies.…”

Paraneoplastiske nevrologiske syndromer

“…50 % av tilfellene (oftest småcellet lungekreft), og ca. 10 % av pasientene med myasthenia gravis har tymom (20,21).…”

LEMS in the shadow of a hereditary polyneuropathy

“…His clinical examination and NCS, however, demonstrated facilitation and fatigability characteristic of LEMS with confirmatory serologic studies. 3,4,6 Three groups have reported the concurrence of myasthenia gravis and CMT, attributing this to chance. 1,2,5 We found no report of the coexistence of LEMS and CMT, and assume this was coincidental.…”