Lambert‐Eaton myasthenic syndrome: I. Early morphological effects of IgG on the presynaptic membrane active zones

Abstract

In the freeze‐fractured presynaptic membrane of the motor end‐plate, the active zones consist of two parallel arrays and each array contains 10‐ to 12‐nm particles arranged in two rows. In the Lambert‐Eaton myasthenic syndrome (LEMS) and in mice treated with 10 mg/day of LEMS IgG, administered intraperitoneally for several weeks, there was a paucity and disorganization of the active zones, and clusters of 10‐ to 12‐nm particles appeared. To further define the changes in the active zones, mice were studied that had been treated over 2 days with 104 to 180 mg of IgG. Treatment transferred the physiological defect of LEMS. Control mice received normal human IgG or no IgG. The spacing and density (number/unit area) of active‐zone particles were evaluated in presynaptic membrane P‐faces using computer‐assisted stereometry. In the normal active zone, the distance between particles in a given row and between adjacent rows of an array was less than, but the distance between the two arrays was greater than, the distance between the two antigen‐binding sites on human IgG. In mice treated with LEMS IgG, the initial alteration in the active zone was a Decemberrease in the distance between particles in a given row and between adjacent rows of an array; the distance between the two arrays remained unaltered. In more affected active zones, the parallel orientation of the rows was disturbed and the arrays became clusters. There was a significantly reduced density of active zones and of large‐membrane particles associated with all active zones and clusters. The findings are consistent with the idea that LEMS IgG binds to the active‐zone particles, cross‐links these particles, and then modulates their density. This interpretation is in agreement with findings of the companion paper which follows in this issue of the Annals in which we immunolocalized LEMS IgG to the active zones at the motor end‐plates.