Elevated titers of serum antibodies against GM1-ganglioside are associated with a variety of autoimmune neuropathies. Although these autoantibodies could play a role in the disease processes, the mechanism of their appearance is unclear. Low-affinity anti-GM1 IgM-antibodies are part of the normal human immunological repertoire. In patients with motor syndromes, we found that in addition to the usual anti-GM1 antibodies, the sera contain IgM antibodies recognizing GM1 with higher affinity and/or different specificity. These different antibodies were not detected in other autoimmune diseases. We studied the fine specificity of both normal and motor disease-associated antibodies using HPTLC immunostaining, soluble antigen binding inhibition, and GM1 affinity columns. Normal low-affinity anti-GM1 antibodies cross-react with GA1 and/or GD1b . In motor syndrome patients, different populations of antibodies characterized by their affinity and cross-reactivity were detected. Although one population is common low-affinity, not cross-reacting with GA1 and GD1b, there are remarkably few sera having the same set of populations. These results suggest that the appearance of the new antibody populations is a random process. We hypothesize that disease-associated antibodies may originate by spontaneous mutation of normal occurring antibodies.