Chronic therapy with neuroleptics is associated with development of antinuclear antibodies, an IgM-lupus anticoagulant, polyclonal elevation of IgM, and antibodies to the GM1 ganglioside. These autoantibodies are found more frequently in patients with the phenotype HLA B44 in association with tardive dyskinesia. Our preliminary data suggest that the extended-haplotype B44-DR7-FC31 carries a special risk for development of severe tardive dyskinesia in those patients with longest exposure to chlorpromazine. We propose to extend our studies on 203 patients already phenotyped and evaluated for the presence of autoantibodies and tardive dyskinesia, and on 67 patients who will be identified during the current year, to determine (1) the clinical relevance of anti-GM1 antibodies, (2) the immunogenetic markers for autoantibody production by typing these patients for the complement proteins, BF, C2, C4A, and C4B (complotypes), and establishing their extended haplotypes by performing HLA A, B, C, DR and complement phenotyping of at least 3 family members. Family members will also be tested for autoantibodies. The neuropsychiatric evaluation will include: psychiatric diagnosis by the RDC Criteria for Schizophrenia and Schizo-Affective Disorders, neuropsychiatric testing to detect impairment in cognitive function, evaluation of movement disorders by the AIMS scale, seizure activity by EEG, and brain atrophy by head computerized tomography. We postulate that there is a genetic predisposition to the production of autoantibodies regulated by the HLA marker B44 or more specifically by the extended haplotype B44-DR7-FC31. This marker is associated with the production of GM1 antibodies that are capable of inducing in humans a similar pathology to that described in experimental animal models with intracerebral and intracysternal injection of antibodies to GM1. The binding of anti-GM1 antibodies to the GM1 ganglioside present in the outer aspect of the synaptic membrane may alter neurotransmitter release leading to movement disorders, cognitive dysfunction, brain atrophy and seizure activity.
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