Effects of anti–glutamic acid decarboxylase antibodies associated with neurological diseases

Objective Glutamic acid decarboxylase (GAD) catalyzes the conversion of glutamic acid into GABA. GAD autoantibodies (GAD‐Ab) have been described in diabetes mellitus and in diseases involving the central nervous system such as stiff‐person syndrome and cerebellar ataxia. However, the pathogenic role of GAD‐Ab in neurological diseases remains a matter of debate. Methods Using neurophysiological and neurochemical methods, we analyzed the effects of intracerebellar and paraspinal administration of GAD‐Ab in rats. Results Intracerebellar administration of IgG from patients with GAD‐Ab and neurological involvement (IgG‐GAD) blocked the potentiation of the corticomotor response normally associated with trains of repetitive peripheral nerve stimulation. When injected in the lumbar paraspinal region, IgG‐GAD induced continuous motor activity with repetitive discharges, abnormal exteroceptive reflexes, and increased excitability of anterior horn neurons, as assessed by F/M ratios. Furthermore, IgG‐GAD significantly reduced the N ‐methyl‐ D ‐aspartate–mediated production of nitric oxide in cerebellar nuclei and impaired the synaptic regulation of glutamate after N ‐methyl‐ D ‐aspartate administration. These effects were not observed after administration of IgG from the following groups: (1) patients with GAD‐Ab, diabetes mellitus, and without neurological complications; and (2) control patients. Interpretation These results indicate that stiff‐person syndrome and cerebellar ataxia are the direct consequence of antibody‐mediated neuronal dysfunction. Ann Neurol 2007;61:544–551