Stiff-man syndrome is a rare disorder of the central nervous system of unknown 
pathogenesis. We have previously reported the presence of autoantibodies against 
glutamic acid decarboxylase (GAD) in a patient with stiff-man syndrome, 
epilepsy, and insulin-dependent diabetes mellitus. GAD is an enzyme selectively 
concentrated in neurons secreting the neurotransmitter gamma-aminobutyric acid 
(GABA) and in pancreatic beta cells. We subsequently observed autoantibodies to 
GABA-ergic neurons in 20 of 33 patients with stiff-man syndrome. GAD was the 
principal autoantigen. In the group of patients positive for autoantibodies 
against GABA-ergic neurons, there was a striking association with organ-specific 
autoimmune diseases, primarily insulin-dependent diabetes mellitus. These 
findings support the hypothesis that stiff-man syndrome is an autoimmune disease 
and suggest that GAD is the primary autoantigen involved in stiff-man syndrome 
and the associated insulin-dependent diabetes mellitus. Our findings also 
indicate that autoantibodies directed against GABA-ergic neurons are a useful 
marker in the diagnosis of the disease.