Stiff-man syndrome (SMS) is a rare neurological disorder characterized by progressive rigidity of the axial musculature with superimposed spasms. Frequently, SMS remains undiagnosed for prolonged periods or the patients are diagnosed of a primary psychiatric disorder. 60% of the SMS patients harbor GAD-autoantibodies (GAD-Ab). We have analyzed the diagnostic value of GAD-Ab in a syndrome whose clinical expression is not well known, but its diagnosis is performed by clinical criteria. Five patients were studied following the established clinical criteria for diagnosis of SMS. GAD-Ab were analyzed by radioimmunoassay (RIA) and immunohistochemistry, and confirmed by immunoblot. The GAD-Ab titers were compared with those of 49 patients with insulin-dependent diabetes mellitus (IDDM), 322 with other neurological disorders, 14 non-IDDM first-degree relatives of IDDM patients with antibodies anti-islet cells and 91 normal subjects. Three patients fulfilled all clinical criteria (typical SMS). Unilateral limb symptoms alone, and acute onset with rapid progression involving the distal limb muscles constituted the atypical features of SMS in the remaining 2 patients. The 5 patients presented several serum organ-specific autoantibodies. All but one also presented autoimmune diseases. By RIA, GAD-Ab titers from all patients were elevated (mean: 24,532 +/- 26,892 U/ml) and significantly higher than the titers of IDDM patients without neurological disorders (mean: 48 +/- 112 U/ml) (p < 0.0001). GAD-Ab were absent in the non-SMS patients and in normal subjects. These findings suggest that clinical expression of SMS is more extensive than that recognized by the established criteria. GAD-Ab are helpful to define the clinical spectrum of SMS.