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From the Neuromuscular Diseases Section, National Institute of Neurological Diseases and Stroke, NIH, Bethesda, MD.
Address correspondence and reprint requests to Dr. Marinos C. Dalakas, Neuromuscular Diseases Section, National Institute Neurological Diseases and Stroke, NIH, Building 10, Room 4N248, 10 Center Drive, MSC 1382, Bethesda, MD 20892-1382; e-mail:dalakasm{at}ninds.nih.gov
Objective: — To characterize the specificity of anti-GAD65 antibodies in patients with stiff person syndrome (SPS), quantify antibody titers, and examine antibody production within the CNS.
Methods: — The authors studied 18 patients with SPS and positive serum immunoreactivity to gamma-aminobutyric acid (GABA)-ergic neurons. The reactivity of serum and CSF to purified GAD antigen was examined by Western blots, and the anti-GAD65 antibody titers in serum and CSF were quantified by ELISA and compared with 70 disease controls (49 with other autoimmune disorders and 11 with insulin-dependent diabetes mellitus). The intrathecal synthesis of anti-GAD65 IgG was calculated, and the functional significance of the antibodies was examined by measuring the GABA levels in the CSF.
Results: — The serum and CSF of all selected patients with SPS had high anti-GAD65 titers (from 7.0 to 215 µg/mL in serum and from 92 to 2500 ng/mL in CSF) and immunoreacted strongly with recombinant GAD65 on Western blots and with GABA-ergic neurons on rat cerebellum. Among controls, only the serum of eight patients with insulin-dependent diabetes mellitus had low anti-GAD65 antibody titers (from 200 to 1760 ng/mL) but no reactivity to recombinant GAD65. The CSF showed oligoclonal IgG bands in 10 (67%) of 15 patients and an increased anti-GAD65-specific IgG index in 11 (85%) of 13. The mean level of GABA in the CSF was lower in patients with SPS than in controls.
Conclusions: — In patients with SPS, there is marked intrathecal antibody response against neuronal GAD65 epitopes, indicating a clonal B cell activation in the CNS. Anti-GAD65 antibodies at high titers, when confirmed with immunoblots, are highly specific for SPS and appear to impair GABA synthesis.
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