Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies.
OBJECTIVE
To characterize the specificity of anti-GAD(65) 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-GAD(65) 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-GAD(65) 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-GAD(65) titers (from 7.0 to 215 microg/mL in serum and from 92 to 2500 ng/mL in CSF) and immunoreacted strongly with recombinant GAD(65) 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-GAD(65) antibody titers (from 200 to 1760 ng/mL) but no reactivity to recombinant GAD(65). The CSF showed oligoclonal IgG bands in 10 (67%) of 15 patients and an increased anti-GAD(65)-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 GAD(65) epitopes, indicating a clonal B cell activation in the CNS. Anti-GAD(65) antibodies at high titers, when confirmed with immunoblots, are highly specific for SPS and appear to impair GABA synthesis.
Dalakas
M C
MC
Neuromuscular Diseases Section, National Institute of Neurological Diseases and Stroke, NIH, Bethesda, MD 20892-1382, USA. dalakasm@ninds.nih.gov
Li
M
M
Fujii
M
M
Jacobowitz
D M
DM
D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood / Q000134:cerebrospinal fluid*; D002531:Cerebellum / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000134:cerebrospinal fluid; D005968:Glutamate Decarboxylase / Q000097:blood / Q000134:cerebrospinal fluid* / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000134:cerebrospinal fluid; D007527:Isoenzymes / Q000097:blood / Q000134:cerebrospinal fluid* / Q000276:immunology*; D051381:Rats; D016750:Stiff-Person Syndrome / Q000134:cerebrospinal fluid* / Q000276:immunology*
D001323:Autoantibodies; D007074:Immunoglobulin G; D007527:Isoenzymes; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2