Antibodies to glutamic acid decarboxylase (GAD) have been associated with several neurological syndromes, including stiff-person syndrome, cerebellar ataxia and epilepsy. These antibodies were first described in 1988, but several controversies about GAD autoimmunity still remain. No criteria exist to establish when a neurological syndrome is pathogenically linked to GAD antibodies, often leading to the assumption that any syndrome in which these antibodies are present is immune mediated, sometimes resulting in misdiagnosis and unnecessary treatment. In this Review, we provide recommendations for assessing the association between a neurological syndrome and the presence of GAD antibodies, and we critically review the evidence on the pathogenicity of GAD antibodies. Given that stiff-person syndrome is usually autoimmune, the presence of GAD antibodies in the cerebrospinal fluid is sufficient to confirm a pathogenic link with GAD autoimmunity. However, for cerebellar ataxia, epilepsy and other syndromes with different aetiologies, we propose that confirmation of a pathogenic link with GAD autoimmunity requires demonstration of intrathecal GAD antibody synthesis. Nevertheless, the evidence that GAD antibodies are directly pathogenic is not yet convincing. Studies in animal models are needed to demonstrate whether neurological syndromes are directly caused by specific disruption of GAD function by GAD antibodies.
The main neurological syndromes associated with high levels of antibodies to glutamic acid decarboxylase (GAD) include stiff-person syndrome, cerebellar ataxia and temporal lobe epilepsy.
Serum levels of GAD antibodies can be considered high when quantitative tests (radioimmunoassays or enzyme-linked immunosorbent assays) and qualitative tests (immunohistochemistry, cell-based assays or line-blot assays) are positive.
Cerebrospinal fluid levels and intrathecal synthesis of GAD antibodies should be determined in all patients with suspected CNS syndromes and high serum levels of GAD antibodies.
We propose that the diagnosis of probable or definite GAD antibody-associated syndrome must be based on the spectrum of symptoms, serum levels of GAD antibodies and demonstration of intrathecal antibody synthesis.
There is no clear evidence that GAD antibodies are pathogenic in any of the associated CNS syndromes (stiff-person syndrome, cerebellar ataxia, temporal lobe epilepsy or limbic encephalitis).
In general, immunotherapy has limited effects on the outcomes of neurological syndromes associated with GAD antibodies.
This is a preview of subscription content, access via your institution
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Solimena, M. et al. Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N. Engl. J. Med. 318, 1012–1020 (1988). The first description of GAD antibodies in SPS.
Dalmau, J., Geis, C. & Graus, F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol. Rev. 97, 839–887 (2017).
David, C., McPherson, P. S., Mundigl, O. & de Camilli, P. A role of amphiphysin in synaptic vesicle endocytosis suggested by its binding to dynamin in nerve terminals. Proc. Natl Acad. Sci. USA 93, 331–335 (1996).
Geis, C. et al. Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain 133, 3166–3180 (2010).
Ohkawa, T. et al. Identification and characterization of GABA(A) receptor autoantibodies in autoimmune encephalitis. J. Neurosci. 34, 8151–8163 (2014).
Kasaragod, V. B. & Schindelin, H. Structure-function relationships of glycine and GABAA receptors and their interplay with the scaffolding protein gephyrin. Front. Mol. Neurosci. 11, 317 (2018).
Floeter, M. K., Valls-Sole, J., Toro, C., Jacobowitz, D. & Hallett, M. Physiologic studies of spinal inhibitory circuits in patients with stiff-person syndrome. Neurology 51, 85–93 (1998).
Khasani, S., Becker, K. & Meinck, H.-M. Hyperekplexia and stiff-man syndrome: abnormal brainstem reflexes suggest a physiological relationship. J. Neurol. Neurosurg. Psychiatry 75, 1265–1269 (2004).
Koerner, C., Wieland, B., Richter, W. & Meinck, H. M. Stiff-person syndromes: motor cortex hyperexcitability correlates with anti-GAD autoimmunity. Neurology 62, 1357–1362 (2004).
Spatola, M. et al. Investigations in GABAA receptor antibody-associated encephalitis. Neurology 88, 1012–1020 (2017).
Petit-Pedrol, M. et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol. 13, 276–286 (2014).
Carvajal-Gonzalez, A. et al. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain 137, 2178–2192 (2014).
Saiz, A. et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain 131, 2553–2563 (2008). This study confirmed that SPS, cerebellar ataxia and epilepsy are the main syndromes associated with GAD antibodies.
Pittock, S. J. et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann. Neurol. 58, 96–107 (2005).
Manto, M., Mitoma, H. & Hampe, C. S. Anti-GAD antibodies and the cerebellum: where do we stand? Cerebellum 18, 153–156 (2019).
Gresa-Arribas, N. et al. Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity. PLoS One 10, e0121364 (2015). This study demonstrated an absence of GAD antibody internalization in cultures of live rat hippocampal neurons.
Chang, T. et al. Neuronal surface and glutamic acid decarboxylase autoantibodies in nonparaneoplastic stiff person syndrome. JAMA Neurol. 70, 1140–1149 (2013).
Tillakaratne, N. J., Erlander, M. G., Collard, M. W., Greif, K. F. & Tobin, A. J. Glutamate decarboxylases in nonneural cells of rat testis and oviduct: differential expression of GAD65 and GAD67. J. Neurochem. 58, 618–627 (1992).
Vincent, S. R. et al. Immunohistochemical studies of the GABA system in the pancreas. Neuroendocrinology 36, 197–204 (1983).
Bu, D. F. et al. Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene. Proc. Natl Acad. Sci. USA 89, 2115–2119 (1992).
Erlander, M. G. & Tobin, A. J. The structural and functional heterogeneity of glutamic acid decarboxylase: a review. Neurochem. Res. 16, 215–226 (1991). A comprehensive review of glutamic acid decarboxylase.
Kaufman, D. L., Houser, C. R. & Tobin, A. J. Two forms of the gamma-aminobutyric acid synthetic enzyme glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions. J. Neurochem. 56, 720–723 (1991).
Christgau, S. et al. Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain. J. Cell Biol. 118, 309–320 (1992).
Patel, A. B., de Graaf, R. A., Martin, D. L., Battaglioli, G. & Behar, K. L. Evidence that GAD65 mediates increased GABA synthesis during intense neuronal activity in vivo. J. Neurochem. 97, 385–396 (2006).
Solimena, M., Folli, F., Aparisi, R., Pozza, G. & De Camilli, P. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N. Engl. J. Med. 322, 1555–1560 (1990).
Baekkeskov, S. et al. Identification of the 64 K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347, 151–156 (1990).
Aanstoot, H. J. et al. Identification and characterization of glima 38, a glycosylated islet cell membrane antigen, which together with GAD65 and IA2 marks the early phases of autoimmune response in type 1 diabetes. J. Clin. Invest. 97, 2772–2783 (1996).
Saiz, A. et al. Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin-dependent diabetes mellitus, and polyendocrine autoimmunity. Neurology 49, 1026–1030 (1997).
Giometto, B. et al. Temporal-lobe epilepsy associated with glutamic-acid-decarboxylase autoantibodies. Lancet 352, 457 (1998).
McKeon, A. & Tracy, J. A. GAD65 neurological autoimmunity. Muscle Nerve 56, 15–27 (2017).
Kim, J. et al. Higher autoantibody levels and recognition of a linear NH2-terminal epitope in the autoantigen GAD65, distinguish stiff-man syndrome from insulin-dependent diabetes mellitus. J. Exp. Med. 180, 595–606 (1994).
Butler, M. H., Solimena, M., Dirkx, R. Jr., Hayday, A. & De Camilli, P. Identification of a dominant epitope of glutamic acid decarboxylase (GAD-65) recognized by autoantibodies in stiff-man syndrome. J. Exp. Med. 178, 2097–2106 (1993).
Richter, W., Shi, Y. & Baekkeskov, S. Autoreactive epitopes defined by diabetes-associated human monoclonal antibodies are localized in the middle and C-terminal domains of the smaller form of glutamate decarboxylase. Proc. Natl Acad. Sci. USA 90, 2832–2836 (1993).
Burbelo, P. D., Groot, S., Dalakas, M. C. & Iadarola, M. J. High definition profiling of autoantibodies to glutamic acid decarboxylases GAD65/GAD67 in stiff-person syndrome. Biochem. Biophys. Res. Commun. 366, 1–7 (2008).
Daw, K., Ujihara, N., Atkinson, M. & Powers, A. C. Glutamic acid decarboxylase autoantibodies in stiff-man syndrome and insulin-dependent diabetes mellitus exhibit similarities and differences in epitope recognition. J. Immunol. 156, 818–825 (1996).
Fouka, P. et al. GAD65 epitope mapping and search for novel autoantibodies in GAD-associated neurological disorders. J. Neuroimmunol. 281, 73–77 (2015).
Luhder, F. et al. Autoantibodies against GAD65 rather than GAD67 precede the onset of type 1 diabetes. Autoimmunity 19, 71–80 (1994).
Seissler, J. et al. Prevalence of autoantibodies to the 65- and 67-kD isoforms of glutamate decarboxylase in insulin-dependent diabetes mellitus. J. Clin. Invest. 92, 1394–1399 (1993).
Kawasaki, E., Yano, M., Abiru, N., Akazawa, S. & Nagataki, S. Detection of recombinant GAD65 and GAD67 antibodies using a simple radioimmunoassay. Diabetes Res. Clin. Pract. 32, 61–69 (1996).
Fenalti, G. & Rowley, M. J. GAD65 as a prototypic autoantigen. J. Autoimmun. 31, 228–232 (2008).
Moersch, F. & Woltman, H. Progressive fluctuating muscular rigidity and spasm (“stiff-man syndrome”): report of a case and some observations in 13 other cases. Mayo Clin. Proc. 31, 421–427 (1956).
Brown, P., Rothwell, J. C. & Marsden, C. D. The stiff leg syndrome. J. Neurol. Neurosurg. Psychiatry 62, 31–37 (1997).
Saiz, A., Graus, F., Valldeoriola, F., Valls-Sole, J. & Tolosa, E. Stiff-leg syndrome: a focal form of stiff-man syndrome. Ann. Neurol. 43, 400–403 (1998).
Meinck, H. M. & Thompson, P. D. Stiff man syndrome and related conditions. Mov. Disord. 17, 853–866 (2002). A comprehensive review of SPS and its variants.
Barker, R. A., Revesz, T., Thom, M., Marsden, C. D. & Brown, P. Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J. Neurol. Neurosurg. Psychiatry 65, 633–640 (1998).
Martinez-Hernandez, E. et al. Clinical and immunological investigations in 121 patients with stiff-person spectrum disorder. JAMA Neurol. 73, 714–720 (2016).
Rakocevic, G., Alexopoulos, H. & Dalakas, M. C. Quantitative clinical and autoimmune assessments in stiff person syndrome: evidence for a progressive disorder. BMC Neurol. 19, 1 (2019).
Dalakas, M. C., Fujii, M., Li, M. & McElroy, B. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology 55, 1531–1535 (2000).
Blum, P. & Jankovic, J. Stiff-person syndrome: an autoimmune disease. Mov. Disord. 6, 12–20 (1991).
Henningsen, P. & Meinck, H. M. Specific phobia is a frequent non-motor feature in stiff man syndrome. J. Neurol. Neurosurg. Psychiatry 74, 462–465 (2003).
Ameli, R., Snow, J., Rakocevic, G. & Dalakas, M. C. A neuropsychological assessment of phobias in patients with stiff person syndrome. Neurology 64, 1961–1963 (2005).
Brown, P. & Marsden, C. D. The stiff man and stiff man plus syndromes. J. Neurol. 246, 648–652 (1999). This study included identification of SPS variants and the proposal of diagnostic criteria for SPS.
Murinson, B. B. & Guarnaccia, J. B. Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 71, 1955–1958 (2008).
Meinck, H. M., Ricker, K. & Conrad, B. The stiff-man syndrome: new pathophysiological aspects from abnormal exteroceptive reflexes and the response to clomipramine, clonidine, and tizanidine. J. Neurol. Neurosurg. Psychiatry 47, 280–287 (1984).
Meinck, H. M. Stiff man syndrome. CNS Drugs 15, 515–526 (2001).
Hadjivassiliou, M. et al. Cerebellar ataxia as a possible organ-specific autoimmune disease. Mov. Disord. 23, 1370–1377 (2008).
Arino, H. et al. Cerebellar ataxia and glutamic acid decarboxylase antibodies: immunologic profile and long-term effect of immunotherapy. JAMA Neurol. 71, 1009–1016 (2014).
Honnorat, J. et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch. Neurol. 58, 225–230 (2001). This study was the first series of cerebellar ataxia and GAD antibodies.
Baizabal-Carvallo, J. F. & Alonso-Juarez, M. Cerebellar disease associated with anti-glutamic acid decarboxylase antibodies: review. J. Neural Transm. 124, 1171–1182 (2017).
Markakis, I., Alexiou, E., Xifaras, M., Gekas, G. & Rombos, A. Opsoclonus-myoclonus-ataxia syndrome with autoantibodies to glutamic acid decarboxylase. Clin. Neurol. Neurosurg. 110, 619–621 (2008).
Tilikete, C., Vighetto, A., Trouillas, P. & Honnorat, J. Potential role of anti-GAD antibodies in abnormal eye movements. Ann. NY Acad. Sci. 1039, 446–454 (2005).
Shaikh, A. G. & Wilmot, G. Opsoclonus in a patient with increased titers of anti-GAD antibody provides proof for the conductance-based model of saccadic oscillations. J. Neurol. Sci. 362, 169–173 (2016).
Baizabal-Carvallo, J. F. & Alonso-Juarez, M. Vertical nystagmus associated with glutamic acid decarboxylase antibodies responding to cyclophosphamide. J. Neuroimmunol. 317, 5–7 (2018).
Vianello, M., Morello, F., Scaravilli, T., Tavolato, B. & Giometto, B. Tremor of the mouth floor and anti-glutamic acid decarboxylase autoantibodies. Eur. J. Neurol. 10, 513–514 (2003).
Rakocevic, G., Raju, R., Semino-Mora, C. & Dalakas, M. C. Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies. Neurology 67, 1068–1070 (2006).
Liimatainen, S. et al. Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy. Epilepsia 51, 760–767 (2010).
Daif, A. et al. Antiglutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy. Epilepsy Behav. 80, 331–336 (2018).
Lilleker, J. B., Biswas, V. & Mohanraj, R. Glutamic acid decarboxylase (GAD) antibodies in epilepsy: diagnostic yield and therapeutic implications. Seizure 23, 598–602 (2014).
Falip, M. et al. Prevalence and immunological spectrum of temporal lobe epilepsy with glutamic acid decarboxylase antibodies. Eur. J. Neurol. 19, 827–833 (2012).
Falip, M. et al. Hippocampus and insula are Targets in epileptic patients with glutamic acid decarboxylase antibodies. Front. Neurol. 9, 1143 (2018).
Malter, M. P., Helmstaedter, C., Urbach, H., Vincent, A. & Bien, C. G. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann. Neurol. 67, 470–478 (2010).
Graus, F. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 15, 391–404 (2016).
Malter, M. P. et al. Suspected new-onset autoimmune temporal lobe epilepsy with amygdala enlargement. Epilepsia 57, 1485–1494 (2016).
Sharma, A., Dubey, D., Sawhney, A. & Janga, K. GAD65 positive autoimmune limbic encephalitis: a case report and review of literature. J. Clin. Med. Res. 4, 424–428 (2012).
Blanc, F. et al. Acute limbic encephalitis and glutamic acid decarboxylase antibodies: a reality? J. Neurol. Sci. 287, 69–71 (2009).
Markakis, I. et al. Immunotherapy-responsive limbic encephalitis with antibodies to glutamic acid decarboxylase. J. Neurol. Sci. 343, 192–194 (2014).
Mirabelli-Badenier, M. et al. Anti-glutamic acid decarboxylase limbic encephalitis without epilepsy evolving into dementia with cerebellar ataxia. Arch. Neurol. 69, 1064–1066 (2012).
Boronat, A., Sabater, L., Saiz, A., Dalmau, J. & Graus, F. GABAB receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders. Neurology 76, 795–800 (2011).
Bataller, L. et al. Cerebellar ataxia associated with neuroendocrine thymic carcinoma and GAD antibodies. J. Neurol. Neurosurg. Psychiatry 80, 696–697 (2009).
Iwata, T. et al. Thymectomy for paraneoplastic stiff-person syndrome associated with invasive thymoma. J. Thorac. Cardiovascular Surg. 132, 196–197 (2006).
Vernino, S. & Lennon, V. A. Autoantibody profiles and neurological correlations of thymoma. Clin. Cancer Res. 10, 7270–7275 (2004).
Arino, H. et al. Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies. JAMA Neurol. 72, 874–881 (2015).
Meinck, H. M. et al. Antibodies against glutamic acid decarboxylase: prevalence in neurological diseases. J. Neurol. Neurosurg. Psychiatry 71, 100–103 (2001).
Walikonis, J. E. & Lennon, V. A. Radioimmunoassay for glutamic acid decarboxylase (GAD65) autoantibodies as a diagnostic aid for stiff-man syndrome and a correlate of susceptibility to type 1 diabetes mellitus. Mayo Clin. Proc. 73, 1161–1166 (1998). The first report to include cut-off values for high levels of GAD antibodies associated with SPS.
Dalakas, M. C., Li, M., Fujii, M. & Jacobowitz, D. M. Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology 57, 780–784 (2001). This study demonstrated specific intrathecal synthesis of GAD65 antibodies in SPS.
Schmidli, R. S., Colman, P. G. & Bonifacio, E. Disease sensitivity and specificity of 52 assays for glutamic acid decarboxylase antibodies. The Second International GADAB Workshop. Diabetes 44, 636–640 (1995).
Nanri, K. et al. Low-titer anti-GAD-antibody-positive cerebellar ataxia. Cerebellum 12, 171–175 (2013).
Virgilio, R. et al. Effect of steroid treatment in cerebellar ataxia associated with anti-glutamic acid decarboxylase antibodies. J. Neurol. Neurosurg. Psychiatry 80, 95–96 (2009).
Pedroso, J. L., Braga-Neto, P., Dutra, L. A. & Barsottini, O. G. Cerebellar ataxia associated to anti-glutamic acid decarboxylase autoantibody (anti-GAD): partial improvement with intravenous immunoglobulin therapy. Arq. Neuropsiquiatr. 69, 993 (2011).
Munoz-Lopetegi, A., et al. Neurologic syndromes related to anti-GAD65: clinical and serologic response to treatment. Neurol. Neuroimmunol. Neuroinflamm. 7, e696 (2020). This study provided confirmation that low levels of GAD antibodies do not associate with immune-responsive neurological disorders.
Baizabal-Carvallo, J. F. & Jankovic, J. Stiff-person syndrome: insights into a complex autoimmune disorder. J. Neurol. Neurosurg. Psychiatry 86, 840–848 (2015).
Björk, E., Velloso, L. A., Kampe, O. & Karlsson, F. A. GAD autoantibodies in IDDM, stiff-man syndrome, and autoimmune polyendocrine syndrome type I recognize different epitopes. Diabetes 43, 161–165 (1994).
Dinkel, K., Meinck, H. M., Jury, K. M., Karges, W. & Richter, W. Inhibition of gamma-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann. Neurol. 44, 194–201 (1998).
Raju, R. et al. Analysis of GAD65 autoantibodies in stiff-person syndrome patients. J. Immunol. 175, 7755–7762 (2005).
Sandbrink, F., Syed, N. A., Fujii, M. D., Dalakas, M. C. & Floeter, M. K. Motor cortex excitability in stiff-person syndrome. Brain 123, 2231–2239 (2000).
Levy, L. M., Levy-Reis, I., Fujii, M. & Dalakas, M. C. Brain gamma-aminobutyric acid changes in stiff-person syndrome. Arch. Neurol. 62, 970–974 (2005).
Ishida, K. et al. Selective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase. Ann. Neurol. 46, 263–267 (1999).
Takenoshita, H. et al. Presynaptic inhibition of cerebellar GABAergic transmission by glutamate decarboxylase autoantibodies in progressive cerebellar ataxia. J. Neurol. Neurosurg. Psychiatry 70, 386–389 (2001).
Vianello, M. et al. Increased spontaneous activity of a network of hippocampal neurons in culture caused by suppression of inhibitory potentials mediated by anti-gad antibodies. Autoimmunity 41, 66–73 (2008).
Stemmler, N. et al. Serum from a patient with GAD65 antibody-associated limbic encephalitis did not alter GABAergic neurotransmission in cultured hippocampal networks. Front. Neurol. 6, 189 (2015).
Mitoma, H., Ishida, K., Shizuka-Ikeda, M. & Mizusawa, H. Dual impairment of GABAA- and GABAB-receptor-mediated synaptic responses by autoantibodies to glutamic acid decarboxylase. J. Neurol. Sci. 208, 51–56 (2003).
Hackert, J. K. et al. Anti-GAD65 containing cerebrospinal fluid does not Alter GABAergic transmission. Front. Cell Neurosci. 10, 130 (2016).
Hampe, C. S. et al. Monoclonal antibodies to 65 kDa glutamate decarboxylase induce epitope specific effects on motor and cognitive functions in rats. Orphanet J. Rare Dis. 8, 82 (2013).
Mitoma, H., Manto, M. & Hampe, C. S. Pathogenic roles of glutamic acid decarboxylase 65 autoantibodies in cerebellar ataxias. J. Immunol. Res. 2017, 2913297 (2017). A comprehensive review of the potential role of GAD antibodies in cerebellar ataxia.
Graus, F. et al. Effect of intraventricular injection of an anti-Purkinje cell antibody (anti-Yo) in a guinea pig model. J. Neurol. Sci. 106, 82–87 (1991).
Planaguma, J. et al. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain 138, 94–109 (2015).
Haselmann, H. et al. Human autoantibodies against the AMPA receptor subunit GluA2 induce receptor reorganization and memory dysfunction. Neuron 100, 91–105 (2018).
Petit-Pedrol, M. et al. LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory. Brain 141, 3144–3159 (2018).
Hillebrand, S. et al. Circulating AQP4-specific auto-antibodies alone can induce neuromyelitis optica spectrum disorder in the rat. Acta Neuropathol. 137, 467–485 (2019).
Dalakas, M. C. Progress and stiff challenges in understanding the role of GAD-antibodies in stiff-person syndrome. Exp. Neurol. 247, 303–307 (2013).
Manto, M. U. et al. Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases. Ann. Neurol. 61, 544–551 (2007).
Manto, M. U., Hampe, C. S., Rogemond, V. & Honnorat, J. Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia. Orphanet J. Rare Dis. 6, 3 (2011).
Manto, M. et al. Disease-specific monoclonal antibodies targeting glutamate decarboxylase impair GABAergic neurotransmission and affect motor learning and behavioral functions. Front. Behav. Neurosci. 9, 78 (2015).
Geis, C. et al. Human stiff-person syndrome IgG induces anxious behavior in rats. PLoS One 6, e16775 (2011).
Hansen, N. et al. Human stiff person syndrome IgG-containing high-titer anti-GAD65 autoantibodies induce motor dysfunction in rats. Exp. Neurol. 239, 202–209 (2013).
Han, G. et al. Active tolerance induction and prevention of autoimmune diabetes by immunogene therapy using recombinant adenoassociated virus expressing glutamic acid decarboxylase 65 peptide GAD(500-585). J. Immunol. 174, 4516–4524 (2005).
Chang, T. et al. Immunization against GAD induces antibody binding to GAD-independent antigens and brainstem GABAergic neuronal loss. PLoS One 8, e72921 (2013).
Liimatainen, S. et al. GAD65 autoantibody characteristics in patients with co-occurring type 1 diabetes and epilepsy may help identify underlying epilepsy etiologies. Orphanet J. Rare Dis. 13, 55 (2018).
Alexopoulos, H., Akrivou, S. & Dalakas, M. C. Glycine receptor antibodies in stiff-person syndrome and other GAD-positive CNS disorders. Neurology 81, 1962–1964 (2013).
Armangue, T. et al. Clinical and immunological features of opsoclonus-myoclonus syndrome in the era of neuronal cell surface antibodies. JAMA Neurol. 73, 417–424 (2016).
Martinez-Hernandez, E. et al. Antibodies to aquaporin 4, myelin-oligodendrocyte glycoprotein, and the glycine receptor alpha1 subunit in patients with isolated optic neuritis. JAMA Neurol. 72, 187–193 (2015).
Raju, R. et al. Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain 129, 3270–3276 (2006).
Bernal, F. et al. Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis. Acta Neuropathol. 103, 509–515 (2002).
Bien, C. G. et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 135, 1622–1638 (2012).
Carreno, M. et al. Epilepsy surgery in drug resistant temporal lobe epilepsy associated with neuronal antibodies. Epilepsy Res. 129, 101–105 (2017).
Ishida, K. et al. Selective loss of Purkinje cells in a patient with anti-glutamic acid decarboxylase antibody-associated cerebellar ataxia. J. Neurol. Neurosurg. Psychiatry 78, 190–192 (2007).
Skorstad, G., Hestvik, A. L. K., Vartdal, F. & Holmoy, T. Cerebrospinal fluid T cell responses against glutamic acid decarboxylase 65 in patients with stiff person syndrome. J. Autoimmun. 32, 24–32 (2009).
Costa, M. et al. T-cell reactivity to glutamic acid decarboxylase in stiff-man syndrome and cerebellar ataxia associated with polyendocrine autoimmunity. Clin. Exp. Immunol. 129, 471–478 (2002).
Burton, A. R. et al. Central nervous system destruction mediated by glutamic acid decarboxylase-specific CD4+ T cells. J. Immunol. 184, 4863–4870 (2010).
Zekzer, D. et al. GAD-reactive CD4+ Th1 cells induce diabetes in NOD/SCID mice. J. Clin. Invest. 101, 68–73 (1998).
El-Abassi, R., Soliman, M. Y., Villemarette-Pittman, N. & England, J. D. SPS: understanding the complexity. J. Neurol. Sci. 404, 137–149 (2019).
Solimena, M. & De Camilli, P. Autoimmunity to glutamic acid decarboxylase (GAD) in Stiff-Man syndrome and insulin-dependent diabetes mellitus. Trends Neurosci. 14, 452–457 (1991).
Makela, K. M., Hietaharju, A., Brander, A. & Peltola, J. Clinical management of epilepsy with glutamic acid decarboxylase antibody positivity: the interplay between immunotherapy and anti-epileptic drugs. Front. Neurol. 9, 579 (2018).
Di Giacomo, R. et al. Predictive value of high titer of GAD65 antibodies in a case of limbic encephalitis. J. Neuroimmunol. 337, 577063 (2019).
Dalakas, M. C. et al. High-dose intravenous immune globulin for stiff-person syndrome. N. Engl. J. Med. 345, 1870–1876 (2001). The first and only randomized study of the value of intravenous immunoglobulins in SPS.
Pagano, M. B., Murinson, B. B., Tobian, A. A. R. & King, K. E. Efficacy of therapeutic plasma exchange for treatment of stiff-person syndrome. Transfusion 54, 1851–1856 (2014).
Fekete, R. & Jankovic, J. Childhood stiff-person syndrome improved with rituximab. Case Rep. Neurol. 4, 92–96 (2012).
Bacorro, E. A. & Tehrani, R. Stiff-person syndrome: persistent elevation of glutamic acid decarboxylase antibodies despite successful treatment with rituximab. J. Clin. Rheumatol. 16, 237–239 (2010).
Qureshi, A. & Hennessy, M. Stiff person syndrome (SPS) complicated by respiratory failure: successful treatment with rituximab. J. Neurol. 259, 180–181 (2012).
Lobo, M. E., Araujo, M. L., Tomaz, C. A. & Allam, N. Stiff-person syndrome treated with rituximab. BMJ Case Rep. 2010, bcr0520103021 (2010).
Baker, M. R., Das, M., Isaacs, J., Fawcett, P. R. W. & Bates, D. Treatment of stiff person syndrome with rituximab. J. Neurol. Neurosurg. Psychiatry 76, 999–1001 (2005).
Dalakas, M. C., Rakocevic, G., Dambrosia, J. M., Alexopoulos, H. & McElroy, B. A double-blind, placebo-controlled study of rituximab in patients with stiff person syndrome. Ann. Neurol. 82, 271–277 (2017).
Mitoma, H., Hadjivassiliou, M. & Honnorat, J. Guidelines for treatment of immune-mediated cerebellar ataxias. Cerebellum Ataxias 2, 14 (2015).
Jones, A. L. et al. Responses to and outcomes of treatment of autoimmune cerebellar ataxia in adults. JAMA Neurol. 72, 1304–1312 (2015).
McKeon, A. et al. Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch. Neurol. 69, 230–238 (2012). This study demonstrated the long-term treatment responses and outcomes in a large series of 99 SPS and variants.
Malter, M. P. et al. Treatment of immune-mediated temporal lobe epilepsy with GAD antibodies. Seizure 30, 57–63 (2015).
Waters, P. et al. Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica. J. Neurol. Neurosurg. Psychiatry 87, 1005–1015 (2016).
Lorish, T. R., Thorsteinsson, G. & Howard, F. M. Jr. Stiff-man syndrome updated. Mayo Clin. Proc. 64, 629–636 (1989).
The work of the authors is supported, in part, by grants from by the Instituto Carlos III–FEDER (FIS 17/00234 and PIE 16/00014 to J.D.), Safra Foundation and Fundació Privada CELLEX (J.D.).
F.G. receives royalties from EUROIMMUN for the use of IgLON5 in an autoantibody test and receives honoraria from MedLink Neurology for his role as an associate editor. J.D. receives royalties from Athena Diagnostics for the use of Ma2 in an autoantibody test and from EUROIMMUN for the use of NMDA receptor, GABAB receptor, GABAA receptor, DPPX and IgLON5 in autoantibody tests. A.S. declares no competing interests.
Peer review information
Nature Reviews Neurology thanks J. Gelfand, H. Mitoma and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Graus, F., Saiz, A. & Dalmau, J. GAD antibodies in neurological disorders — insights and challenges. Nat Rev Neurol 16, 353–365 (2020). https://doi.org/10.1038/s41582-020-0359-x
This article is cited by
Seizure semiology and predictors of outcomes in Chinese patients with glutamic acid decarboxylase antibody-associated neurological syndrome
BMC Neurology (2023)
Nature Reviews Nephrology (2023)
Annals of Nuclear Medicine (2023)
The Cerebellum (2023)
Relapsing remitting encephalomyelitis with glutamic acid decarboxylase antibodies following autologous haematopoietic stem cell transplantation—coincidence or consequence?
Neurological Sciences (2023)