GAD antibodies in neurological disorders — insights and challenges

Abstract

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.

Key points

  • 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.

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Fig. 1: Autoimmune targets at the inhibitory synapse and the associated neurological disorders.
Fig. 2: Assessment of GAD65 antibody levels with different techniques.
Fig. 3: Disorders associated with high and low levels of GAD65 antibodies.
Fig. 4: Determining the likelihood of an autoimmune cause for neurological disorders accompanied by GAD antibodies in serum.

References

  1. 1.

    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.

    CAS  PubMed  Google Scholar 

  2. 2.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    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).

    CAS  PubMed  Google Scholar 

  4. 4.

    Geis, C. et al. Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain 133, 3166–3180 (2010).

    PubMed  Google Scholar 

  5. 5.

    Ohkawa, T. et al. Identification and characterization of GABA(A) receptor autoantibodies in autoimmune encephalitis. J. Neurosci. 34, 8151–8163 (2014).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    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).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    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).

    CAS  PubMed  Google Scholar 

  8. 8.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    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).

    PubMed  Google Scholar 

  10. 10.

    Spatola, M. et al. Investigations in GABAA receptor antibody-associated encephalitis. Neurology 88, 1012–1020 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Carvajal-Gonzalez, A. et al. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain 137, 2178–2192 (2014).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    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.

    PubMed  Google Scholar 

  14. 14.

    Pittock, S. J. et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann. Neurol. 58, 96–107 (2005).

    PubMed  Google Scholar 

  15. 15.

    Manto, M., Mitoma, H. & Hampe, C. S. Anti-GAD antibodies and the cerebellum: where do we stand? Cerebellum 18, 153–156 (2019).

    PubMed  Google Scholar 

  16. 16.

    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.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Chang, T. et al. Neuronal surface and glutamic acid decarboxylase autoantibodies in nonparaneoplastic stiff person syndrome. JAMA Neurol. 70, 1140–1149 (2013).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    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).

    CAS  PubMed  Google Scholar 

  19. 19.

    Vincent, S. R. et al. Immunohistochemical studies of the GABA system in the pancreas. Neuroendocrinology 36, 197–204 (1983).

    CAS  PubMed  Google Scholar 

  20. 20.

    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).

    CAS  PubMed  Google Scholar 

  21. 21.

    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.

    CAS  PubMed  Google Scholar 

  22. 22.

    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).

    CAS  PubMed  Google Scholar 

  23. 23.

    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).

    CAS  PubMed  Google Scholar 

  24. 24.

    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).

    CAS  PubMed  Google Scholar 

  25. 25.

    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).

    CAS  PubMed  Google Scholar 

  26. 26.

    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).

    CAS  PubMed  Google Scholar 

  27. 27.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    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).

    CAS  PubMed  Google Scholar 

  29. 29.

    Giometto, B. et al. Temporal-lobe epilepsy associated with glutamic-acid-decarboxylase autoantibodies. Lancet 352, 457 (1998).

    CAS  PubMed  Google Scholar 

  30. 30.

    McKeon, A. & Tracy, J. A. GAD65 neurological autoimmunity. Muscle Nerve 56, 15–27 (2017).

    CAS  PubMed  Google Scholar 

  31. 31.

    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).

    CAS  PubMed  Google Scholar 

  32. 32.

    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).

    CAS  PubMed  Google Scholar 

  33. 33.

    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).

    CAS  PubMed  Google Scholar 

  34. 34.

    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).

    CAS  PubMed  Google Scholar 

  35. 35.

    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).

    CAS  PubMed  Google Scholar 

  36. 36.

    Fouka, P. et al. GAD65 epitope mapping and search for novel autoantibodies in GAD-associated neurological disorders. J. Neuroimmunol. 281, 73–77 (2015).

    CAS  PubMed  Google Scholar 

  37. 37.

    Luhder, F. et al. Autoantibodies against GAD65 rather than GAD67 precede the onset of type 1 diabetes. Autoimmunity 19, 71–80 (1994).

    CAS  PubMed  Google Scholar 

  38. 38.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    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).

    CAS  PubMed  Google Scholar 

  40. 40.

    Fenalti, G. & Rowley, M. J. GAD65 as a prototypic autoantigen. J. Autoimmun. 31, 228–232 (2008).

    CAS  PubMed  Google Scholar 

  41. 41.

    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).

    CAS  Google Scholar 

  42. 42.

    Brown, P., Rothwell, J. C. & Marsden, C. D. The stiff leg syndrome. J. Neurol. Neurosurg. Psychiatry 62, 31–37 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    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).

    CAS  PubMed  Google Scholar 

  44. 44.

    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.

    PubMed  Google Scholar 

  45. 45.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Martinez-Hernandez, E. et al. Clinical and immunological investigations in 121 patients with stiff-person spectrum disorder. JAMA Neurol. 73, 714–720 (2016).

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    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).

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    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).

    CAS  PubMed  Google Scholar 

  49. 49.

    Blum, P. & Jankovic, J. Stiff-person syndrome: an autoimmune disease. Mov. Disord. 6, 12–20 (1991).

    CAS  PubMed  Google Scholar 

  50. 50.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    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).

    PubMed  Google Scholar 

  52. 52.

    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.

    CAS  PubMed  Google Scholar 

  53. 53.

    Murinson, B. B. & Guarnaccia, J. B. Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 71, 1955–1958 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Meinck, H. M. Stiff man syndrome. CNS Drugs 15, 515–526 (2001).

    CAS  PubMed  Google Scholar 

  56. 56.

    Hadjivassiliou, M. et al. Cerebellar ataxia as a possible organ-specific autoimmune disease. Mov. Disord. 23, 1370–1377 (2008).

    PubMed  Google Scholar 

  57. 57.

    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).

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    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.

    CAS  PubMed  Google Scholar 

  59. 59.

    Baizabal-Carvallo, J. F. & Alonso-Juarez, M. Cerebellar disease associated with anti-glutamic acid decarboxylase antibodies: review. J. Neural Transm. 124, 1171–1182 (2017).

    CAS  PubMed  Google Scholar 

  60. 60.

    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).

    PubMed  Google Scholar 

  61. 61.

    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).

    CAS  PubMed  Google Scholar 

  62. 62.

    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).

    PubMed  Google Scholar 

  63. 63.

    Baizabal-Carvallo, J. F. & Alonso-Juarez, M. Vertical nystagmus associated with glutamic acid decarboxylase antibodies responding to cyclophosphamide. J. Neuroimmunol. 317, 5–7 (2018).

    CAS  PubMed  Google Scholar 

  64. 64.

    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).

    CAS  PubMed  Google Scholar 

  65. 65.

    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).

    PubMed  Google Scholar 

  66. 66.

    Liimatainen, S. et al. Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy. Epilepsia 51, 760–767 (2010).

    PubMed  Google Scholar 

  67. 67.

    Daif, A. et al. Antiglutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy. Epilepsy Behav. 80, 331–336 (2018).

    PubMed  Google Scholar 

  68. 68.

    Lilleker, J. B., Biswas, V. & Mohanraj, R. Glutamic acid decarboxylase (GAD) antibodies in epilepsy: diagnostic yield and therapeutic implications. Seizure 23, 598–602 (2014).

    PubMed  Google Scholar 

  69. 69.

    Falip, M. et al. Prevalence and immunological spectrum of temporal lobe epilepsy with glutamic acid decarboxylase antibodies. Eur. J. Neurol. 19, 827–833 (2012).

    CAS  PubMed  Google Scholar 

  70. 70.

    Falip, M. et al. Hippocampus and insula are Targets in epileptic patients with glutamic acid decarboxylase antibodies. Front. Neurol. 9, 1143 (2018).

    PubMed  Google Scholar 

  71. 71.

    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).

    PubMed  Google Scholar 

  72. 72.

    Graus, F. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 15, 391–404 (2016).

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Malter, M. P. et al. Suspected new-onset autoimmune temporal lobe epilepsy with amygdala enlargement. Epilepsia 57, 1485–1494 (2016).

    CAS  PubMed  Google Scholar 

  74. 74.

    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).

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Blanc, F. et al. Acute limbic encephalitis and glutamic acid decarboxylase antibodies: a reality? J. Neurol. Sci. 287, 69–71 (2009).

    CAS  PubMed  Google Scholar 

  76. 76.

    Markakis, I. et al. Immunotherapy-responsive limbic encephalitis with antibodies to glutamic acid decarboxylase. J. Neurol. Sci. 343, 192–194 (2014).

    CAS  PubMed  Google Scholar 

  77. 77.

    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).

    PubMed  Google Scholar 

  78. 78.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Bataller, L. et al. Cerebellar ataxia associated with neuroendocrine thymic carcinoma and GAD antibodies. J. Neurol. Neurosurg. Psychiatry 80, 696–697 (2009).

    CAS  PubMed  Google Scholar 

  80. 80.

    Iwata, T. et al. Thymectomy for paraneoplastic stiff-person syndrome associated with invasive thymoma. J. Thorac. Cardiovascular Surg. 132, 196–197 (2006).

    Google Scholar 

  81. 81.

    Vernino, S. & Lennon, V. A. Autoantibody profiles and neurological correlations of thymoma. Clin. Cancer Res. 10, 7270–7275 (2004).

    CAS  PubMed  Google Scholar 

  82. 82.

    Arino, H. et al. Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies. JAMA Neurol. 72, 874–881 (2015).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Meinck, H. M. et al. Antibodies against glutamic acid decarboxylase: prevalence in neurological diseases. J. Neurol. Neurosurg. Psychiatry 71, 100–103 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    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.

    CAS  PubMed  Google Scholar 

  85. 85.

    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.

    CAS  PubMed  Google Scholar 

  86. 86.

    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).

    CAS  PubMed  Google Scholar 

  87. 87.

    Nanri, K. et al. Low-titer anti-GAD-antibody-positive cerebellar ataxia. Cerebellum 12, 171–175 (2013).

    CAS  PubMed  Google Scholar 

  88. 88.

    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).

    CAS  PubMed  Google Scholar 

  89. 89.

    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).

    PubMed  Google Scholar 

  90. 90.

    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.

  91. 91.

    Baizabal-Carvallo, J. F. & Jankovic, J. Stiff-person syndrome: insights into a complex autoimmune disorder. J. Neurol. Neurosurg. Psychiatry 86, 840–848 (2015).

    PubMed  Google Scholar 

  92. 92.

    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).

    PubMed  Google Scholar 

  93. 93.

    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).

    CAS  PubMed  Google Scholar 

  94. 94.

    Raju, R. et al. Analysis of GAD65 autoantibodies in stiff-person syndrome patients. J. Immunol. 175, 7755–7762 (2005).

    CAS  PubMed  Google Scholar 

  95. 95.

    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).

    PubMed  Google Scholar 

  96. 96.

    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).

    PubMed  Google Scholar 

  97. 97.

    Ishida, K. et al. Selective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase. Ann. Neurol. 46, 263–267 (1999).

    CAS  PubMed  Google Scholar 

  98. 98.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    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).

    CAS  PubMed  Google Scholar 

  100. 100.

    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).

    PubMed  PubMed Central  Google Scholar 

  101. 101.

    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).

    CAS  PubMed  Google Scholar 

  102. 102.

    Hackert, J. K. et al. Anti-GAD65 containing cerebrospinal fluid does not Alter GABAergic transmission. Front. Cell Neurosci. 10, 130 (2016).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    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).

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    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.

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    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).

    CAS  PubMed  Google Scholar 

  106. 106.

    Planaguma, J. et al. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain 138, 94–109 (2015).

    PubMed  Google Scholar 

  107. 107.

    Haselmann, H. et al. Human autoantibodies against the AMPA receptor subunit GluA2 induce receptor reorganization and memory dysfunction. Neuron 100, 91–105 (2018).

    CAS  PubMed  Google Scholar 

  108. 108.

    Petit-Pedrol, M. et al. LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory. Brain 141, 3144–3159 (2018).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    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).

    CAS  PubMed  Google Scholar 

  110. 110.

    Dalakas, M. C. Progress and stiff challenges in understanding the role of GAD-antibodies in stiff-person syndrome. Exp. Neurol. 247, 303–307 (2013).

    CAS  PubMed  Google Scholar 

  111. 111.

    Manto, M. U. et al. Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases. Ann. Neurol. 61, 544–551 (2007).

    CAS  PubMed  Google Scholar 

  112. 112.

    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).

    PubMed  PubMed Central  Google Scholar 

  113. 113.

    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).

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Geis, C. et al. Human stiff-person syndrome IgG induces anxious behavior in rats. PLoS One 6, e16775 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    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).

    CAS  PubMed  Google Scholar 

  116. 116.

    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).

    CAS  PubMed  Google Scholar 

  117. 117.

    Chang, T. et al. Immunization against GAD induces antibody binding to GAD-independent antigens and brainstem GABAergic neuronal loss. PLoS One 8, e72921 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    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).

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    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).

    PubMed  Google Scholar 

  120. 120.

    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).

    PubMed  PubMed Central  Google Scholar 

  121. 121.

    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).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Raju, R. et al. Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain 129, 3270–3276 (2006).

    PubMed  Google Scholar 

  123. 123.

    Bernal, F. et al. Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis. Acta Neuropathol. 103, 509–515 (2002).

    CAS  PubMed  Google Scholar 

  124. 124.

    Bien, C. G. et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 135, 1622–1638 (2012).

    PubMed  Google Scholar 

  125. 125.

    Carreno, M. et al. Epilepsy surgery in drug resistant temporal lobe epilepsy associated with neuronal antibodies. Epilepsy Res. 129, 101–105 (2017).

    PubMed  Google Scholar 

  126. 126.

    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).

    PubMed  Google Scholar 

  127. 127.

    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).

    CAS  PubMed  Google Scholar 

  128. 128.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Burton, A. R. et al. Central nervous system destruction mediated by glutamic acid decarboxylase-specific CD4+ T cells. J. Immunol. 184, 4863–4870 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Zekzer, D. et al. GAD-reactive CD4+ Th1 cells induce diabetes in NOD/SCID mice. J. Clin. Invest. 101, 68–73 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    El-Abassi, R., Soliman, M. Y., Villemarette-Pittman, N. & England, J. D. SPS: understanding the complexity. J. Neurol. Sci. 404, 137–149 (2019).

    CAS  PubMed  Google Scholar 

  132. 132.

    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).

    CAS  PubMed  Google Scholar 

  133. 133.

    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).

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    Di Giacomo, R. et al. Predictive value of high titer of GAD65 antibodies in a case of limbic encephalitis. J. Neuroimmunol. 337, 577063 (2019).

    PubMed  Google Scholar 

  135. 135.

    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.

    CAS  PubMed  Google Scholar 

  136. 136.

    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).

    PubMed  Google Scholar 

  137. 137.

    Fekete, R. & Jankovic, J. Childhood stiff-person syndrome improved with rituximab. Case Rep. Neurol. 4, 92–96 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    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).

    PubMed  Google Scholar 

  139. 139.

    Qureshi, A. & Hennessy, M. Stiff person syndrome (SPS) complicated by respiratory failure: successful treatment with rituximab. J. Neurol. 259, 180–181 (2012).

    CAS  PubMed  Google Scholar 

  140. 140.

    Lobo, M. E., Araujo, M. L., Tomaz, C. A. & Allam, N. Stiff-person syndrome treated with rituximab. BMJ Case Rep. 2010, bcr0520103021 (2010).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Mitoma, H., Hadjivassiliou, M. & Honnorat, J. Guidelines for treatment of immune-mediated cerebellar ataxias. Cerebellum Ataxias 2, 14 (2015).

    PubMed  PubMed Central  Google Scholar 

  144. 144.

    Jones, A. L. et al. Responses to and outcomes of treatment of autoimmune cerebellar ataxia in adults. JAMA Neurol. 72, 1304–1312 (2015).

    PubMed  Google Scholar 

  145. 145.

    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.

    PubMed  Google Scholar 

  146. 146.

    Malter, M. P. et al. Treatment of immune-mediated temporal lobe epilepsy with GAD antibodies. Seizure 30, 57–63 (2015).

    CAS  PubMed  Google Scholar 

  147. 147.

    Waters, P. et al. Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica. J. Neurol. Neurosurg. Psychiatry 87, 1005–1015 (2016).

    PubMed  PubMed Central  Google Scholar 

  148. 148.

    Lorish, T. R., Thorsteinsson, G. & Howard, F. M. Jr. Stiff-man syndrome updated. Mayo Clin. Proc. 64, 629–636 (1989).

    CAS  PubMed  Google Scholar 

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Acknowledgements

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.).

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All authors contributed equally to all stages of preparing this manuscript.

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Correspondence to Josep Dalmau.

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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.

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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

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