Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2011

Open Access 01-12-2011 | Research

Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia

Authors: Mario U Manto, Christiane S Hampe, Véronique Rogemond, Jérome Honnorat

Published in: Orphanet Journal of Rare Diseases | Issue 1/2011

Login to get access

Abstract

Background

To investigate whether Stiff-person syndrome (SPS) and cerebellar ataxia (CA) are associated with distinct GAD65-Ab epitope specificities and neuronal effects.

Methods

Purified GAD65-Ab from neurological patients and monoclonal GAD65-Ab with distinct epitope specificities (b78 and b96.11) were administered in vivo to rat cerebellum. Effects of intra-cerebellar administration of GAD65-Ab were determined using neurophysiological and neurochemical methods.

Results

Intra-cerebellar administration of GAD65-Ab from a SPS patient (Ab SPS) impaired the NMDA-mediated turnover of glutamate, but had no effect on NMDA-mediated turnover of glycerol. By contrast, GAD65-Ab from a patient with cerebellar ataxia (Ab CA) markedly decreased the NMDA-mediated turnover of glycerol. Both GAD65-Ab increased the excitability of the spinal cord, as assessed by the F wave/M wave ratios. The administration of BFA, an inhibitor of the recycling of vesicles, followed by high-frequency stimulation of the cerebellum, severely impaired the cerebello-cortical inhibition only when Ab CA was used. Moreover, administration of transcranial direct current stimulation (tDCS) of the motor cortex revealed a strong disinhibition of the motor cortex with Ab CA. Monoclonal antibodies b78 and b96.11 showed distinct effects, with greater effects of b78 in terms of increase of glutamate concentrations, impairment of the adaptation of the motor cortex to repetitive peripheral stimulation, disinhibition of the motor cortex following tDCS, and increase of the F/M ratios. Ab SPS shared antibody characteristics with b78, both in epitope recognition and ability to inhibit enzyme activity, while Ab CA had no effect on GAD65 enzyme activity.

Conclusions

These results suggest that, in vivo, neurological impairments caused by GAD65-Ab could vary according to epitope specificities. These results could explain the different neurological syndromes observed in patients with GAD65-Ab.
Appendix
Available only for authorised users
Literature
1.
Raju R, Hampe CS: Immunobiology of stiff-person syndrome. Int Rev Immunol. 2008, 27 (1-2): 79-92. 10.1080/08830180701883240.CrossRefPubMed
2.
Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, de Andres C, Maestre J, Fabien N, Vighetto A, Casamitjana R, Thivolet C, Tavolato B, Antoine J, Trouillas P, Graus F: Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol. 2001, 58 (2): 225-30. 10.1001/archneur.58.2.225.CrossRefPubMed
3.
Vianello M, Tavolato B, Armani M, Giometto B: Cerebellar ataxia associated with anti-glutamic acid decarboxylase autoantibodies. Cerebellum. 2003, 2 (1): 77-9. 10.1080/14734220309432.CrossRefPubMed
4.
Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, De Camilli P: Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature. 1990, 347 (6289): 151-6. 10.1038/347151a0.CrossRefPubMed
5.
Dinkel K, Meinck H, Jury KM, Karges W, Richter W: Inhibition of gamma-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Annals of Neurology. 1998, 44 (2): 194-201. 10.1002/ana.410440209.CrossRefPubMed
6.
Bjork E, Velloso LA, Kampe O, Karlsson FA: GAD autoantibodies in IDDM, stiff-man syndrome, and autoimmune polyendocrine syndrome type I recognize different epitopes. Diabetes. 1994, 43 (1): 161-5. 10.2337/diabetes.43.1.161.CrossRefPubMed
7.
Kanaani J, Diacovo MJ, El-Husseini Ael D, Bredt DS, Baekkeskov S: Palmitoylation controls trafficking of GAD65 from Golgi membranes to axon-specific endosomes and a Rab5a-dependent pathway to presynaptic clusters. J Cell Sci. 2004, 117 (Pt 10): 2001-13. 10.1242/jcs.01030.CrossRefPubMed
8.
Kanaani J, Patterson G, Schaufele F, Lippincott-Schwartz J, Baekkeskov S: A palmitoylation cycle dynamically regulates partitioning of the GABA-synthesizing enzyme GAD65 between ER-Golgi and post-Golgi membranes. J Cell Sci. 2008, 121 (Pt 4): 437-49. 10.1242/jcs.011916.CrossRefPubMed
9.
Levy LM, Dalakas MC, Floeter MK: The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of gamma-aminobutyric acid. Ann Intern Med. 1999, 131 (7): 522-30.CrossRefPubMed
10.
Hill KE, Clawson SA, Rose JW, Carlson NG, Greenlee JE: Cerebellar Purkinje cells incorporate immunoglobulins and immunotoxins in vitro: implications for human neurological disease and immunotherapeutics. J Neuroinflammation. 2009, 6:31. 10.1186/1742-2094-6-31.PubMedCentralCrossRefPubMed
11.
Meneses PI, Zupa-Fernandez A, Maronski M, Dichter MA, Dalmau J, Rosenfeld MR: Onconeuronal and control antibodies are internalized by hippocampal neurons resulting in cell death. Neurology. 2005, 64 (suppl1): A52.
12.
Manto MU, Laute MA, Aguera M, Rogemond V, Pandolfo M, Honnorat J: Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases. Ann Neurol. 2007, 61 (6): 544-51. 10.1002/ana.21123.CrossRefPubMed
13.
Oulad Ben Taib N, Manto M, Laute MA, Brotchi J: The cerebellum modulates rodent cortical motor output after repetitive somatosensory stimulation. Neurosurgery. 2005, 56 (4): 811-20, discussion 811-20. 10.1227/01.NEU.0000156616.94446.00.CrossRefPubMed
14.
Luft AR, Kaelin-Lang A, Hauser TK, Buitrago MM, Thakor NV, Hanley DF, Cohen LG: Modulation of rodent cortical motor excitability by somatosensory input. Exp Brain Res. 2002, 142 (4): 562-9. 10.1007/s00221-001-0952-1.CrossRefPubMed
15.
Oulad Ben Taib N, Laute MA, Pandolfo M, Manto MU: Interaction between repetitive stimulation of the sciatic nerve and functional ablation of cerebellar nucleus interpositus in the rat. Cerebellum. 2004, 3 (1): 21-6. 10.1080/14734220410028660.CrossRefPubMed
16.
Sommer C, Weishaupt A, Brinkhoff J, Biko L, Wessig C, Gold R, Toyka KV: Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet. 2005, 365 (9468): 1406-11. 10.1016/S0140-6736(05)66376-3.CrossRefPubMed
17.
Geis C, Weishaupt A, Hallermann S, Grunewald B, Wessig C, Wultsch T, Reif A, Byts N, Beck M, Jablonka S, Boettger MK, Uceyler N, Fouquet W, Gerlach M, Meinck HM, Siren AL, Sigrist SJ, Toyka KV, Heckmann M, Sommer C: Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain. 2010, 133 (11): 3166-80. 10.1093/brain/awq253.CrossRefPubMed
18.
Kono S, Miyajima H, Sugimoto M, Suzuki Y, Takahashi Y, Hishida A: Stiff-person syndrome associated with cerebellar ataxia and high glutamic acid decarboxylase antibody titer. Intern Med. 2001, 40 (9): 968-71. 10.2169/internalmedicine.40.968.CrossRefPubMed
19.
Ishida K, Mitoma H, Wada Y, Oka T, Shibahara J, Saito Y, Murayama S, Mizusawa H: Selective loss of Purkinje cells in a patient with anti-glutamic acid decarboxylase antibody-associated cerebellar ataxia. Journal of Neurology, Neurosurgery and Psychiatry. 2007, 78 (2): 190-2. 10.1136/jnnp.2006.091116.PubMedCentralCrossRefPubMed
20.
Rakocevic G, Raju R, Semino-Mora C, Dalakas MC: Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies. Neurology. 2006, 67 (6): 1068-70. 10.1212/01.wnl.0000237558.83349.d0.CrossRefPubMed
21.
Abele M, Weller M, Mescheriakov S, Burk K, Dichgans J, Klockgether T: Cerebellar ataxia with glutamic acid decarboxylase autoantibodies. Neurology. 1999, 52 (4): 857-9.CrossRefPubMed
22.
Lauria G, Pareyson D, Pitzolu MG, Bazzigaluppi E: Excellent response to steroid treatment in anti-GAD cerebellar ataxia. Lancet Neurol. 2003, 2 (10): 634-5. 10.1016/S1474-4422(03)00534-9.CrossRefPubMed
23.
Scheuber A, Rudge R, Danglot L, Raposo G, Binz T, Poncer JC, Galli T: Loss of AP-3 function affects spontaneous and evoked release at hippocampal mossy fiber synapses. Proc Natl Acad Sci USA. 2006, 103 (44): 16562-7. 10.1073/pnas.0603511103.PubMedCentralCrossRefPubMed
24.
Radulescu AE, Siddhanta A, Shields D: A role for clathrin in reassembly of the Golgi apparatus. Mol Biol Cell. 2007, 18 (1): 94-105. 10.1091/mbc.E06-06-0532.PubMedCentralCrossRefPubMed
25.
Raju R, Foote J, Banga JP, Hall TR, Padoa CJ, Dalakas MC, Ortqvist E, Hampe CS: Analysis of GAD65 Autoantibodies in Stiff-Person Syndrome Patients. J Immunol. 2005, 175 (11): 7755-62.CrossRefPubMed
26.
Tremble J, Morgenthaler NG, Vlug A, Powers AC, Christie MR, Scherbaum WA, Banga JP: Human B cells secreting immunoglobulin G to glutamic acid decarboxylase- 65 from a nondiabetic patient with multiple autoantibodies and Graves' disease: a comparison with those present in type 1 diabetes. J Clin Endocrinol Metab. 1997, 82 (8): 2664-70. 10.1210/jc.82.8.2664.PubMed
27.
Padoa CJ, Banga JP, Madec AM, Ziegler M, Schlosser M, Ortqvist E, Kockum I, Palmer J, Rolandsson O, Binder KA, Foote J, Luo D, Hampe CS: Recombinant Fabs of human monoclonal antibodies specific to the middle epitope of GAD65 inhibit type 1 diabetes-specific GAD65Abs. Diabetes. 2003, 52 (11): 2689-95. 10.2337/diabetes.52.11.2689.CrossRefPubMed
28.
Grubin CE, Daniels T, Toivola B, Landin-Olsson M, Hagopian WA, Li L, Karlsen AE, Boel E, Michelsen B, Lernmark Å: A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM. Diabetologia. 1994, 37: 344-350. 10.1007/BF00408469.CrossRefPubMed
29.
Falorni A, Örtqvist E, Persson B, Lernmark Å: Radioimmunoassays for glutamic acid decarboxylase (GAD65) and GAD65 autoantibodies using 35S or 3H recombinant human ligands. J Immunol Methods. 1995, 186: 89-99. 10.1016/0022-1759(95)00139-2.CrossRefPubMed
30.
Hampe CS, Hammerle LP, Falorni A, Robertson J, Lernmark A: Site-directed mutagenesis of K396R of the 65 kDa glutamic acid decarboxylase active site obliterates enzyme activity but not antibody binding. FEBS Lett. 2001, 488 (3): 185-9. 10.1016/S0014-5793(00)02429-7.CrossRefPubMed
31.
Manto M, Laute MA: A possible mechanism for the beneficial effect of ethanol in essential tremor. Eur J Neurol. 2008, 15 (7): 697-705. 10.1111/j.1468-1331.2008.02150.x.CrossRefPubMed
32.
Ben Taib NO, Manto M: Trains of transcranial direct current stimulation antagonize motor cortex hypoexcitability induced by acute hemicerebellectomy. J Neurosurg. 2009, 111 (4): 796-806. 10.3171/2008.2.17679.CrossRefPubMed
33.
Molina-Luna K, Buitrago MM, Hertler B, Schubring M, Haiss F, Nisch W, Schulz JB, Luft AR: Cortical stimulation mapping using epidurally implanted thin-film microelectrode arrays. J Neurosci Methods. 2007, 161 (1): 118-25. 10.1016/j.jneumeth.2006.10.025.CrossRefPubMed
34.
Oulad Ben Taib N, Manto M: Effects of trains of high-frequency stimulation of the premotor/supplementary motor area on conditioned corticomotor responses in hemicerebellectomized rats. Exp Neurol. 2008, 212 (1): 157-65. 10.1016/j.expneurol.2008.03.016.CrossRefPubMed
35.
Fregni F, Liebetanz D, Monte-Silva KK, Oliveira MB, Santos AA, Nitsche MA, Pascual-Leone A, Guedes RC: Effects of transcranial direct current stimulation coupled with repetitive electrical stimulation on cortical spreading depression. Exp Neurol. 2007, 204 (1): 462-6. 10.1016/j.expneurol.2006.09.019.CrossRefPubMed
36.
Boggio PS, Bermpohl F, Vergara AO, Muniz AL, Nahas FH, Leme PB, Rigonatti SP, Fregni F: Go-no-go task performance improvement after anodal transcranial DC stimulation of the left dorsolateral prefrontal cortex in major depression. J Affect Disord. 2007, 101 (1-3): 91-8. 10.1016/j.jad.2006.10.026.CrossRefPubMed
37.
Ugawa Y, Genba-Shimizu K, Rothwell JC, Iwata M, Kanazawa I: Suppression of motor cortical excitability by electrical stimulation over the cerebellum in ataxia. Ann Neurol. 1994, 36 (1): 90-6. 10.1002/ana.410360117.CrossRefPubMed
38.
Gozariu M, Roth V, Keime F, Le Bars D, Willer JC: An electrophysiological investigation into the monosynaptic H-reflex in the rat. Brain Res. 1998, 782 (1-2): 343-7. 10.1016/S0006-8993(97)01402-9.CrossRefPubMed
39.
Ben Taib NO, Manto M, Pandolfo M, Brotchi J: Hemicerebellectomy blocks the enhancement of cortical motor output associated with repetitive somatosensory stimulation in the rat. J Physiol. 2005, 567 (Pt 1): 293-300.PubMed
40.
Ishida K, Mitoma H, Song SY, Uchihara T, Inaba A, Eguchi S, Kobayashi T, Mizusawa H: Selective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase. Ann Neurol. 1999, 46 (2): 263-7. 10.1002/1531-8249(199908)46:2<263::AID-ANA19>3.0.CO;2-0.CrossRefPubMed
41.
Mitoma H, Song SY, Ishida K, Yamakuni T, Kobayashi T, Mizusawa H: Presynaptic impairment of cerebellar inhibitory synapses by an autoantibody to glutamate decarboxylase. J Neurol Sci. 2000, 175 (1): 40-4. 10.1016/S0022-510X(00)00272-0.CrossRefPubMed
42.
Tian N, Petersen C, Kash S, Baekkeskov S, Copenhagen D, Nicoll R: The role of the synthetic enzyme GAD65 in the control of neuronal gamma-aminobutyric acid release. Proc Natl Acad Sci USA. 1999, 96 (22): 12911-6. 10.1073/pnas.96.22.12911.PubMedCentralCrossRefPubMed
43.
Wu H, Jin Y, Buddhala C, Osterhaus G, Cohen E, Jin H, Wei J, Davis K, Obata K, Wu JY: Role of glutamate decarboxylase (GAD) isoform, GAD65, in GABA synthesis and transport into synaptic vesicles-Evidence from GAD65-knockout mice studies. Brain Res. 2007, 1154: 80-3. 10.1016/j.brainres.2007.04.008.CrossRefPubMed
44.
Buddhala C, Hsu CC, Wu JY: A novel mechanism for GABA synthesis and packaging into synaptic vesicles. Neurochem Int. 2009, 55 (1-3): 9-12. 10.1016/j.neuint.2009.01.020.CrossRefPubMed
45.
Yarlagadda A, Helvink B, Chou C, Clayton AH: Blood Brain Barrier: The Role of GAD Antibodies in Psychiatry. Psychiatry (Edgmont). 2007, 4 (6): 57-9.
46.
Raju R, Rakocevic G, Chen Z, Hoehn G, Semino-Mora C, Shi W, Olsen R, Dalakas MC: Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain. 2006, 129 (Pt 12): 3270-6. 10.1093/brain/awl245.CrossRefPubMed
47.
Nitsche MA, Paulus W: Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology. 2001, 57 (10): 1899-901.CrossRefPubMed
48.
Sanes JN, Donoghue JP: Plasticity and primary motor cortex. Annu Rev Neurosci. 2000, 23: 393-415. 10.1146/annurev.neuro.23.1.393.CrossRefPubMed
Metadata
Title
Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia
Authors
Mario U Manto
Christiane S Hampe
Véronique Rogemond
Jérome Honnorat
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2011
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/1750-1172-6-3

Other articles of this Issue 1/2011

Orphanet Journal of Rare Diseases 1/2011 Go to the issue

Research

Consequences of a global enzyme shortage of agalsidase beta in adult Dutch Fabry patients

Case Report

Prenatal manifestation and management of a mother and child affected by spondyloperipheral dysplasia with a C-propeptide mutation in COL2A1: case report

Review

Atypical hemolytic uremic syndrome

Review

Autosomal recessive primary microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum

Research

A combination of transcriptome and methylation analyses reveals embryologically-relevant candidate genes in MRKH patients

Research

MR spectroscopy-based brain metabolite profiling in propionic acidaemia: metabolic changes in the basal ganglia during acute decompensation and effect of liver transplantation