Abstract
Objectives
To explore different neurological manifestations with suspicion of being associated to serum glutamate decarboxylase antibodies (GAD-Abs) in order to better characterize anti-GAD neurological syndromes.
Methods
Observational retrospective study including all patients for whom GAD65-Abs titers in serum were requested by the Neurology Department at La Paz University Hospital between 2015 and 2019. GAD-Abs were measured by ELISA. Demographic data, neurological symptoms, comorbidity with diabetes mellitus (DM) or with another autoimmune disease, and GAD-Abs titers were studied. Stiff-person syndrome, ataxia, encephalitis, and epilepsy were considered typical anti-GAD neurological syndromes and were compared to other atypical manifestations.
Results
A total of 173 patients (51.7% men, mean age 51.62) were included. A progressive increase in requests of serum GAD-Abs has occurred over the last 5 years, especially in patients with atypical neurological manifestations. GAD-Abs were found in the serum of 22 patients (12.7%); of those, 15 (68.18%) suffered a typical anti-GAD syndrome. Presence of DM or another organ-specific autoimmune disease was predictive of GAD-AB seropositivity (p < 0.001). 6.6% of requested patients with an atypical syndrome had GAD-Abs, but serum levels were significantly lower than those found in patients with a typical syndrome (706.67 vs 1430.23 UI/mL; Mann-Whitney U, p = 0.034), and were finally diagnosed with another neurological disease.
Conclusion
Serum GAD-Abs were infrequently found in patients with clinical phenotypes other than those classically described as anti-GAD disorders, and with very low titers. In typical anti-GAD syndromes, there is a high comorbidity with DM and with other autoimmune diseases, and high serum GAD-Abs levels are usually present.





References
Solimena M, Folli F, Denis-Donini S, Comi GC, Pozza G, De Camilli P, Vicari y AM (1988) Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med 318(16):1012–1020. https://doi.org/10.1056/NEJM198804213181602
Blum P, Jankovic y J (1991) Stiff-person syndrome: an autoimmune disease. Mov Disord 6(1):12–20. https://doi.org/10.1002/mds.870060104
Honnorat J, Trouillas P, Thivolet C, Aguera M, Belin y M-F (1995) Autoantibodies to glutamate decarboxylase in a patient with cerebellar cortical atrophy, peripheral neuropathy, and slow eye movements. Arch Neurol 52(5):462–468. https://doi.org/10.1001/archneur.1995.00540290050017
Saiz A, Arpa J, Sagasta A, Casamitjana R, Zarranz JJ, Tolosa E, Graus y F (1997) Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin-dependent diabetes mellitus, and polyendocrine autoimmunity. Neurology 49(4):1026–1030. https://doi.org/10.1212/WNL.49.4.1026.5
Giometto B, Nicolao P, Macucci M, Tavolato B, Foxon R, Bottazzo y G (1998) Temporal-lobe epilepsy associated with glutamic-acid-decarboxylase autoantibodies. Lancet 352(9126):457. https://doi.org/10.1016/S0140-6736(05)79192-3
fPeltola J, Kulmala P, Isojarvi J, Saiz A, Latvala K, Palmio J, Savola K, Knip M, Keranen T, Graus y F (2000) Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy. Neurology 55(1):46–50. https://doi.org/10.1212/WNL.55.1.46
Sharma (2012) GAD65 positive autoimmune limbic encephalitis: a case report and review of literature. J Clin Med Res. https://doi.org/10.4021/jocmr1080w
Jensen K, Beylergil SB, Shaikh y AG (2019) Slow saccades in cerebellar disease. Cerebellum & Ataxias 6(1):1. https://doi.org/10.1186/s40673-018-0095-9
Velardo D, Nuara A, Martinelli V, Comi G, Fazio y R (2015) Anti-GAD antibody-positive myoclonic leg jerks. Neurol Sci 36(4):647–648. https://doi.org/10.1007/s10072-014-2058-0
Pietrini V, Pavesi G, Andreetta y F (2013) Miller Fisher syndrome with positivity of anti-GAD antibodies. Clin Neurol Neurosurg 115(8):1479–1481. https://doi.org/10.1016/j.clineuro.2012.11.008
Barbagallo G, Arabia G, Valentino P, Rodolico C, Quattrone y A (2015) Anti-GAD-associated inflammatory myopathy presenting with dropped head syndrome. Neurol Sci 36(8):1517–1519. https://doi.org/10.1007/s10072-015-2185-2
Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki y H (2002) GABA and GABA receptors in the central nervous system and other organs. En International Review of Cytology 213:1–47. Elsevier. https://doi.org/10.1016/S0074-7696(02)13011-7
Tohid H (2016) Anti-glutamic acid decarboxylase antibody positive neurological syndromes. Neurosciences 21(3):215–222. https://doi.org/10.17712/nsj.2016.3.20150596
Dinkel K, Meinck HM, Jury KM, Karges W, Richter y W (1998) Inhibition of gamma-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol 44(4):194–201. https://doi.org/10.1002/ana.410440209
Hansen N, Grünewald B, Weishaupt A, Colaço MN, Toyka KV, Sommer C, Geis y C (2013) Human stiff person syndrome IgG-containing high-titer anti-GAD65 autoantibodies induce motor dysfunction in rats. Exp Neurol 239:202–209. https://doi.org/10.1016/j.expneurol.2012.10.013
Hampe CS, Petrosini L, De Bartolo P, Caporali P, Cutuli D, Laricchiuta D, Foti F et al (2013) Monoclonal antibodies to 65kDa glutamate decarboxylase induce epitope specific effects on motor and cognitive functions in rats. Orphanet Journal of Rare Diseases 8:82. https://doi.org/10.1186/1750-1172-8-82
Gresa-Arribas N, Ariño H, Martínez-Hernández E, Petit-Pedrol M, Sabater L, Saiz A, Dalmau J, Graus y F (2015) Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity. Editado por Klemens Ruprecht. PLoS One 10(3):e0121364. https://doi.org/10.1371/journal.pone.0121364
Tuomi T (2005) Type 1 and type 2 diabetes: what do they have in common? Diabetes 54(Supplement 2):S40–S45. https://doi.org/10.2337/diabetes.54.suppl_2.S40
Nakajima H, Nakamura Y, Inaba Y, Tsutsumi C, Unoda K, Hosokawa T, Kimura F, Hanafusa T, Date M, Kitaoka y H (2018) Neurologic disorders associated with anti-glutamic acid decarboxylase antibodies: a comparison of anti-GAD antibody titers and time-dependent changes between neurologic disease and type I diabetes mellitus. J Neuroimmunol 317:84–89. https://doi.org/10.1016/j.jneuroim.2018.01.007
Vianello M, Keir G, Giometto B, Betterle C, Tavolato B, Thompson y EJ (2005) Antigenic differences between neurological and diabetic patients with anti-glutamic acid decarboxylase antibodies. Eur J Neurol 12(4):294–299. https://doi.org/10.1111/j.1468-1331.2004.00933.x
Manto M, Honnorat J, Hampe CS, Guerra-Narbona R, López-Ramos JC, Delgado-García JM, Saitow F et al (2015) Disease-specific monoclonal antibodies targeting glutamate decarboxylase impair GABAergic neurotransmission and affect motor learning and behavioral functions. Front Behav Neurosci 9. https://doi.org/10.3389/fnbeh.2015.00078
Ariño H, Höftberger R, Gresa-Arribas N, Martínez-Hernández E, Armangue T, Kruer MC, Arpa J et al (2015) Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies. JAMA Neurology 72(8):874. https://doi.org/10.1001/jamaneurol.2015.0749
Baizabal-Carvallo JF (2019) The neurological syndromes associated with glutamic acid decarboxylase antibodies. J Autoimmun 101:35–47. https://doi.org/10.1016/j.jaut.2019.04.007
Meinck H-M (2001) Antibodies against glutamic acid decarboxylase: prevalence in neurological diseases. J Neurol Neurosurg Psychiatry 71(1):100–103. https://doi.org/10.1136/jnnp.71.1.100
Muñoz-Lopetegi A, de Bruijn MAAM, Boukhrissi S, Bastiaansen AEM, Nagtzaam MMP, Hulsenboom ESP, Boon AJW et al (2020) Neurologic syndromes related to anti-GAD65: clinical and serologic response to treatment. Neurology - Neuroimmunology Neuroinflammation 7(3):e696. https://doi.org/10.1212/NXI.0000000000000696
Nemni R, Braghi S, Natali-Sora MG, Lampasona V, Bonifacio E, Comi G, Canal y N (1994) Autoantibodies to glutamic acid decarboxylase in palatal myoclonus and epilepsy. Ann Neurol 36(4):665–667. https://doi.org/10.1002/ana.410360419
Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R, Ramió-Torrentà L, Graus y F (2008) Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain 131(10):2553–2563. https://doi.org/10.1093/brain/awn183
Lastras Fernández-Escandón C, Lacruz Ballester L, Pastor Yvorra S, Rodríguez Fraga O, Rodríguez de Rivera Garrido F.J, Puertas I, Alonso Singer P, Fuentes Gimeno, B. (2019).Anticuerpos anti-GAD como causa de un síndrome neurológico: ¿cuándo y por qué debemos sospecharlo?. En E.Díez Tejedor (Presidencia), LXXI Reunión Anual de la Sociedad Española de Neurología. Reunión llevada a cabo en Sevilla, España.
Graus F, Saiz A, Dalmau y J (2020) GAD antibodies in neurological disorders — insights and challenges. Nat Rev Neurol 26. https://doi.org/10.1038/s41582-020-0359-x
Vulliemoz S, Vanini G, Truffert A, Chizzolini C, Seeck y M (2009) Epilepsy and cerebellar ataxia associated with anti-glutamic acid decarboxylase antibodies. Case Reports 2009(1):bcr0920080977. https://doi.org/10.1136/bcr.09.2008.0977
Takagi M, Yamasaki H, Endo K, Yamada T, Kaneko K, Oka Y, Mori y E (2011) Cognitive decline in a patient with anti-glutamic acid decarboxylase autoimmunity; case report. BMC Neurol 11:156. https://doi.org/10.1186/1471-2377-11-156
Çoban A, Küçükali Cİ, Bilgiç B, Yalçınkaya N, Haytural H, Ulusoy C, Turan S et al (2014) Evaluation of incidence and clinical features of antibody-associated autoimmune encephalitis mimicking dementia. Behav Neurol. https://doi.org/10.1155/2014/935379
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Informed consents are not required in view of the retrospective nature of the study and all the procedures being performed were part of the routine care, and as long as information is anonymized and the submission does not include images that may identify the person.
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Ethical approval was obtained from the Local Ethics Committee of La Paz University Hospital (Date 8/10/2019; N° PI-3818).
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Lacruz Ballester, L., Fernandez-Fournier, M., Puertas Muñoz, I. et al. Serum glutamate decarboxylase antibodies and neurological disorders: when to suspect their association?. Neurol Sci 43, 633–641 (2022). https://doi.org/10.1007/s10072-021-05281-4
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DOI: https://doi.org/10.1007/s10072-021-05281-4