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Familial autoimmunity in neurological patients with GAD65 antibodies: an interview-based study

Abstract

The common co-occurrence of autoimmune systemic diseases in patients with neurological disorders and antibodies against glutamic acid decarboxylase 65 (GAD65) suggests a shared genetic predisposition to these disorders. However, the nature and frequency of familial aggregation of autoimmune diseases, which might also support this hypothesis, have been poorly investigated. Herein, an exploratory, interview-based study was conducted with the aim of describing the autoimmune diseases displayed by the relatives of GAD65 neurological patients, their frequency, kinship, and potential patterns of inheritance. Patients were enrolled only if they had GAD65 antibodies in the cerebrospinal fluid and typical clinical phenotypes associated with such antibodies (stiff-person syndrome, cerebellar ataxia, limbic encephalitis, or temporal lobe epilepsy). A total of 65 patients were included in the study, and 44/65 (67.7%) reported family history of autoimmunity, including first-degree relatives in 36/65 (55.4%); the sibling recurrence risk (λS) was 5.5, reinforcing the hypothesis of an underlying strong genetic predisposition. Most pedigrees with familial autoimmunity (38/44, 86.4%) showed multiple autoimmune diseases, all but 2 of them with diabetes mellitus or autoimmune thyroid disease, therefore resembling autoimmune polyendocrine syndromes. Inheritance patterns were diverse, possibly autosomal dominant in 17/44 (38.6%) pedigrees or autosomal recessive in 5/44 (11.4%), and un-defined or complex in 24/44 (54.5%). However, a total of 21/65 (32.3%) patients had no identified family history of autoimmunity. In conclusion, these results suggest a variable and heterogeneous genetic predisposition to GAD65 neurological disorders, possibly involving multiple loci and modes of inheritance with different contribution in each family.

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References

  1. 1.

    Dalakas MC, Fujii M, Li M, McElroy B (2000) The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology 55:1531–1535. https://doi.org/10.1212/wnl.55.10.1531

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Martinez-Hernandez E, Ariño H, McKeon A et al (2016) Clinical and immunologic investigations in patients with stiff-person spectrum disorder. JAMA Neurol 73:714. https://doi.org/10.1001/jamaneurol.2016.0133

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Honnorat J, Saiz A, Giometto B et al (2001) Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol 58:225–230. https://doi.org/10.1001/archneur.58.2.225

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Ariño H, Gresa-Arribas N, Blanco Y et al (2014) Cerebellar ataxia and glutamic acid decarboxylase antibodies: immunologic profile and long-term effect of immunotherapy. JAMA Neurol 71:1009. https://doi.org/10.1001/jamaneurol.2014.1011

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Malter MP, Helmstaedter C, Urbach H et al (2010) Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 67:470–478. https://doi.org/10.1002/ana.21917

    Article  PubMed  Google Scholar 

  6. 6.

    García García ME, Castrillo SM, Morales IG et al (2013) Acute amnesia and seizures in a young female. Epileptic Disord 15:455–460. https://doi.org/10.1684/epd.2013.0607

    Article  PubMed  Google Scholar 

  7. 7.

    Joubert B, Belbezier A, Haesebaert J et al (2020) Long-term outcomes in temporal lobe epilepsy with glutamate decarboxylase antibodies. J Neurol. https://doi.org/10.1007/s00415-020-09807-2

    Article  PubMed  Google Scholar 

  8. 8.

    Saiz A, Blanco Y, Sabater L et al (2008) Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain 131:2553–2563. https://doi.org/10.1093/brain/awn183

    Article  PubMed  Google Scholar 

  9. 9.

    Gresa-Arribas N, Ariño H, Martínez-Hernández E et al (2015) Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity. PLoS ONE 10:e0121364. https://doi.org/10.1371/journal.pone.0121364

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Muñoz-Lopetegi A, de Bruijn MAAM, Boukhrissi S et al (2020) Neurologic syndromes related to anti-GAD65: clinical and serologic response to treatment. Neurol Neuroimmunol Neuroinflammation 7:e696. https://doi.org/10.1212/NXI.0000000000000696

    Article  Google Scholar 

  11. 11.

    Burns TM, Jones HR, Phillips LH et al (2003) Clinically disparate stiff-person syndrome with GAD65 autoantibody in a father and daughter. Neurology 61:1291–1293. https://doi.org/10.1212/01.wnl.0000092016.98256.21

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Kuchling J, Shababi-Klein J, Nümann A et al (2014) GAD Antibody-associated late-onset cerebellar ataxia in two female siblings. Case Rep Neurol 6:264–270. https://doi.org/10.1159/000369784

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Xiao Z, Shan J, Huang X et al (2015) Familial case reports of stiff-person syndrome. Clin Neurophysiol 126:2408–2409. https://doi.org/10.1016/j.clinph.2015.03.010

    Article  PubMed  Google Scholar 

  14. 14.

    Belbezier A, Joubert B, Montero-Martin G et al (2018) Multiplex family with GAD65-Abs neurologic syndromes. Neurol - Neuroimmunol Neuroinflammation 5:e416. https://doi.org/10.1212/NXI.0000000000000416

    Article  Google Scholar 

  15. 15.

    Saiz A, Arpa J, Sagasta A et al (1997) Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin-dependent diabetes mellitus, and polyendocrine autoimmunity. Neurology 49:1026–1030. https://doi.org/10.1212/WNL.49.4.1026

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Fourlanos S, Dotta F, Greenbaum CJ et al (2005) Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia 48:2206–2212. https://doi.org/10.1007/s00125-005-1960-7

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Risch N (1990) Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet 46:222–228

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Cooper GS, Stroehla BC (2003) The epidemiology of autoimmune diseases. Autoimmun Rev 2:119–125. https://doi.org/10.1016/s1568-9972(03)00006-5

    Article  PubMed  Google Scholar 

  19. 19.

    Muñiz-Castrillo S, Ambati A, Dubois V et al (2020) Primary DQ effect in the association between HLA and neurological syndromes with anti-GAD65 antibodies. J Neurol 267:1906–1911. https://doi.org/10.1007/s00415-020-09782-8

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Cárdenas-Roldán J, Rojas-Villarraga A, Anaya J-M (2013) How do autoimmune diseases cluster in families? A systematic review and meta-analysis. BMC Med 11:73. https://doi.org/10.1186/1741-7015-11-73

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Michels AW, Gottlieb PA (2010) Autoimmune polyglandular syndromes. Nat Rev Endocrinol 6:270–277. https://doi.org/10.1038/nrendo.2010.40

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Husebye ES, Anderson MS, Kämpe O (2018) Autoimmune polyendocrine syndromes. N Engl J Med 378:2543–2544. https://doi.org/10.1056/NEJMc1805308

    Article  PubMed  Google Scholar 

  23. 23.

    Kopczak A, Schumacher A-M, Nischwitz S et al (2017) GAD antibody-associated limbic encephalitis in a young woman with APECED. Endocrinol Diabetes Metab Case Rep. https://doi.org/10.1530/EDM-17-0010

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Cervato S, Mariniello B, Lazzarotto F et al (2009) Evaluation of the autoimmune regulator (AIRE) gene mutations in a cohort of Italian patients with autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) and in their relatives. Clin Endocrinol (Oxf) 70:421–428. https://doi.org/10.1111/j.1365-2265.2008.03318.x

    Article  Google Scholar 

  25. 25.

    Oftedal BE, Hellesen A, Erichsen MM et al (2015) Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases. Immunity 42:1185–1196. https://doi.org/10.1016/j.immuni.2015.04.021

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Kim T-J, Lee S-T, Moon J et al (2017) Anti-LGI1 encephalitis is associated with unique HLA subtypes: HLA Subtypes in Anti-LGI1 Encephalitis. Ann Neurol 81:183–192. https://doi.org/10.1002/ana.24860

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    van Sonderen A, Roelen DL, Stoop JA et al (2017) Anti-LGI1 encephalitis is strongly associated with HLA-DR7 and HLA-DRB4: Anti-LGI1 Encephalitis. Ann Neurol 81:193–198. https://doi.org/10.1002/ana.24858

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Binks SNM, Klein CJ, Waters P et al (2018) LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes. J Neurol Neurosurg Psychiatry 89:526–534. https://doi.org/10.1136/jnnp-2017-315720

    Article  PubMed  Google Scholar 

  29. 29.

    Muñiz-Castrillo S, Joubert B, Elsensohn M-H et al (2020) Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features. J Neurol Neurosurg Psychiatry 91:1076–1084. https://doi.org/10.1136/jnnp-2020-323226

    Article  PubMed  Google Scholar 

  30. 30.

    Thaler FS, Bangol B, Biljecki M et al (2020) Possible link of genetic variants to autoimmunity in GAD-antibody-associated neurological disorders. J Neurol Sci 413:116860. https://doi.org/10.1016/j.jns.2020.116860

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Redondo MJ, Hagopian WA, Oram R et al (2020) The clinical consequences of heterogeneity within and between different diabetes types. Diabetologia 63:2040–2048. https://doi.org/10.1007/s00125-020-05211-7

    Article  PubMed  Google Scholar 

  32. 32.

    American Diabetes Association (2020) 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2020. Diabetes Care 43:S14–S31. https://doi.org/10.2337/dc20-S002

    Article  Google Scholar 

  33. 33.

    Mishra R, Hodge KM, Cousminer DL et al (2018) A global perspective of latent autoimmune diabetes in adults. Trends Endocrinol Metab TEM 29:638–650. https://doi.org/10.1016/j.tem.2018.07.001

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Hjort R, Alfredsson L, Andersson T et al (2017) Family history of type 1 and type 2 diabetes and risk of latent autoimmune diabetes in adults (LADA). Diabetes Metab 43:536–542. https://doi.org/10.1016/j.diabet.2017.05.010

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Cervin C, Lyssenko V, Bakhtadze E et al (2008) Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes. Diabetes 57:1433–1437. https://doi.org/10.2337/db07-0299

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Mishra R, Chesi A, Cousminer DL et al (2017) Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes. BMC Med 15:88. https://doi.org/10.1186/s12916-017-0846-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Cousminer DL, Ahlqvist E, Mishra R et al (2018) First genome-wide association study of latent autoimmune diabetes in adults reveals novel insights linking immune and metabolic diabetes. Diabetes Care 41:2396–2403. https://doi.org/10.2337/dc18-1032

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We want to thank all the patients for their participation, as well as Pr Achille Aouba (CHU Caen), Dr Alexandre Bonnet (CHU Rennes), Dr Svetoslav Botev (CH Chartres), Dr Christophe Breuilly (CH Cornouaille), Dr Philippe Casenave (CH Libourne), Dr Emmanuel Chatelus (CHRU Strasbourg), Dr Laurence Chaton (CHRU Lille), Dr Sakahla Conde (CHU Clermont-Ferrand), Dr Coline Duwicquet (CHU Tours), Pr Alain Créange (APHP Henri Mondor), Dr Pauline Cuisenier-Maillot (CHU Grenoble), Dr Aude Doan (CHU Rouen), Dr Serge Evrard (Hôpital Foch), Dr Lou Grangeon (CHU Rouen), Dr Déborah Grosset-Janin (CH Annecy), Dr Antoine Gueguen (Fondation Rothschild), Dr Alexandre Halb (CHU Besançon), Pr Jean-Luc Houeto (CHU Poitiers), Dr Ahmed Idbaih (APHP Pitié-Salpêtrière), Dr Ioana Maria Ion (CHU Nimes), Dr Valérie Jaillon-Rivière (CHU Caen), Dr Anne-Laure Kaminsky (CHRU Nancy), Dr Louis-Charles Kraidy (CHU Cocody), Pr Laurent Magy (CHU Limoges), Dr Solveig Montaut (CHRU Strasbourg), Dr Thierry Muller (CH Verdun Saint-Michel), Dr Maud Pallix-Guyot (CHR Orleans), Dr Jeremie Papassin (CHU Grenoble), Pr Jérémie Pariente (CHU Toulouse), Dr Claire Ricordeau (CHU Rennes), Dr Audrey Riou (CHU Rennes), Dr Claudia Vaduva (CH Saint Brieuc), Dr Mathieu Vaillant (CHU Grenoble), Pr Marie Vidailhet (APHP Pitié-Salpêtrière). We thank Hélène Boyer for help in manuscript preparation (Direction de la Recherche Clinique, Hospices Civils de Lyon).

Funding

This work has been developed within the BETPSY project, which is supported by a public grant overseen by the Agence Nationale de la Recherche (ANR, French national research agency), as part of the second “Investissements d´Avenir” program (Reference ANR-18-RHUS-0012). SM-C is supported by a research grant from Fundación Alfonso Martín Escudero (Spain).

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Contributions

Study conception and design: SM-C and JH. Acquisition of data: SM-C, AV, CM, BJ, MB, OC, HC, LH, H-ML, VN, BT, RU, DG, NF, FD, CJ, and JH. Analysis and interpretation of data: SM-C, AV, CM, CJ, and JH. Drafting of the manuscript: SM-C and JH. Critical revision of the manuscript for important intellectual content: SM-C, AV, CM, BJ, MB, OC, HC, LH, H-ML, VN, BT, RU, DG, NF, FD, CJ, and JH. Study supervision: JH. All authors read and approved the final manuscript.

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Correspondence to Jérôme Honnorat.

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All procedures were performed in accordance with the institutional ethics committee and the Declaration of Helsinki.

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Muñiz-Castrillo, S., Vogrig, A., Montagnac, C. et al. Familial autoimmunity in neurological patients with GAD65 antibodies: an interview-based study. J Neurol 268, 2515–2522 (2021). https://doi.org/10.1007/s00415-021-10424-w

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Keywords

  • Glutamic-acid decarboxylase
  • Antibodies
  • Limbic encephalitis
  • Cerebellar ataxia
  • Stiff-person syndrome
  • Genetics