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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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).
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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The authors declare that they have no conflicts of interest.
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
- Glutamic-acid decarboxylase
- Limbic encephalitis
- Cerebellar ataxia
- Stiff-person syndrome