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GAD antibodies in neurological disorders — insights and challenges

Nature Reviews Neurology volume 16, pages 353–365 (2020)Cite this article

Subjects

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.

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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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Authors and Affiliations

  1. Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain

    Francesc Graus, Albert Saiz & Josep Dalmau

  2. Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain

    Albert Saiz

  3. Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA

    Josep Dalmau

  4. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    Josep Dalmau

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  1. Francesc Graus
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  2. Albert Saiz
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All authors contributed equally to all stages of preparing this manuscript.

Corresponding author

Correspondence to Josep Dalmau.

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Competing interests

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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