Immunology of stiff person syndrome and other GAD-associated neurological disorders

Abstract

Antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of GABA, are associated with an array of distinct, mostly autoimmune, neurological conditions. In all associated syndromes, namely stiff person syndrome, cerebellar ataxia, epilepsy, limbic encephalitis or abnormal eye movements, anti-GAD antibodies are detected at high titers and play a fundamental role in diagnosis, but do not correlate with disease severity, diversity of symptomatology or response to therapies. Despite considerable efforts, including in vitro (enzymatic assays) and in vivo (animal models) systems, the pathogenicity of anti-GAD antibodies has not been unequivocally proven for any specific condition. The search for the responsible autoantigen has revealed a few other antigenic targets, particularly for SPS, localized in the pre- or post-synaptic inhibitory neuronal synapses. Cumulative clinical and laboratory evidence indicates that anti-GAD and related antibodies define a novel group of syndromes, collectively known as ‘hyperexcitability disorders’.

Keywords::

• autoantibodies
• autoimmunity
• cerebellar ataxia
• epilepsy
• GABA
• GAD
• limbic encephalitis
• stiff person syndrome

Financial & competing interests disclosure

MC Dalakas serves on the Scientific Advisory Board or has received speaking honoraria from Baxter, Novartis, Grifols, CSL, Servis and Octapharma. MC Dalakas has acted as a consultant for Therapath, and has received honoraria from TAND (Therapeutic Advances in Neurological Disorders) for serving as Associate Editor. MC Dalakas has received institutional grant support to the University of Athens from Genesis, Merck-Serono and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Anti-glutamic acid decarboxylase (GAD) autoantibodies are associated with an array of distinct neurological syndromes.

• • In all of the associated syndromes (stiff person syndrome [SPS], cerebellar ataxia, epilepsy, limbic encephalitis, abnormal eye movements), anti-GAD antibodies are usually in high titer and important for diagnosis.

• • SPS patients respond to immunotherapy, especially intravenous immunoglobulin based on a controlled trial.

• • Anti-GAD antibodies do not correlate with disease severity or diversity of symptoms and are generally not useful in predicting responses to therapy.

• • Despite considerable efforts using both in vitro and in vivo systems the pathogenicity of anti-GAD antibodies has not been unequivocally proven either in SPS or in any of the other conditions.

• • A few other antigenic targets, particularly for SPS, have been identified and all localized in the pre- or post-synaptic neurons of inhibitory synapses.

Notes