Although
antibodies against
Glutamic Acid Decarboxylase (GAD) were originally associated with
Stiff Person Syndrome (SPS), they now denote the "GAD antibody-spectrum disorders (GAD-SD)" that include
Cerebellar Ataxia, Autoimmune
Epilepsy,
Limbic Encephalitis, PERM and
eye movement disorder. In spite of the unique clinical phenotype that each of these disorders has, there is significant overlapping symptomatology characterized by autoimmune neuronal excitability. In addition to GAD, three other
autoantibodies, against
glycine receptors,
amphiphysin and
gephyrin, are less frequently or rarely associated with SPS-SD. Very high serum anti-GAD antibody titers are a key diagnostic feature for all GAD-SD, commonly associated with the presence of GAD
antibodies in the CSF, a reduced CSF
GABA level and increased anti-GAD-specific
IgG intrathecal synthesis denoting stimulation of B-cell clones in the CNS. Because anti-GAD
antibodies from the various hyperexcitability syndromes recognize the same dominant GAD
epitope, the clinical heterogeneity among GAD-SD patients remains unexplained. The paper highlights the
biologic basis of autoimmune hyperexcitability connected with the phenomenon of reciprocal inhibition as the fundamental mechanism of the patients' muscle stiffness and
spasms; addresses the importance of high-GAD antibody titers in diagnosis, pinpointing the diagnostic challenges in patients with low-GAD titers or their distinction from functional disorders; and discusses whether high GAD-
antibodies are disease markers or pathogenic in the context of their association with reduced
GABA level in the brain and CSF. Finally, it focuses on
therapies providing details on symptomatic
GABA-enhancing drugs and the currently available
immunotherapies in a step-by-step approach. The prospects of future immunotherapeutic options with antibody
therapies are also summarized.