GAD antibody-spectrum disorders: progress in clinical phenotypes, immunopathogenesis and therapeutic interventions

Abstract

Antibodies against glutamic acid decarboxylase (GAD), originally linked to stiff person syndrome (SPS), now denote the "GAD antibody-spectrum disorders" (GAD-SD) that also include autoimmune epilepsy, limbic encephalitis, cerebellar ataxia and nystagmus with overlapping symptomatology highlighting autoimmune neuronal excitability disorders. The reasons for the clinical heterogeneity among GAD-antibody associated syndromes remain still unsettled, implicating variable susceptibility of GABAergic neurons to anti-GAD or other still unidentified autoantibodies. Although anti-GAD antibody titers do not correlate with clinical severity, very high serum titers, often associated with intrathecal synthesis of anti-GAD-specific IgG, point to in-situ effects of GAD or related autoantibodies within the central nervous system. It remains, however, uncertain what drives these antibodies, why they persist and whether they are disease markers or have pathogenic potential. The review, focused on these concerns, describes the widened clinical manifestations and overlapping features of all GAD-SD; addresses the importance of GAD antibody titers and potential significance of GAD epitopes; summarizes the biologic basis of autoimmune hyperexcitability; highlights the electrophysiological basis of reciprocal inhibition in muscle stiffness; and provides practical guidelines on symptomatic therapies with gamma-aminobutyric acid-enhancing drugs or various immunotherapies.

Keywords: GAD autoimmunity; autoantibodies; cerebellar ataxia; encephalitis; hyperexcitability; stiff person syndrome.

Figure 1.

Reciprocal inhibition and stiffness generation in stiff person syndrome patients. (a) Normal function: when one muscle is contracted, its antagonist is automatically inhibited. Afferent Ia sensory neuron fires, bringing information to the spinal cord, and stimulates the gamma neurons. Then, the gamma-motor neurons of the agonist muscle send signals to the spindle to contract [1], while the gamma motor neurons of the antagonist muscle do not discharge (X) due to inhibition of GABA interneuron [3]. As a result, the alpha-motor neuron of antagonist stretches (relaxes) the muscle (2) (interneuron: releases inhibitory mediators).(b) Pathology: if the motor neuron is continuously firing signals, while there is no inhibition of the GABA interneuron to the antagonist muscle, the whole muscle will continuously be stimulated and will become hypertonic (spastic), without the ability to stretch (relax), due to concurrent contraction of the agonist and the antagonist muscles, as happens in stiff person syndrome that presents with stiffness and hyperexcitability.

Figure 2.

Autoantigenic targets associated with the Central Nervous System inhibitory synapses in patients with stiff person syndrome. The pre-synaptic antigens are GAD (1), the enzyme that synthesizes GABA, the main inhibitory neurotransmitter, and amphiphysin (2), a synaptic vesicle protein responsible for endocytosis of plasma membranes following GABA release. Post-synaptically, the main targets are GABA-A Receptor Associated Protein (GABARAP) (3), gephyrin (4), a tubulin-binding protein needed for clustering both GABA-A (5) and glycine receptors (6). The most common antigen in stiff person syndrome is GAD followed by glycine receptor (vesicular inhibitory amino acid transporter; VIAAT). Modified from Dalakas. GABA, gamma-aminobutyric acid; GAD, glutamic acid decarboxylase.