Neurologic syndromes related to anti-GAD65

Antibodies against glutamic-acid-decarboxylase 65 (anti-GAD65) are associated with several neurologic syndromes, including stiff person syndrome and limbic encephalitis. However, their pathogenic role remains controversial. A group led by Dr. Maarten Titulaer (Erasmus University, the Netherlands) studied the clinical relevance of different anti-GAD65 concentrations in patients with neurological disorders and their response to treatment.

The group showed that patients with high anti-GAD65 concentrations presented with a limited number of neurologic syndromes, including stiff person syndrome, cerebellar ataxia, epilepsy, and limbic encephalitis. The patients with low concentrations of anti-GAD65 presented with a broader scope of neurologic symptoms. Immunotherapy was effective in 2/3 of the patients with a high concentration of anti-GAD65 antibodies, although none of them made a complete recovery. The clinical improvement was reflected in a reduction of anti-GAD65 concentrations in both serum and CSF.

There still is a lot unknown as to the role GAD65 antibodies play in neuroinflammation. Antibodies that block GAD65 could interfere with GABA (gamma-aminobutyric acid) synthesis and impair the inhibitory effect GABA has on the CNS. However, GAD65 is located in the cell and may not be easily accessible for extracellular antibodies. There are also no successful animal models to support the pathogenicity of GAD65 antibodies in the brain. Moreover, several studies report poor responses to immunotherapy targeting different GAD65 syndromes compared to other neurological disorders caused by antibodies targeting extracellular neuronal structures. Again, questioning the direct pathogenic effect of the GAD65 antibody.

Even though the mechanism and role of the anti-GAD65 antibody remains unclear, the results of this study showed improvement after several rounds of immunotherapy in patients with high concentrations of anti-GAD65 with specific neurologic disorders, including limbic encephalitis. The group would consider repeated doses or combinations of different treatments to better evaluate outcomes, even though results should be weighed carefully as this was a partially retrospective and unblinded study without a proper control therapy.

GAD is a crucial enzyme involved in the production of a neurotransmitter named GABA. GABA is the major inhibitory neurotransmitter in the CNS. Functions of GABA are closely related to mood and emotions. It acts as a brake to excitatory neurotransmitters; thus, when it is abnormally low, this can lead to anxiety. It is widely distributed in the brain and plays a principal role in reducing neuronal excitability throughout the nervous system.

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