GAD65Ab Autoantibody Sheds Light on Epilepsy's Etiologies

Approximately 20% of patients with epilepsy have a co-occurring autoimmune disorder, and autoantibodies directed against the smaller isoform of glutamate decarboxylase (GAD65Ab) have been found in patients with epilepsy, as well as in patients with stiff person syndrome and type 1 diabetes.

Approximately 20% of patients with epilepsy have a co-occurring autoimmune disorder, and autoantibodies directed against the smaller isoform of glutamate decarboxylase (GAD65Ab) have been found in patients with epilepsy, as well as in patients with stiff person syndrome (SPS, a rare disorder characterized by fluctuating muscle rigidity and heightened sensitivity to stimuli) and type 1 diabetes (T1D). The fact that epilepsy is 4- to 6-fold more prevalent among patients with T1D than the general population has led researchers to investigate the possible role of these GAD65Ab in these diseases.

Researchers, reporting findings in the Orphanet Journal of Rare Diseases, collected sera from patients with autoimmune epilepsy (n = 38) from the T1D Exchange program at 3 centers in Finland, France, and the United States. Ten of these patients also had T1D. Sera from 42 patients with T1D who did not have other autoimmune disorders and sera from 20 patients with SPS were also collected.

In examining these sera, the researchers found that the GAD65Ab titers of patients with T1D were lower than those of patients with SPS or epilepsy. An epitope analysis showed that the GAD65Ab epitopes recognized among the groups had notable differences; GAD65Ab in patients with T1D recognized epitopes in the middle region, while in SPS, they preferably bound to epitopes at the C-terminus and N-terminus. In patients with autoimmune epilepsy, GAD65Ab shared some characteristics with GAD65Ab present in patients with SPS. However, they did not recognize the linear epitope at amino acids 4 to 22, while GAD65Ab in patients with SPS did.

The researchers also found that the sera of all patients with SPS inhibited GAD65 enzyme activity, while only 69% of the sera from patients with epilepsy did so, leading them to conclude that GAD65Ab differs significantly in the different disease states.

They also concluded that patients who are diagnosed with both T1D and epilepsy may present 2 different epileptic etiologies; in the former group, T1D may co-occur with nonautoimmune epilepsy, and the latter group may have an underlying autoimmune component that contributes to the epileptic condition. Patients who fall into this second group, suggest the authors, may benefit from immunotherapy even if they do not respond well to conventional antiepileptic drugs.

Reference

Liimatainen S, Honnorat J, Pittock SJ, McKeon A, Manto M, Radtke JR. GA65 autoantibody characteristics in patients with co-occurring type 1 diabetes and epilepsy may help identify underlying epilepsy etiologies. Orphanet J Rare Dis. 2018;13(55). doi: 10.1186/s13023-018-0787-5.