Abstract
BackgroundAutoantibodies against the smaller isoform of glutamate decarboxylase (GAD65Ab) reflect autoimmune etiologies in Type 1 diabetes (T1D) and several neurological disorders, including Stiff Person Syndrome (SPS). GAD65Ab are also reported in cases of epilepsy, indicating an autoimmune component. GAD65Ab in patients with co-occurring T1D, epilepsy or SPS may be part of either autoimmune pathogenesis. To dissect the etiologies associated with GAD65Ab, we analyzed GAD65Ab titer, epitope specificity and enzyme inhibition in GAD65Ab-positive patients diagnosed with epilepsy (n = 28), patients with epilepsy and T1D (n = 10), patients with SPS (n = 20), and patients with T1D (n = 42).ResultsGAD65Ab epitope pattern in epilepsy differed from T1D and SPS patients. Four of 10 patients with co-occurring T1D and epilepsy showed GAD65Ab profiles similar to T1D patients, while lacking GAD65Ab characteristics found in GAD65Ab-positive epilepsy patients. One of these patients responded well to anti-epileptic drugs (AEDs), while another patient did not require medication for seizure control. The third patient was refractory due to a diagnosis of meningioma. The response of the remaining patient to AEDs was unknown. GAD65Ab in the remaining six patients with T1D and epilepsy showed profiles similar to those in epilepsy patients.ConclusionsDifferent autoimmune responses associated with T1D, epilepsy and SPS are reflected by disease-specific GAD65Ab patterns. Moreover, the epileptic etiology in patients diagnosed with both T1D and epilepsy may present two different etiologies regarding their epileptic condition. In one group T1D co-occurs with non-autoimmune epilepsy. In the other group GAD65Ab are part of an autoimmune epileptic condition.
Highlights
Autoantibodies against the smaller isoform of glutamate decarboxylase (GAD65Ab) reflect autoimmune etiologies in Type 1 diabetes (T1D) and several neurological disorders, including Stiff Person Syndrome (SPS)
Autoimmune epilepsy is prevalent in patients with refractory seizures [3, 4] and the underlying autoimmune etiology may contribute to the failure of anti-epileptic drug treatment in these patients
Binding of GAD65Ab in patients with epilepsy was significantly more reduced by recombinant Fab (rFab) DPD, and b78 as compared to patients with T1D, while binding was less reduced by rFab 221–442 and rFab DPC
Summary
Autoantibodies against the smaller isoform of glutamate decarboxylase (GAD65Ab) reflect autoimmune etiologies in Type 1 diabetes (T1D) and several neurological disorders, including Stiff Person Syndrome (SPS). The observation that nearly 20% of patients with epilepsy have a coexisting autoimmune disorder has led to the hypothesis of an autoimmune mechanism contributing to the pathogenesis of some forms of epilepsy [1, 2]. GAD65 autoimmunity may exert epileptogenic activity by decreasing the conversion of glutamate into GABA, and/or interference with the release of GABAergic synaptic vesicles, increasing the dominance of excitatory neurotransmitters [15]. Such interference with GABAergic neurotransmission in the hippocampus is supported by studies carried out in hippocampal neurons incubated with GAD65Ab-positive sera from patients with epilepsy [16]
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