High titers of autoantibodies to glutamate decarboxylase in type 1 diabetes patients: epitope analysis and inhibition of enzyme activity

Autoantibodies to glutamate decarboxylase (GAD65Ab) are found in patients with autoimmune neurological disorders or type 1 diabetes. The correct diagnosis of GAD65Ab-associated neurological disorders is often delayed by the variability of symptoms and a lack of diagnostic markers. We hypothesized that the frequency of neurological disorders with high GAD65Ab titers is significantly higher than currently recognized. We analyzed GAD65Ab titer, GAD65 enzyme activity inhibition, and GAD65Ab epitope pattern in a cohort of type 1 diabetes patients (n = 100) and correlated our findings with neurological symptoms and diseases. Overall, 43% (43/100) of patients had detectable GAD65Ab titers (median = 400 U/mL, range: 142-250,000 U/mL). The GAD65Ab titers in 10 type 1 diabetes patients exceeded the 90th percentile of the cohort (2,000-250,000 U/mL). Sera of these 10 patients were analyzed for their GAD65Ab epitope specificity and their ability to inhibit GAD65 enzyme activity in vitro. GAD65Ab of 5 patients inhibited the enzyme activity significantly (by 34-55%). Three patients complained of muscle stiffness and pain, which was documented in 2 of these patients. Based on our findings, we suggest that neurological disorders with high GAD65Ab titers are more frequent in type 1 diabetes patients than currently recognized.