To study clinicopathological parameters in a  3-generation family with high-titer anti-glutamic acid decarboxylase (GAD)  antibodies.

Sera from three family members (female index patient, her father and her paternal grandmother) were serially tested for anti-GAD  antibodies using ELISA, Western Blot (WB) and immunohistochemistry (IHC) on  mouse brain and primary hippocampal neurons. Patients were examined and their  medical histories assessed.

All patients had high-titer anti-GAD antibodies (>20,000 IU/ml-ELISA). The index patient, a 25-year-old woman, presented in 2012 with autoimmune epilepsy treated successfully with steroids and low-doses levetiracetam. Her serum immunoreacted strongly to cultured hippocampal neurons and brain cerebellum, cortex, hippocampus and striatum. By 2017, she developed typical SPS, without DM1. Her anti-GAD titers remained persistently high (2,5-4,6 x 10⁶ IU/ml) but the immunostaining intensity to hippocampal neurons, cerebellum and striatum diminished. Her father and  grandmother have DM1 with very high-GAD titers (1,8 x 10⁶ and 0,7 x 10⁶ IU/ml respectively), never observed in DM1 patients alone without neurological manifestations, up to a-5-year follow-up. Their sera did not immunostain hippocampal neurons but bound to cerebellum, similarly to the index case. Preliminary WB data on brain extracts showed the same immunoreactivity pattern, presumably recognizing linear epitopes, in all 3 patients.

This is the first family with very high anti-GAD titers in 3 generations. Whereas the index patient presented with autoimmune epilepsy that evolved into SPS without DM1, her family members had only DM1 and very high anti-GAD antibodies without neurological disease, even though their serum recognized neuronal epitopes similar to the index case. Whether patients with very high-GAD titers can develop neurological disease over a longer observational period, remains to be determined.