Authors :
Presenting Author: Annika Breuer, M.Sc. – University Hospital Bonn
Tobias Baumgartner, Department of Epileptology – University Hospital Bonn; Albert Becker, Department of Neuropathology – University Hospital Bonn; Juliane Berns, Department of Epileptology – University Hospital Bonn; Chiara Hummel, Department of Epileptology; Department of Neuropathology – University Hospital Bonn; Wolfram Kunz, Inst. of Experimental Epileptology and Cognition Research – University Hospital Bonn; Julika Pitsch, Department of Epileptology – University Hospital Bonn; Afaf Said, Inst. of Experimental Epileptology and Cognition Research – University Hospital Bonn; Susanne Schoch, Department of Neuropathology – University Hospital Bonn; Rainer Surges, Department of Epileptology – University Hospital Bonn
Rationale: Mutations in pyruvate dehydrogenase (PDH) A1
, the gene encoding the PDH E1 subunit, and the resulting mitochondrial dysfunction have been associated with epilepsy. On the other hand, specific anti-mitochondrial autoantibodies (AMAs) have so far not been associated with epilepsy, therefore, patients which presented with a differential diagnosis of autoimmune encephalitis and with psychiatric symptoms and/or seizures were screened for the presence and functional relevance of specific AMAs directed against the PDH complex. The aim of this study was to decipher their possible role in the onset, progression and prognosis of the disease.Methods: We screened for anti-PDH autoantibodies in serum samples from 565 patients who presented to the University Hospital of Bonn, Germany, with clinical symptoms of autoimmune encephalitis, manifested by either psychiatric symptoms and/or epileptic seizures, but without any known pathogenic autoantibody present. Patients with temporal lobe epilepsy (TLE) of unknown aetiology were also included. We combined a variety of approaches including immunoblotting, immunoprecipitation, mass spectrometry, immunohistochemistry, and
in vitro assays of neuronal uptake, viability, and PDH enzyme activity.
Results: All three subunits of the intramitochondrial PDH complex, pyruvate dehydrogenase, dihydrolipoyl acetyltransferase and dihydrolipoyl dehydrogenase, were identified as target proteins by mass spectrometry in serum samples from three different index patients with psychiatric symptoms or seizures and suspected autoimmune encephalitis. Subsequently, a total of 17 patients in our cohort were identified as positive for anti-PDH complex autoantibodies by immunoblotting. Localization of the target structures in the brain revealed that the PDH complex is widely distributed in the cortex, cerebellum and hippocampus as well as at pre- and postsynapses of inhibitory and excitatory neurons. Finally, exposure to specific anti-PDH antibodies leads to neuronal uptake and impaired enzyme activity
in vitro.
Conclusions: Anti-PDH complex autoantibodies appear to play a functional role in patients with suspected autoimmune encephalitis who present with psychiatric symptoms and/or epileptic seizures as core manifestation.
Funding: This work was supported by the German Research Foundation (SFB1089, FOR2715), Else Kröner-Fresenius-Stiftung, and the BONFOR programme of the University Hospital Bonn.