Pyruvate dehydrogenase autoantibodies in autoantibody-negative patients with seizures are associated with reduced pyruvate dehydrogenase activity.

objectiveWe investigated the presence and potential functional relevance of antimitochondrial autoantibodies in patients suspicious for autoimmune encephalitis (AIE) associated with psychiatric symptoms and/or seizures, who were negative for known antineuronal autoantibodies.

methodsWe screened serum samples from 387 patients autoantibody-negative for known antineuronal autoantibodies with psychiatric disturbances and/or epileptic seizures, including patients with temporal lobe epilepsy of unknown etiology. Various techniques, including immunoblotting, immunoprecipitation, mass spectrometry, immunohistochemistry, and in vitro assays assessing neuronal autoantibody uptake, neuronal viability, pyruvate dehydrogenase (PDH) enzyme activity, and mitochondrial DNA levels in biofluids were applied.

resultsMass spectrometry detected all three subunits of the intramitochondrial PDHc-pyruvate dehydrogenase, dihydrolipoyl acetyltransferase, and dihydrolipoyl dehydrogenase-as targets of antibodies present in serum samples from three index patients suspicious for AIE with psychiatric symptoms or seizures. The presence of the anti-PDHc autoantibodies was confirmed by immunoblotting in 12 of 387 patients. Exposure of cultured primary neurons to commercial anti-PDH antibodies resulted in neuronal uptake and loss of neuronal viability. Patient-derived autoantibodies also impaired PDH enzyme activity in vitro. Additionally, cell-free mitochondrial DNA fragment levels were elevated in the serum and cerebrospinal fluid of PDH-positive patients compared to controls. SIGNIFICANCE: Anti-PDH autoantibodies were detected in patients suspicious for AIE with seizures and/or psychiatric symptoms as core manifestation in the absence of known antineuronal autoantibodies. These autoantibodies bind neuronal structures and reduce PDH enzyme activity under experimental conditions, supporting mechanistic plausibility of a functional role in disease.