To expand the clinical spectrum of neurological autoimmunity associated with antibodies to phosphodiesterase 10A (PDE10A-IgG) and explore pathogenic mechanisms.

We reviewed all PDE10A-IgG-positive cases (2017-2025) from a neural antibody clinical service laboratory. PDE10A-IgG was identified by the typical basal ganglia-predominant murine-brain tissue indirect immunofluorescence and confirmed by cell-based assay. CSF binding to live and fixed rat hippocampal neurons was used to assess antibody pathogenic potential; cytotoxic T-cell responses were evaluated with activation-induced marker assays.

Twenty-three cases with clinical data available were identified (eight previously published). Median age was 69 years (range 48-81); 52% were female. Malignancy was found in 76% (16/21) of those assessed, most commonly renal cell carcinoma. Immune checkpoint inhibitors (ICIs) were used prior to symptom onset in 8/21 (38%). Clinical presentations included encephalopathy in 12/23 (52%), movement disorders in 9/23 (39%), peripheral nervous system symptoms in 5/23 (22%), and ataxia or seizures in 2/23 each (9%). PDE10A-IgG were thought to be relevant for either neurological or oncological associations in 18/23 (78%). CSF from seven patients did not bind live neuronal cultures; three of these were tested on fixed cultures and showed staining that colocalized with a commercial PDE10A-IgG. Of three patients tested, one demonstrated a PDE10A-specific T-cell response.

While some PDE10A-IgG-positive patients present with autoimmune movement disorders, potentially reflecting injury to PDE10A-expressing basal ganglia neurons, in others antibodies likely represent a marker of cancer and/or ICI exposure. The lack of binding in live cultures, along with preliminary evidence of a PDE10A-specific T-cell response, favor a cytotoxic rather than antibody-mediated pathomechanism in the former group.