Case report plus systematic review (19 patients) describing SEZ6L2 autoimmunity as a rare cause of subacute cerebellar ataxia frequently accompanied by cognitive dysfunction and parkinsonism, with ~47% showing partial improvement after immunotherapy.

Identifies an antibody-associated, immunotherapy-responsive syndrome that can present with parkinsonism and cognitive decline, offering a diagnostic biomarker (SEZ6L2 antibodies) and a potential immunomodulatory treatment angle for a subset of PD-like presentations.

Since the initial report of seizure‑related 6 homolog-like 2 (SEZ6L2) autoimmunity in a patient with cerebellar ataxia and retinopathy, subsequent reports have expanded the phenotype. Although rare, timely recognition is essential because this condition is immunotherapy-responsive. To describe a case of SEZ6L2 autoimmunity and conduct a systematic review (2014-2025) to characterize this rare disease. An 87-year-old man presented with subacute gait disturbance and cognitive decline, progressing to wheelchair dependence within 4 months. Examination showed dysarthria, appendicular and axial ataxia, dysmetria, tremor, and postural instability. Brief Ataxia Rating Scale (BARS) was 19.5. CSF studies and brain MRI were unremarkable, whereas FDG-PET demonstrated diffuse cerebellar hypometabolism. Malignancy screening was negative. After empiric intravenous immunoglobulin (IVIg) 2 g/kg, SEZ6L2 antibody assays returned positive in serum and CSF. Monthly IVIg was continued with mild improvement (BARS 18 at 7 months). Systematic review identified 12 articles (18 patients). Including our case, 19 patients (median age 60 years, 63% female) were analyzed. All had subacute cerebellar ataxia. Cognitive dysfunction and Parkinsonism were seen in 78.9% and 42.1%, respectively. Other symptoms included depression, pyramidal signs, nausea, tremor, sleep disturbance, and dysautonomia. Treatment was heterogeneous, with 47.4% showing partial improvement. SEZ6L2 autoimmunity is a rare, immunotherapy-responsive cause of subacute cerebellar ataxia, often with parkinsonism and cognitive changes. Presentations may extend beyond these manifestations.