Clinical Spectrum of SEZ6L2 Autoimmunity: A Case Report and Systematic Review
Clinical Snapshot
PICO Framework
| P — Population | Patients with SEZ6L2 autoimmunity presenting with neurological symptoms |
| I — Intervention | Immunotherapy (primarily intravenous immunoglobulin) |
| C — Comparator | No specific comparator (descriptive systematic review) |
| O — Outcomes | Clinical phenotype characterization, treatment response, functional improvement measured by Brief Ataxia Rating Scale |
Bottom Line
This systematic review characterizes SEZ6L2 autoimmunity as a rare but treatable cause of subacute cerebellar ataxia. The condition typically affects older adults (median age 60) with a female predominance, presenting with cerebellar dysfunction, cognitive impairment (78.9%), and parkinsonism (42.1%). While the evidence base is limited to 19 cases, the consistent phenotype and immunotherapy responsiveness (47.4% partial improvement) make this an important differential diagnosis. Australian clinicians should consider SEZ6L2 antibody testing in patients with subacute cerebellar ataxia, especially when accompanied by cognitive decline or movement disorders. Early recognition enables prompt immunotherapy initiation, though treatment responses are often partial. The rarity of this condition necessitates high clinical suspicion and specialized laboratory testing for diagnosis.
Key Findings
P Value: Not applicable (descriptive study)
Effect Size: 47.4% of patients showed partial improvement with immunotherapy
Primary Outcome: Clinical phenotype of SEZ6L2 autoimmunity characterized in 19 patients
Nnt Or Sensitivity: Treatment response rate: 47.4% partial improvement
Confidence Interval: Not reported
Clinical Application
SEZ6L2 antibody testing available in specialized laboratories; IVIg readily accessible Relevant to Australian neurologists; IVIg covered by PBS for autoimmune neurological conditions; testing available through specialized immunology laboratories Patients presenting with subacute cerebellar ataxia, particularly with cognitive dysfunction or parkinsonism
Abstract
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.
References
- 1.Hoshina, Y., Kobayashi, G., & Reda, H. (2026). Clinical spectrum of SEZ6L2 autoimmunity: A case report and systematic review. Cerebellum, advance online publication. https://doi.org/10.1016/j.neulet.2018.07.005
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