Objective: We aimed to establish a method for measuring anti-Sez6l2 antibody and to clarify how many patients with anti-Sez6l2 antibody-associated cerebellar ataxia (CA) exist in Japan and its clinical features.

Background: CA can be categorized by its mechanisms into hereditary, infectious, drug-induced, neurodegenerative and immune-mediated. Immune-mediated cerebellar ataxias (IMCAs) are very important to distinguish these mechanisms in CA patients. We detected anti-Sez6l2 antibody in a patient with subacute CA and retinopathy in 2014 for the first time in the world. We showed that the Sez6l2 protein binds directly to the AMPA receptor and that the Sez6l2 antibody inhibits the binding. After that, 6 CA cases with anti-Sez6l2 antibody were reported by other research groups in Europe. The Sez6l2 protein has been reported to be involved in complementation and to be a prognostic factor in malignant diseases.

Method: We used a cell-based assay (CBA) of HEK293T cells transfected with Sez6l2 to evaluate the serum of 162 patients with cerebellar ataxia in whom other neuronal antibodies had not been detected and 77 patients with different neurologic disorders such as multiple system atrophy. We performed immunoblot analysis as an additional study in 8 of those using Sez6l2 protein.

Results: Anti-Sez6l2 antibodies were identified by the CBA and immunoblot analysis using FLAG-Sez6l2 in 2 of the 162 patients with CA but in none of the 77 controls. On the other hand, these 2 cases were negative in a CBA of HEK293T cells transfected with FLAG-TRIM67, which was reported to be one of the autoantibodies for CA. Those 2 patients were both middle-aged males. One patient had subacute gait ataxia and the other patient had subacute dysarthria. Both of the patients showed cerebellar atrophy at the initial visit, and mild elevation of CSF protein was found in one patient. The first patient we reported in 2014 was followed up for 11 years. The symptoms in that patient had not worsened and that is not a typical clinical course of multiple system atrophy.

Conclusion: We showed two more patients with anti-Sez6l2 antibody-associated CA in Japan. Since immunotherapy may improve the symptoms, it is useful to measure this antibody for correct diagnosis and therapy. We should evaluate anti-Sez6l2 antibody in patients with subacute CA.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/japanese-cases-of-sez6l2-autoimmunity/