A 38-year-old man was admitted for acute onset of headache, nausea, vomiting, and confusion. He rapidly developed a pancerebellar syndrome and complex partial seizures with secondary generalization. Neurological examination demonstrated drowsiness, dysarthria, bilateral horizontal nystagmus, moderate limb dysmetria, and gait ataxia. Optic fundus examination disclosed bilateral papilledema. Lumbar puncture revealed elevated opening pressure (36 cm H2O), mild pleocytosis (white blood cell count, 60/μL [to convert to ×109 per liter, multiply by 0.001], 78% lymphocytes), elevated protein level (0.111 g/dL; to convert to grams per liter, multiply by 10), negative oligoclonal bands, and normal IgG index. Results on brain magnetic resonance imaging (MRI) and screening for antigliadin antibodies, viral and bacterial infections, tumor, and systemic, metabolic, and thyroid diseases were negative. The patient was treated with cycles of intravenous immunoglobulins and steroids with partial improvement. Later, he received oral steroids for 24 months. Currently, the patient is on a daily dose of 7.5 mg of prednisone. He has mild dysarthria and gait ataxia, but he is able to walk without help and can independently carry out basic daily activities. Repeated screening for neoplasia has been negative, and the last brain MRI showed mild atrophy of the vermis and cerebellar hemispheres (Figure 1). Results of screening the patient's serum (CSF was not available) for antibodies to neuronal cell surface antigens (N -methyl-D-aspartate receptor [NMDAR], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor [AMPAR], γ-aminobutyric acid B receptor [GABABR], mGluR1, mGluR5, leucine-rich glioma inactivated 1 [LGI1], and contactin-associated protein 2 [Caspr2]), onconeural antigens (Hu, Yo, Ri, CV2, Tr, amphiphysin, and Ma2), and glutamic acid decarboxylase were negative. Indirect immunohistochemistry on rat brain sections showed an intense immunostaining of the molecular layer of the cerebellum and weaker reactivity with the cytoplasm of Purkinje cells. This pattern of immunostaining was identical to that seen in a previous patient with Homer-3 antibodies.6 To confirm the presence of these antibodies, we developed an immunoblot with purified Homer-3 protein fused with a glutathione S-transferase tag. Briefly, the complementary DNA fragment encoding the Homer-3 was subcloned to the pGEX-4T3 plasmid (GE Healthcare Life Sciences) that contains a glutathione S-transferase tag. Glutathione sepharose 4B (GE Healthcare Life Sciences) was used to purify the expressed protein. Immunoblot with purified Homer-3 showed that the patient's serum identified a protein band of 73 kDa corresponding to Homer-3 (Figure 2A). A similar band was identified using serum of the previously described patient with Homer-3 and a commercial Homer-3 antibody (Santa Cruz Biotechnology, Inc) but was not identified with 45 control serum samples, including samples from patients with ataxia (23 samples) and healthy subjects (22 samples). Positive serum samples did not recognize the glutathione S-transferase tag (Figure 2B).