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Abstract
Objectives: To identify an autoreactivity in a 66-year-old woman who presented with combined brainstem and cerebellar syndrome including vertical gaze palsy, severe progressive ataxia, and spastic tetraparesis, an acute deterioration of vision, dysarthria, and dysphagia with concurrent diagnosis of a colon adenocarcinoma.
Methods: Patient's serum and CSF underwent comprehensive autoantibody screening by indirect immunofluorescence assay and immunoblot. For autoantigen purification, a histo-immunoprecipitation technique was developed followed by mass spectrometrical analysis. Recombinant candidate antigens were expressed in HEK293 and used to verify the identification.
Results: Indirect immunofluorescence assay screening revealed strong immunoglobulin G reactivity with neural tissues in serum and CSF, but not with a panel of 28 recombinantly expressed established neural autoantigens. The hitherto unknown target antigen was identified as the neuronal Na+/K+ ATPase. Epitope mapping and competitive inhibition experiments showed that the autoantibodies were directed against the membrane-spanning alpha 3 subunit (ATP1A3) of the enzyme but did not bind to extracellular epitopes. Immunohistochemical analysis revealed overexpression of this subunit in the patient's tumor.
Conclusions: We describe a case of an anti-ATP1A3–associated neurologic disorder. Mutations in the gene encoding this neuronal surface protein have already been recognized as the cause of infantile alternating hemiplegia, rapid-onset dystonia parkinsonism, and CAPOS syndrome. Although the autoantibodies are unlikely to be pathogenic, they are likely to be rare biomarkers for the apparently paraneoplastic neurologic syndrome or for the tumor itself.
GLOSSARY
- ATPase=
- adenosine triphosphatase;
- ATP1A3=
- alpha 3 subunit of neuronal Na+/K+ ATPase;
- ATP1B1=
- beta 1 subunit of Na+/K+ ATPase;
- ATP1G=
- gamma subunit of Na+/K+ ATPase;
- ATP4=
- gastric H+/K+ ATPase;
- ATP4A=
- alpha subunit of ATP4;
- ATP4B=
- beta subunit of ATP4;
- CAPOS=
- cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss;
- IFA=
- indirect immunofluorescence assay;
- IgG=
- immunoglobulin G;
- PBS=
- phosphate-buffered saline;
- PCA=
- parietal cell antigen;
- SDS-PAGE=
- sodium dodecyl sulfate–polyacrylamide gel electrophoresis
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at Neurology.org
- Received August 18, 2014.
- Accepted in final form January 12, 2015.
- © 2015 American Academy of Neurology
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