William Oliver Tobin1, Vanda A Lennon1, Lars Komorowski1, Christian Probst1, Stacey Lynn Clardy1, Allen J Aksamit1, Juan Pablo Appendino1, Claudia F Lucchinetti1, Joseph Y Matsumoto1, Sean J Pittock1, Paola Sandroni1, Maja Tippmann-Peikert1, Elaine C Wirrell1, Andrew McKeon2. 1. From the Departments of Neurology (W.O.T., V.A.L., S.L.C., A.J.A., C.F.L., J.Y.M., S.J.P., P.S., M.T.-P., E.C.W., A.M.), Laboratory Medicine and Pathology (V.A.L., S.J.P., A.M.), Immunology (V.A.L.), and Pediatrics (E.C.W.), College of Medicine, Mayo Clinic, Rochester, MN; Euroimmun AG (L.K., C.P.), Lübeck, Germany; and Neurology (J.P.A.), Faculty of Medicine, University of Manitoba, Canada. 2. From the Departments of Neurology (W.O.T., V.A.L., S.L.C., A.J.A., C.F.L., J.Y.M., S.J.P., P.S., M.T.-P., E.C.W., A.M.), Laboratory Medicine and Pathology (V.A.L., S.J.P., A.M.), Immunology (V.A.L.), and Pediatrics (E.C.W.), College of Medicine, Mayo Clinic, Rochester, MN; Euroimmun AG (L.K., C.P.), Lübeck, Germany; and Neurology (J.P.A.), Faculty of Medicine, University of Manitoba, Canada. mckeon.andrew@mayo.edu.
Abstract
OBJECTIVE: To describe the detection frequency and clinical associations of immunoglobulin G (IgG) targeting dipeptidyl-peptidase-like protein-6 (DPPX), a regulatory subunit of neuronal Kv4.2 potassium channels. METHODS: Specimens from 20 patients evaluated on a service basis by tissue-based immunofluorescence yielded a synaptic immunostaining pattern consistent with DPPX-IgG (serum, 20; CSF, all 7 available). Transfected HEK293 cell-based assay confirmed DPPX specificity in all specimens. Sixty-nine patients with stiff-person syndrome and related disorders were also evaluated by DPPX-IgG cell-based assay. RESULTS: Of 20 seropositive patients, 12 were men; median symptom onset age was 53 years (range, 13-75). Symptom onset was insidious in 15 and subacute in 5. Twelve patients reported prodromal weight loss. Neurologic disorders were multifocal. All had one or more brain or brainstem manifestations: amnesia (16), delirium (8), psychosis (4), depression (4), seizures (2), and brainstem disorders (15; eye movement disturbances [8], ataxia [7], dysphagia [6], dysarthria [4], respiratory failure [3]). Nine patients reported sleep disturbance. Manifestations of central hyperexcitability included myoclonus (8), exaggerated startle (6), diffuse rigidity (6), and hyperreflexia (6). Dysautonomia involved the gastrointestinal tract (9; diarrhea [6], gastroparesis, and constipation [3]), bladder (7), cardiac conduction system (3), and thermoregulation (1). Two patients had B-cell neoplasms: gastrointestinal lymphoma (1), and chronic lymphocytic leukemia (1). Substantial neurologic improvements followed immunotherapy in 7 of 11 patients with available treatment data. DPPX-IgG was not detected in any of the stiff-person syndrome patients. CONCLUSIONS: DPPX-IgG is a biomarker for an immunotherapy-responsive multifocal neurologic disorder of the central and autonomic nervous systems.
OBJECTIVE: To describe the detection frequency and clinical associations of immunoglobulin G (IgG) targeting dipeptidyl-peptidase-like protein-6 (DPPX), a regulatory subunit of neuronal Kv4.2 potassium channels. METHODS: Specimens from 20 patients evaluated on a service basis by tissue-based immunofluorescence yielded a synaptic immunostaining pattern consistent with DPPX-IgG (serum, 20; CSF, all 7 available). Transfected HEK293 cell-based assay confirmed DPPX specificity in all specimens. Sixty-nine patients with stiff-person syndrome and related disorders were also evaluated by DPPX-IgG cell-based assay. RESULTS: Of 20 seropositive patients, 12 were men; median symptom onset age was 53 years (range, 13-75). Symptom onset was insidious in 15 and subacute in 5. Twelve patients reported prodromal weight loss. Neurologic disorders were multifocal. All had one or more brain or brainstem manifestations: amnesia (16), delirium (8), psychosis (4), depression (4), seizures (2), and brainstem disorders (15; eye movement disturbances [8], ataxia [7], dysphagia [6], dysarthria [4], respiratory failure [3]). Nine patients reported sleep disturbance. Manifestations of central hyperexcitability included myoclonus (8), exaggerated startle (6), diffuse rigidity (6), and hyperreflexia (6). Dysautonomia involved the gastrointestinal tract (9; diarrhea [6], gastroparesis, and constipation [3]), bladder (7), cardiac conduction system (3), and thermoregulation (1). Two patients had B-cell neoplasms: gastrointestinal lymphoma (1), and chronic lymphocytic leukemia (1). Substantial neurologic improvements followed immunotherapy in 7 of 11 patients with available treatment data. DPPX-IgG was not detected in any of the stiff-person syndromepatients. CONCLUSIONS:DPPX-IgG is a biomarker for an immunotherapy-responsive multifocal neurologic disorder of the central and autonomic nervous systems.
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