DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients

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.

Figure 1. Synaptic pattern of DPPX immunoreactivity in mouse central and enteric nervous system revealed by IgG in serum or CSF of patients by tissue immunofluorescence assay

(A) IgG binds more prominently to the cerebellar granular layer (G) than molecular layer (M); Purkinje neurons are not reactive. (B) In hippocampus (Hi), the mossy fibers of the stratum lucidum (arrows) stain most brightly. In the cerebrum (C), the cortex (Cx) and striatum (S) are reactive. (D) IgG binds to ganglionic neurons in the myenteric plexus of the gut wall (arrowheads). DPPX = dipeptidyl-peptidase-like protein-6; IgG = immunoglobulin G.

Figure 2. Patient 14: Radiologic evidence of gastrointestinal hypomotility

The patient defecated at 3-week intervals. Coronal (A), and axial (B and C) CT of the abdomen demonstrates marked gastric distension (A and B), and gross colonic loading with feces (A and C). Fluorodeoxyglucose (FDG)-PET demonstrates retention of food bolus in the gastric fundus secondary to gastroparesis, as well as normal excretion of FDG by the kidneys into the bladder (D).