Encephalitis and antibodies to dipeptidyl‐peptidase–like protein‐6, a subunit of Kv4.2 potassium channels

Abstract

Objective To report a novel cell-surface autoantigen of encephalitis that is a critical regulatory subunit of the Kv4.2 potassium channels. Methods Four patients with encephalitis of unclear etiology and antibodies with a similar pattern of neuropil brain immunostaining were selected for autoantigen characterization. Techniques included immunoprecipitation, mass spectrometry, cell-base experiments with Kv4.2 and several dipeptidyl-peptidase-like protein-6 (DPPX) plasmid constructs, and comparative brain immunostaining of wild-type and DPPX-null mice. Results Immunoprecipitation studies identified DPPX as the target autoantigen. A cell based assay confirmed that all 4 patients, but not 210 controls, had DPPX antibodies. Symptoms included agitation, confusion, myoclonus, tremor, and seizures (one case with prominent startle response). All patients had pleocytosis, and three had severe prodromal diarrhea of unknown etiology. Given that DPPX “tunes up” the Kv4.2 potassium channels (involved in somatodendritic signal integration and attenuation of dendritic backpropagation of action potentials), we determined the epitope distribution in DPPX, DPP10 (a protein homologous to DPPX) and Kv4.2. Patients’ antibodies were found specific for DPPX, without reacting with DPP10 or Kv4.2. The unexplained diarrhea led to demonstrate a robust expression of DPPX in the myenteric plexus, which strongly reacted with patients’ antibodies. The course of neuropsychiatric symptoms was prolonged and often associated with relapses while decreasing immunotherapy. Long-term follow-up showed substantial improvement in 3 patients (1 is lost to follow-up). Interpretation Antibodies to DPPX associate with a protracted encephalitis characterized by CNS hyperexcitability (agitation, myoclonus, tremor, seizures), pleocytosis, and frequent diarrhea at symptom onset. The disorder is potentially treatable with immunotherapy.

Anti-DPPX encephalitis

“…[1][2][3] DPPX is a membrane glycoprotein involved in increasing the surface expression and channel conductance of Kv4.2 channels. [4][5][6] Although its function and the expression of DPPX in *These authors contributed equally to this work.…”

“…1 An additional 3 patients with anti-DPPX antibodies and a distinct syndrome resembling progressive encephalomyelitis with rigidity and myoclonus (PERM) were subsequently described. 2 Recently, clinical features and outcomes were characterized in 20 patients with anti-DPPX encephalitis.…”

“…3 Remarkably, 14 of the 27 patients with anti-DPPX encephalitis reported so far had pronounced gastrointestinal symptoms, including severe diarrhea in 10 and constipation in 4 patients. [1][2][3] DPPX is a membrane glycoprotein involved in increasing the surface expression and channel conductance of Kv4.2 channels. [4][5][6] Although its function and the expression of DPPX in hippocampus, cerebellum, striatum, and myenteric plexus 1,7 are compatible with the clinical symptoms of anti-DPPX encephalitis, the pathogenic mechanisms of anti-DPPX antibodies have not been characterized.…”

Voltage Gated Potassium Channel Antibody Encephalitis Associated with Hyperglycemia

“…The CASPR2 subtype, on the other hand, is often responsible for the peripheral variants of this syndrome. More recently, a variant with antibodies to dipeptidyl-peptidase-like protein-6 (DPPX), a cell surface auxiliary unit of the Kv4.2 potassium channel, was reported in four patients with subacute central nervous system hyperexcitability (agitation, myoclonus, tremor and seizures) neuropsychiatric and prominent gastrointestinal symptoms [11]. There was a robust expression of this protein in the myenteric plexus, providing an explanation for the associated gastrointestinal symptoms.…”

“The more we know”

“…This disorder results in neuropsychiatric symptoms, CNS hyperexcitability (tremor, myoclonus, and seizures, among others), and frequent hyperekplexia, which may suggest the diagnosis; however, it is the accompaniment of prodromal gastrointestinal dysfunction, diarrhea, and weight loss (not cancerrelated) that commonly leads to the diagnosis. 12 The patient presented in this issue by Stoeck et al 13 had diarrhea and dramatic weight loss; she was undiagnosed for 1.5 years yet still responded to immunotherapy with azathioprine and steroids. This outcome is in contrast to that of classic paraneoplastic syndromes, which rarely respond to therapy.…”