Mutations in the gene encoding the K ϩ channel KCNQ2 cause neonatal epilepsy and myokymia, indicating that KCNQ2 regulates the excitability of CNS neurons and motor axons, respectively. We show here that KCNQ2 channels are functional components of axon initial segments and nodes of Ranvier, colocalizing with ankyrin-G and voltage-dependent Na ϩ channels throughout the CNS and PNS. Retigabine, which opens KCNQ channels, diminishes axonal excitability. Linopirdine, which blocks KCNQ channels, prolongs the repolarization of the action potential in neonatal nerves. The clustering of KCNQ2 at nodes and initial segments lags that of ankyrin-G during development, and both ankyrin-G and KCNQ2 can be coimmunoprecipitated in the brain. KCNQ3 is also a component of some initial segments and nodes in the brain. The diminished activity of mutant KCNQ2 channels accounts for neonatal epilepsy and myokymia; the cellular locus of these effects may be axonal initial segments and nodes.

Objective: We report the clinical and serologic features of Japanese patients with chronic inflammatory demyelinating polyneuropathy (CIDP) displaying anti-neurofascin-155 (NF155) immunoglobulin G4 (IgG4) antibodies. Methods:In sera from 533 patients with CIDP, anti-NF155 IgG4 antibodies were detected by ELISA. Binding of IgG antibodies to central and peripheral nerves was tested.Results: Anti-NF155 IgG4 antibodies were identified in 38 patients (7%) with CIDP, but not in disease controls or normal participants. These patients were younger at onset as compared to 100 anti-NF155-negative patients with CIDP. Twenty-eight patients (74%) presented with sensory ataxia, 16 (42%) showed tremor, 5 (13%) presented with cerebellar ataxia associated with nystagmus, 3 (8%) had demyelinating lesions in the CNS, and 20 of 25 (80%) had poor response to IV immunoglobulin. The clinical features of the antibody-positive patients were statistically more frequent as compared to negative patients with CIDP (n 5 100). Anti-NF155 IgG antibodies targeted similarly central and peripheral paranodes.Conclusion: Anti-NF155 IgG4 antibodies were associated with a subgroup of patients with CIDP showing a younger age at onset, ataxia, tremor, CNS demyelination, and a poor response to IV immunoglobulin. The autoantibodies may serve as a biomarker to improve patients' diagnosis and guide treatments. Neurology ® 2016;86:800-807 GLOSSARY Caspr1 5 contactin-associated protein-1; CCPD 5 combined central and peripheral demyelination; CI 5 confidence interval; CIDP 5 chronic inflammatory demyelinating polyneuropathy; CNTN1 5 contactin 1; GBS 5 Guillain-Barré syndrome; IgG4 5 immunoglobulin G4; IVIg 5 IV immunoglobulin; MS 5 multiple sclerosis; NF155 5 neurofascin-155; OR 5 odds ratio; PNS 5 peripheral nervous system.Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common acquired immune-mediated neuropathy worldwide and is clinically heterogeneous.1 Proven treatments for CIDP include corticosteroids, plasma exchange, and IV immunoglobulin (IVIg). However, the response rates to treatments are highly heterogeneous between patients. This emphasizes that patients and clinicians require biomarkers to identify CIDP subgroups and guide specific immunotherapeutic options.Immunoglobulin G4 (IgG4) autoantibodies to neurofascin-155 (NF155) were recently documented in patients with CIDP.2,3 NF155 belongs to the L1 family of adhesion molecules and is expressed at paranodes by the terminal loops of myelin and associates with the axonal cell adhesion molecules CNTN1 and contactin-associated protein-1 (Caspr1). 4 This ternary complex of glycoproteins is required for the rapid propagation of the nerve impulses along myelinated axons. 5,6 Three of 4 patients with anti-NF155 IgG4 showed disabling tremor and all showed poor response to IVIg. 3 This suggested that IgG4 autoantibodies participate in CIDP pathogenesis; nonetheless, the low number of reactive patients precluded statistical correlation.

Chronic inflammatory demyelination polyneuropathy is a heterogeneous and treatable immune-mediated disorder that lacks biomarkers to support diagnosis. Recent evidence indicates that paranodal proteins (contactin 1, contactin-associated protein 1, and neurofascin-155) are the targets of autoantibodies in subsets of patients showing distinct clinical presentations. Here, we identified neurofascin-186 and neurofascin-140 as the main targets of autoantibodies in five patients presenting IgG reactivity against the nodes of Ranvier. Four patients displayed predominantly IgG4 antibodies, and one patient presented IgG3 antibodies that activated the complement pathway in vitro. These patients present distinct clinical features compared to those with anti-neurofascin-155 IgG4. Most patients had a severe phenotype associated with conduction block or decreased distal motor amplitude. Four patients had a subacute-onset and sensory ataxia. Two patients presented with nephrotic syndromes and one patient with an IgG4-related retroperitoneal fibrosis. Intravenous immunoglobulin and corticosteroids were effective in three patients, and one patient remitted following rituximab treatment. Clinical remission was associated with autoantibody depletion and with recovery of conduction block and distal motor amplitude suggesting a nodo-paranodopathy. Our data demonstrate that the pathogenic mechanisms responsible for chronic inflammatory demyelination polyneuropathy are broad and may include dysfunctions at the nodes of Ranvier in a subgroup of patients.