Autoimmune channelopathies in paraneoplastic neurological syndromes.

Paraneoplastic neurological syndromes and autoimmune encephalitides are immune neurological disorders occurring or not in association with a cancer. They are thought to be due to an autoimmune reaction against neuronal antigens ectopically expressed by the underlying tumour or by cross-reaction with an unknown infectious agent. In some instances, paraneoplastic neurological syndromes and autoimmune encephalitides are related to an antibody-induced dysfunction of ion channels, a situation that can be labelled as autoimmune channelopathies. Such functional alterations of ion channels are caused by the specific fixation of an autoantibody upon its target, implying that autoimmune channelopathies are usually highly responsive to immuno-modulatory treatments. Over the recent years, numerous autoantibodies corresponding to various neurological syndromes have been discovered and their mechanisms of action partially deciphered. Autoantibodies in neurological autoimmune channelopathies may target either directly ion channels or proteins associated to ion channels and induce channel dysfunction by various mechanisms generally leading to the reduction of synaptic expression of the considered channel. The discovery of those mechanisms of action has provided insights on the regulation of the synaptic expression of the altered channels as well as the putative roles of some of their functional subdomains. Interestingly, patients' autoantibodies themselves can be used as specific tools in order to study the functions of ion channels. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

Acquired neuromyotonia heralding recurrent thymoma in myasthenia gravis.

IMPORTANCE: Acquired neuromyotonia is increasingly recognized as an autoimmune disorder, frequently associated with antibodies against voltage-gated potassium channel complex proteins.We present a case of acquired neuromyotonia as the heralding symptom of recurrent thymoma in a patient with myasthenia gravis. OBSERVATIONS: A report of a single case of a 53-year-old man with myasthenia gravis and a prior thymectomy presenting with 2 months of diffuse, involuntary muscle twitching in the absence of myasthenic symptoms, electrophysiologically confirmed to be neuromyotonia. Further evaluation revealed the recurrence of malignant thymoma, accompanied by refractory arrhythmia. Serologic and cerebrospinal fluid testing confirmed the presence of antibodies directed against 2 voltage-gated potassium channel­associated proteins: LGI1 and Caspr2. CONCLUSIONS AND RELEVANCE: This case highlights the overlap of myasthenia, neuromyotonia, and thymoma, emphasizing the importance of appropriate tumor screening in the presence of either of the former 2 conditions.

Role of Kenae/CCDC125 in cell motility through the deregulation of RhoGTPase.

Isaac's syndrome is a movement disorder characterized by hyperexcitability of peripheral motor nerves. Patients with Isaac's syndrome often develop auto-antibodies to voltage-gated potassium channels (VGKCs) which block their function. However, anti-VGKC antibodies are not detected in all patients with Isaac's syndrome, suggesting the existence of another etiology. In this study, we performed immunoscreening using the serum from a patient with Isaac's syndrome and identified the novel gene named Kenae/CCDC125. Expression analysis of Kenae/CCDC125 revealed that its transcript was highly expressed in tissues associated with the immune system, such as the thymus, spleen and bone marrow. In cells stably expressing Kenae/CCDC125, delay in cell motility and deregulation of RhoGTPase (RhoA, Rac1 and cdc42) activity to extracellular stimuli were demonstrated. These results suggest that the novel gene, Kenae/CCDC125, acts as a regulator of cell motility through RhoA, Rac1 and cdc42.

A defective SERCA1 protein is responsible for congenital pseudomyotonia in Chianina cattle.

Recently, a muscular disorder defined as "congenital pseudomyotonia" was described in Chianina cattle, one of the most important Italian cattle breeds for quality meat and leather. The clinical phenotype of this disease is characterized by an exercise-induced muscle contracture that prevents animals from performing muscular activities. On the basis of clinical symptoms, Chianina pseudomyotonia appeared related to human Brody's disease, a rare inherited disorder of skeletal muscle function that results from a sarcoplasmic reticulum Ca(2+)-ATPase (SERCA1) deficiency caused by a defect in the ATP2A1 gene that encodes SERCA1. SERCA1 is involved in transporting calcium from the cytosol to the lumen of the sarcoplasmic reticulum. Recently, we identified the genetic defect underlying Chianina cattle pseudomyotonia. A missense mutation in exon 6 of the ATP2A1 gene, leading to an R164H substitution in the SERCA1 protein, was found. In this study, we provide biochemical evidence for a selective deficiency in SERCA1 protein levels in sarcoplasmic reticulum membranes from affected muscles, although mRNA levels are unaffected. The reduction of SERCA1 levels accounts for the reduced Ca(2+)-ATPase activity without any significant change in Ca(2+)-dependency. The loss of SERCA1 is not compensated for by the expression of the SERCA2 isoform. We believe that Chianina cattle pseudomyotonia might, therefore, be the true counterpart of human Brody's disease, and that bovine species might be used as a suitable animal model.

Mechanism of action of voltage-gated K+ channel antibodies in acquired neuromyotonia.

Acquired neuromyotonia (ANM) is associated with antibodies to voltage-gated K+ channels (VGKCs). ANM sera reduce the number of K+ currents in neuronal cell lines, but it is not clear how the antibodies act. Here, we show by using the NB-1 cell line that the reduction in K+ currents by IgG is independent of added complement. IgG Fc and Fab fragments from ANM sera had no effect, but three of four ANM F(ab')2 fragments significantly reduced K+ currents. Thus, cross-linking of the channels by divalent antibodies is likely to be an important mechanism in reducing K+ currents.