| Summary: | <p>Voltage-gated potassium channel antibodies (VGKC-Abs) have been described in a spectrum of immunotherapy-responsive neurological diseases. These include neuromyotonia (NMT), a peripheral nervous system disease, limbic encephalitis (LE) a central nervous system disease, and Morvan's syndrome which affects both the peripheral and central nervous systems. Occasionally, these diseases can be associated with tumours. VGKC-Abs are defined by their ability to precipitate VGKCs from 2% digitonin-solubilised rabbit brain membranes labelled with <sup>125</sup>I-α-dendrotoxin. α-dendrotoxin is known to bind Kv1.1, 1.2 and 1.6. We asked whether the clinical heterogeneity could be explained by the specificity of the patient antibodies for the different Kv1 channels.</p><p>We received clinical data regarding 113 VGKC-antibody positive cases: 78 had LE/Epilepsy, 17 had NMT, 13 had MoS and five had other syndromes. In addition, we collected clinical data about 26 patients with a unique form of dystonic epilepsy in association with VGKC-Abs.</p><p>Surprisingly, a series of biochemical and immunohistochemical experiments in both brain tissue and in Kv1-transfected cells showed that potassium channels were the target of only 3% of the 113 'VGKC'-Ab positive sera. We proposed that the 'VGKC'-antibodies were not directed against Kv1s but against other proteins in the <sup>125</sup>I-α-dendrotoxin labelled rabbit brain complexes.</p><p>Lgi1 (leucine-rich glioma inactivated 1), CASPR2 (contactin-associated protein 2) and contactin-2 were found within these complexes and, when individually expressed in a heterologous mammalian cell line, were found to be the direct target of the 'VGKC'-Abs. Lgi1-antibodies were found in 58% of the cases with LE/Epilepsy, 71% of the dystonic epilepsy patients and 15% of the MoS cases. By contrast, CASPR2 antibodies were found in 85% of the MoS, 61% of the NMT and 12% of the LE/Epilepsy cases. CASPR2 antibodies had a 99% negative predictive value for the presence of an underlying tumour. Contactin-2 antibodies were found uniquely in 2 of 113 cases.</p><p>These findings describe novel antigenic targets which help to explain the clinical heterogeneity seen in 'VGKC-complex'-antibody associated diseases. In addition, they offer a method to predict the cases with underlying tumours. These findings have important implications for understanding the biology of these diseases.</p>
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