Antibodies that immunoprecipitate (125)I-alpha-dendrotoxin-labelled
voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with
neuromyotonia, Morvan's syndrome,
limbic encephalitis and a few cases of adult-onset
epilepsy. These conditions often improve following
immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with
potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96
potassium channel antibody positive patients (titres >400 pM). Five had
thymomas and one had an endometrial
adenocarcinoma. To define the antibody specificities, we looked for binding of serum
antibodies and their effects on
potassium channel currents using human embryonic kidney cells expressing the
potassium channel subunits. Surprisingly, only three of the patients had
antibodies directed against the
potassium channel subunits. By contrast, we found
antibodies to three
proteins that are complexed with (125)I-alpha-dendrotoxin-labelled
potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii)
leucine-rich,
glioma inactivated 1
protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/
contactin-2 that associates with contactin-associated protein-2.
Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to
leucine-rich,
glioma inactivated 1
protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other
antibodies. The remaining 18 sera were negative for
potassium channel subunits and associated
proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had
neuromyotonia or Morvan's syndrome, compared with only 3 of the 55
leucine-rich,
glioma inactivated 1
protein-antibody positive patients (P < 0.0001), who predominantly had
limbic encephalitis. The responses to
immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2
protein antibodies. This study confirms that the majority of patients with high
potassium channel antibodies have
limbic encephalitis without tumours. The identification of
leucine-rich,
glioma inactivated 1
protein and contactin-associated protein-2 as the major targets of
potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2
antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.