Anti-voltage-gated potassium channel antibodies

 

Synonyms: Anti-VGKC, VGKC Ab

Clinical associations:

Peripheral nerve hyperexcitability (acquired neuromyotonia or Isaac’s disease), autonomic involvement, Morvan’s syndrome, limbic syndromes

 

Tumor associations

Principally thymoma (around 20%) and small cell lung cancer (<5%). Most cases do not have a tumour. Frequency of anti-VGKC antibodies in patients with appropriate clinical syndromes without evidence of cancer is high (>80%)

 

Screening test:

High titres of VGKC antibodies may be detected by immunohistochemistry showing characteristic staining of molecular layer of the cerebellum (Fig 1a), or hippocampus (Fig 1b). These should be confirmed by immunoprecipitation assay using 125I-dendrotoxin-labelled VGKCs extracted from human or rodent brain tissue. Lower titres of VGKC antibodies are only detected by this immunoprecipitation assay. This assay only measures antibodies to the dendrotoxin-binding Kv1.1, 1.2 and 1.6 forms of VGKCs.

 

Figure 1a. (Taken from Vincent et al Brain 2004). Rat cerebellum immunoreacted with a VGKC- antibody- positive serum. ML: molecular layer, PC: Purkinje cell; GL: granular layer.
Figure 1b (Courtesy of Dr Camilla Buckley). Rat hippocampus immunoreacted with a VGKC- antibody- positive serum

 

Confirmatory test:

No commercial tests or recombinant proteins available currently.

 

Immunologic associations:

Patients with VGKC antibodies may have associated myasthenia gravis with or without acetylcholine receptor antibodies, or may have acetylcholine receptor antibodies without myasthenia gravis. Other thymoma-related antibodies (eg. Interferon alpha, IL-12) may be present. Acquired neuromyotonia has been reported in patients following bone marrow transfer, with systemic sclerosis and with other autoimmune diseases.

 

VGKCs

VGKCs are a family of voltage-gated shaker-like potassium channels. They are membrane proteins and responsible for controlling the cell membrane potential. They are made up of tetramers and are usually hetero-tetramers of different subtypes. Dendrotoxin binds to Kv1.1, 1.2 and 1.6 principally, and therefore it is thought that these subtypes are the most likely targets for the VGKC antibodies. VGKCs are expressed by a wide range of different cells, but are most important in the control of membrane excitability in the nervous system.

 

References

 

• Buckley C, Oger J, Clover L, Tuzun E, Carpenter K, Jackson M, et al. Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol 2001; 50: 73-8.
• Hart IK, Maddison P, Newsom-Davis J, Vincent A, Mills KR. Phenotypic variants of autoimmune peripheral nerve hyperexcitability. Brain 2002; 125: 1887-95.
• Liguori R, Vincent A, Clover L, Avoni P, Plazzi G, Cortelli P, et al. Morvan's syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 2001; 124: 2417-26.
• Pozo-Rosich P, Clover L, Saiz A, Vincent A, Graus F. Voltage-gated potassium channel antibodies in idiopathic and paraneoplastic limbic encephalitis. Ann Neurol. 2003 54:530-3.
• Schott JM, Harkness K, Barnes J, della Rocchetta AI, Vincent A, Rossor MN. Amnesia, cerebral atrophy, and autoimmunity. Lancet 2003; 361: 1266.
• Wang H, Kunkel DD, Schwartzkroin PA, Tempel BL. Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain. J Neurosci 1994; 14: 4588-99.
• Vincent A, Buckley C, Schott JM, Baker I, Dewar BK, Detert N, et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004; 127:701-712.