Anti-VGCC antibodies

Synonyms: None. Full name: Anti-P/Q type voltage-gated calcium channel antibody

Clinical associations: Associations are with Lambert-Eaton myasthenic syndrome or paraneoplastic cerebellar degeneration. See also text on Lambert-Eaton myasthenic syndrome.

Tumor associations: See table. Presence of anti-P/Q type anti-VGCC serum antibodies predicts the presence of a tumour, mostly a small cell lung cancer, in just more than 50% of the patients. This is based on the following findings: close to 100% of tumour associated LEMS is anti-VGCC antibody positive, and around 90% of non-tumour associated LEMS. In half of the LEMS patients a tumour, mostly small-cell lung cancer, will be detected.

Frequency of anti-VGCC antibodies in patients with small-cell lung cancer without PNS: 0-5% with titers similar to those of patients with PNS. One series reported 18%.

Screening test:
None. Routine immunohistochemistry on frozen brain does not detect polyclonal human serum anti-VGCC antibodies.

Confirmatory test:
RIA using extracts from cerebellum. Available in research labs and as commercial assay.

Immunologic associations:
Patients with paraneoplastic syndromes and anti-VGCC antibodies may develop concurrent antibodies to other onconeuronal antigens. They include, anti-Hu, anti-amphiphysin, or anti-Ri antibodies.

VGCC antigens
The main target of the anti-VGCC antibodies are the P/Q-type voltage-gated calcium channels. Binding of serum antibodies from LEMS patients to N-type VGCCs has also been reported. VGCCs consist of a transmembrane alfa-1 subunit (175 kD), an intracellular beta subunit (50 kD), a subunit dimer alfa2/delta (143 KD and 27 kD), and a transmembrane gamma subunit. Several subtypes of these subunits are known. P-type and Q-type VGCCs use a different splice-form of the same alfa-1 subunit encoded by a single CACNA1A gene. VGCCs are located presynaptically and have an important role in transmitter release. The alfa-1 subunit is the pore-forming part and also contains the voltage-sensor. Antibody binding to complete VGCCs extracted from cerebellum has been demonstrated in a RIA. In addition, antibodies from LEMS sera also bind peptides representing extracellular parts of the alfa1-subunit. Antibodies to the VGCC beta-subunit have been demonstrated.

The human VGCCs are expressed in the central nervous system, at the neuromuscular synapses, in the autonomic nervous system, as well as by small-cell lung cancers.

References

• Antoine JC, Absi L, Honnorat J, et al. Antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors. Arch Neurol. 1999;56:172-7.
• Iwasa K, Takamori M, Komai K, Mori Y. Recombinant calcium channel is recognized by Lambert-Eaton myasthenic syndrome antibodies. Neurology. 2000;54:757-9.
• Lennon VA, Kryzer TJ, Griesmann GE, et al. Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. N Engl J Med. 1995;332:1467-74.
• Monstad SE, Drivsholm L, Storstein A, et al.. Hu and voltage-gated calcium channel (VGCC) antibodies related to the prognosis of small-cell lung cancer. J Clin Oncol. 2004;22:795-800
• Motomura M, Lang B, Johnston I, et al. Incidence of serum anti-P/O-type and anti-N-type calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome. J Neurol Sci 1997;147:35-42.
• O'Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain. 1988;111:577-96.
• Pittock SJ, Lucchinetti CF, Lennon VA. Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol. 2003;53:580-7.
• Verschuuren JJ, Dalmau J, Tunkel R, et al.. Antibodies against the calcium channel beta-subunit in Lambert-Eaton myasthenic syndrome. Neurology. 1998;50:475-9.

Table
Cancers found in 141 patients with Lambert-Eaton myasthenic syndrome.
Adapted from Wirtz et al. Clin Neurol Neurosurg. 2002;104:359

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