Voltage-gated Calcium Channel Antibody (VGCCA)

Voltage-Gated Calcium Channels (VGCCs) are transmembrane protein structures that are activated by changes in local electrical membrane potential.¹ Multiple types of VGCCs have been described in both the central nervous system and peripheral tissue.^1,2 Activation induces changes in protein conformation allowing the influx of calcium ions into cells. VGCCs are classified according to their pharmacological properties as P/Q-, N-, L-, T- or R-type channels.³ P-type VGCCs are associated with Purkinje neurons of the cerebellum and Q-type VGCCs with cerebellar granule neurons.¹ Together, P/Q-type VGCCs are primarily involved in acetylcholine release from motor nerve terminals.^2,4

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission with distinctive pathophysiological, clinical, electrophysiological and laboratory features.^4-8 Pathologic antibodies cause a down-regulation of P/Q-type VGCCs diminishing the acetylcholine-mediated transmission of the signal from the presynaptic nerve to skeletal muscles and thus, impairing muscle contraction.^4,6-10 Patients with LEMS invariably experience progressive proximal muscle weakness, often accompanied by general fatigue, autonomic symptoms and areflexia.^5,6 The majority of cases occur as a paraneoplastic disorder (P-LEMS) associated with a malignant tumor that is most frequently a small cell lung cancer (SCLC).^4-7,9,11 Other malignancies that have occasionally been associated with Lambert-Eaton myasthenic syndrome including non-small cell and mixed lung carcinoma, prostate cancer, thymoma and lymphoproliferative disorders.^7,13 SCLC is a poorly differentiated, neuroendocrine tumor that expresses P/Q-type (as well as N- and L-type) VGCC.^4,7,10-14 In P-LEMS, the initial humoral autoimmune response is generated against the VGCC of tumor cells and engenders pathologic antibodies that cross-react with VGCC of presynaptic nerve endings. ^4,6,7,10,12 The onset of neurological symptoms in LEMS patients will often predate the detection of the tumor, and the survival time of the P-LEMS patients is significantly longer than that of those with SCLC without neurological dysfunction.^6,7,13,15,16 Prognosis is related to the presence of cancer or autoimmune disease and the severity/distribution of muscle weakness.⁶ Cause of death in patients with SCLC associated LEMS is typically tumor progression, whereas LEMS that is not associated with malignancy does not reduce life expectancy.⁶