Ganglionic Acetylcholine Receptor Autoantibody

Nicotinic acetylcholine receptors (AChRs) are ligand-gated, cation-selective ion channels found throughout the central and peripheral nervous system.⁸ These transmembrane structures are formed by the radial association of five protein subunits to create a central ion channel pore. AChRs all include at least two α subunits that provide binding sites for acetylcholine. The binding of acetylcholine causes a change in the three-dimensional structure of the complex to allow ion migration through the pore. The ganglionic AChR (g-AChR) that mediates fast synaptic transmission in all peripheral autonomic ganglia (sympathetic, parasympathetic and enteric ganglia) are composed of two α3 subunits in combination with three β subunits. These g-AChRs are structurally similar to the AChR at the neuromuscular junction of the skeletal muscles (m-AChR). However, g-AChR are genetically and immunologically distinct from m-AChR that are composed of two α1 subunits complexed with β, δ and ε (or fetal γ) subunits.⁸

Autoimmune autonomic ganglionopathy (AAG) is an acquired neurological disorder that classically manifests with widespread autonomic failure involving sympathetic, parasympathetic and enteric functions.^2,3,4,9 AAG and myasthenia gravis (MG) are both autoimmune channelopathies mediated by antibodies directed against nicotinic acetylcholine receptors. While both diseases target acetylcholine receptors, skeletal muscle and ganglionic receptor subtypes have key immunologic and genetic distinctions.¹⁰ MG and AAG are distinct autoimmune channelopathies mediated by pathologic antibodies directed against the α1 subunits of muscle AChR and the α3 subunits of ganglionic AChR, respectively.⁸ Although muscle and ganglionic AChRs are structurally very similar, patients with AAG typically do not have weakness or other clinical features of MG, and patients with MG typically do not have prominent autonomic dysfunction.^3,8 The exceptions are rare patients with an overlap syndrome of myasthenia with subacute autonomic failure often associated with thymoma.^11,12 Otherwise, autoantibody cross-reactivity is uncommon and generally weak.^8,10

The incidence of AAG is unknown and diagnosis is often difficult due to the multi-compartmental nature of the autonomic nervous system—sympathetic, parasympathetic and enteric components—with variable severity and number of components affected.⁴ Diagnostic confidence is increased when ganglionic acetylcholine receptor (g-AChR) autoantibodies are detected. Up to 50 percent of patients with the acute or subacute form of this disorder have detectable levels of autoantibodies to g-AChR.^2,13 When present, g-AChR autoantibodies are directly pathological, causing receptor internalization and removal from the postganglionic neuronal plasma membrane surface (i.e., immunomodulation).⁴ The clinical features of AAG include orthostatic hypotension, inability to sweat, reduced lacrimation and salivation, bowel disturbances (ileus, abdominal colic, diarrhea and constipation), atonic bladder, impotence and a fixed heart rate. Presentation with tonic pupils that do not react to light and/or gastrointestinal dysmotility in the setting of other autonomic symptoms is highly suggestive of AAG.^14,15 Serum g-AChR autoantibody levels correlate with clinical features and extent of autonomic neuropathy in patients with AAG.^2,14,16,17 A decrease in antibody levels is associated with improvement in autonomic function.² Immunomodulatory therapies such as plasmapheresis to remove autoantibodies or immunosuppressant drugs can produce a dramatic improvement in autonomic function in some cases.^18-22