Acquired slow–channel syndrome: A form of myasthenia gravis with prolonged open time of the acetylcholine receptor channel

Abstract

A 32-year-old female presented with a 2-year history of fluctuating generalized weakness including extraocular, bulbar, and limb muscles, suggesting myasthenia gravis, but with poor response to pyridostigmine and unusual electromyographic findings. After rest, power increased on repeated maximal contractions, followed by progressive weakness. There were decremental responses at low-frequency stimulation, but incremental responses at high frequencies, and single stimuli evoked repetitive compound muscle action potentials. Plasmapheresis was ineffective. In a conventional assay, antibodies against acetylcholine receptors (AChRs) were borderline. However, in an assay using cells expressing mainly adult-type human AChRs, the patient's serum was positive. Thymectomy revealed a hyperplastic thymus. An intercostal muscle specimen revealed small miniature end-plate potentials, 0.22+/-0.02 mV instead of 0.56+/-0.05 mV in controls. The number of 125I-alpha-bungarotoxin binding sites was normal. The decay time constant of end-plate potentials was increased from 5.3+/-0.6 msec in controls to 23+/-3.6 msec in the patient. Ultrastructurally, there was no destruction of the end plate. Transfer of the patient's plasma to mice in vivo produced similar physiological changes in their diaphragms. We conclude that the patient has an immune-mediated disorder, in which an antibody specific to the adult form of the AChRs alters the channel properties, reducing total current and slowing the closure. We propose the name "acquired slow-channel syndrome" for this variant of myasthenia gravis.

Neuronal Surface Autoantibodies in Neuropsychiatric Disorders: Are There Implications for Depression?

“…Autoantibodies against the γ subunit of the AChR which is only present in embryonic forms of the receptor have been reported in some cases to block the AChR function and cause arthrogryposis multiplex congenita (67). Conversely, AChR antibodies can also induce prolonged open time of the AChR leading to muscle weakness by excitotoxicity at the neuromuscular junction (68). Anti-AMPAR (GluR3B subunit) autoantibodies (anti-AMPA-GluR3B) can activate AMPAR that contains the GluR3B subunit, leading to the spontaneous occurrence of ion currents (69, 70).…”

Pathophysiology of weakness in a patient with congenital end‐plate acetylcholinesterase deficiency

“…Repetitive muscle discharge in response to a single nerve stimulus usually implies re‐excitation of muscle fibers by prolonged EPPs 3, 6, 7, 9. This is seen not only in congenital end‐plate AChE deficiency but also in other entities, such as organophosphate poisoning,1, 9 exposure to other anti‐acetylcholinesterases,3, 14 another form of congenital myasthenia called slow‐channel syndrome,6 and acquired slow‐channel syndrome 16. All of these conditions are characterized by prolonged end‐plate depolarization, which results from excess ACh caused by depression of AChE or abnormal channel kinetics of receptors.…”

The auto-antigen repertoire in myasthenia gravis

“…Consequently, it is conceivable that the ability of the muscle to compensate for the loss of nAChR and its associated proteins during the attack by anti-nAChR antibodies ultimately influences the severity of the disease [39]. Fourthly, some antibodies may interfere with the function of the muscle nAChR, and it has been reported that antibodies can block the binding of ACh [40,41] or affects the opening of the ion channel [42,43].…”

“…Apparently, the antibody was directed to the 1-subunit of the adult nAChR or its interface with neighboring subunits [43].…”