The name of the syndrome originates from the abnormally slow decay of synaptic currents caused by abnormally prolonged opening burst of the AChR channel (). The clinical phenotypes vary. Some slow-channel CMS present in early life and cause severe disability by the end of the first decade; others present later in life and progress slowly, resulting in little disability even in the sixth or seventh decade of life. Most patients show selectively severe involvement of cervical and of wrist and finger extensor muscles. Except for severely affected patients, the cranial muscles tend to be spared. Progressive spinal deformities and respiratory embarrassment are common complications during the evolution of the illness.
Figure 3 Slow-channel syndromes. a Schematic diagram of AChR subunits with slow-channel mutation. b Single-channel currents from wild-type and slow-channel (αV249F) AChRs expressed in HEK cells. c MEPC recorded from EPs of a control subject and a patient (more ...)
In the kinships observed to date, mutations in the channel domain caused more severe disease than those at the ACh binding site, but the phenotypic expressivity varied between and within kinships harboring the same mutation. Thus, although suggestive, phenotypic severity is not a fully reliable predictor of mutation site.
Patch clamp studies at the EP, mutation analysis, and expression studies in human embryonic kidney (HEK) cells indicate that the αG153S mutation near the extracellular ACh binding site (Sine et al. 1995
) and the αN217K (Wang et al. 1997
) as well as εL221F (Hatton et al. 2003
) mutations in the N-terminal part of the M1 domain act mainly by enhancing affinity for ACh. This slows dissociation of ACh from the binding site and results in repeated channel reopenings during the prolonged receptor occupancy. Mutations in the M2 domain that line the channel pore, such as βV266M, εL269F, εT264P, and αV249F, promote the open state by affecting channel opening and closing steps (Ohno et al. 1995
; Engel et al. 1996b
; Milone et al. 1997
), especially by slowing the channel closing rate α
and variably speeding the channel opening rate β
. Some M2 domain mutations also increase affinity for ACh; this is most marked in the case of αV249F (Milone et al. 1997
), pronounced with εL269F (Engel et al. 1996b
) and εT264P (Ohno et al. 1995
), and not apparent in the case of βV266M (Engel et al. 1996b
The prolonged synaptic currents predispose to cationic overloading of the postsynaptic region. This instigates an EP myopathy associated with the destruction of the junctional folds, degeneration of postsynaptic organelles, and apoptosis of the junctional nuclei ().
For the normal adult human AChR, 7% of the synaptic current is carried by Ca2+
; this is higher than for human fetal AChR or for muscle AChR of other species and predisposes to postsynaptic Ca2+
overloading when the synaptic current is prolonged (Fucile et al. 2006
). However, at least two slow-channel mutations in the ε M2 domain of AChR (εT264P and εV259F) increase the Ca2+
permeability 1.5-fold and twofold, respectively (Di Castro et al. 2007
) and further enhance the deleterious effects of the prolonged synaptic currents and the intrinsically high Ca2+
permeability of human AChR.
The safety margin of neuromuscular transmission is compromised by the EP myopathy which destroys junctional folds, causes loss of AChR, and alters the EP geometry; by staircase summation of markedly prolonged EPPs that cause a depolarization block at physiologic rates of stimulation; and by an increased propensity of the mutant receptors to become desensitized. The slow-channel syndrome can be effectively treated by long-lived open-channel blockers of AChR, such as quinidine and fluoxetine (Harper and Engel 1998
; Fukudome et al. 1998
; Harper et al. 2003