Presynaptic failure of neuromuscular transmission and synaptic remodeling in EA2.
OBJECTIVE
To further investigate the basis of abnormal neuromuscular transmission in two patients with congenital myasthenic syndrome associated with episodic ataxia type 2 (EA2) using stimulated single fiber EMG (SFEMG) and in vitro microelectrode studies.


METHODS
Two patients with genetically characterized EA2 previously shown to have abnormal neuromuscular transmission by voluntary SFEMG were studied with stimulated SFEMG and anconeus muscle biopsy with microelectrode studies and electron microscopy of the neuromuscular junction.


RESULTS
In vivo stimulated SFEMG showed signs of presynaptic failure, with jitter and blocking that improved with increased stimulation frequency. Additional evidence of presynaptic failure was provided by the in vitro microelectrode studies, which showed marked reduction of the end plate potential quantal content in both patients. Of note, the end plate potentials showed high sensitivity to N-type blockade with omega-conotoxin not seen in controls. The ultrastructural studies revealed some evidence of small nerve terminals apposed to normal or mildly overdeveloped postsynaptic membranes, suggesting an ongoing degenerative process.


CONCLUSIONS
The authors demonstrated presynaptic failure of neurotransmission in patients with heterozygous nonsense mutations in CACNA1A. The contribution of non-P-type calcium channels to the process of neurotransmitter release in these patients likely represents a compensatory mechanism, which is insufficient to restore normal neuromuscular transmission.
Maselli
R A
RA
Neurology Department, University of California Davis, USA. ramaselli@ucdavis.edu
Wan
J
J
Dunne
V
V
Graves
M
M
Baloh
R W
RW
Wollmann
R L
RL
Jen
J
J
D000110:Acetylcholinesterase / Q000378:metabolism; D000328:Adult; D001259:Ataxia / Q000150:complications / Q000175:diagnosis* / Q000503:physiopathology*; D001667:Binding, Competitive; D001706:Biopsy; D002121:Calcium Channel Blockers; D015220:Calcium Channels / Q000187:drug effects / Q000235:genetics; D004558:Electric Stimulation; D004576:Electromyography; D006801:Humans; D008297:Male; D008875:Middle Aged; D009045:Motor Endplate / Q000201:enzymology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000294:innervation / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000150:complications / Q000175:diagnosis* / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D013569:Synapses / Q000473:pathology* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics*; D020864:Calcium Channels, N-Type
D000110:Acetylcholinesterase; D002121:Calcium Channel Blockers; D015220:Calcium Channels; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type