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NEUROLOGY 2003;61:1743-1748
© 2003 American Academy of Neurology

Presynaptic failure of neuromuscular transmission and synaptic remodeling in EA2

R.A. Maselli, MD, J. Wan, PhD, V. Dunne, BS, M. Graves, MD, R.W. Baloh, MD, R.L. Wollmann, MD PhD and J. Jen, MD PhD

From the Neurology Department (Dr. Maselli and V. Dunne), University of California Davis; Neurology Department (Drs. Wan, Graves, Baloh, and Jen), University of California Los Angeles; and Pathology Department (Dr. Wollmann), The University of Chicago, IL.

Address correspondence and reprint requests to Dr. Ricardo A. Maselli, 1515 Newton Court, Room 510, Davis, CA 95616; e-mail: ramaselli{at}ucdavis.edu; or Dr. Joanna Jen, UCLA Neurology, 710 Westwood Plaza, Los Angeles, CA 90095-1769; e-mail: jjen@ucla.edu

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.

Received December 18, 2002. Accepted in final form August 27, 2003.




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[Abstract] [Full Text] [PDF]


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