CMT1A: Axonal degeneration in the Trembler-j mouse demonstrated by stimulated si

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Muscle Nerve. 2007 Apr 18

Axonal degeneration in the Trembler-j mouse demonstrated by

stimulated single-fiber electromyography.

Meekins GD, GT, Emery MJ, Weiss MD.

Department of Neurology, University of Washington Medical Center,

Box 356115, 1959 NE Pacific Street, Seattle, Washington 98195, USA.

The Trembler-j (Tr-j) mouse is a naturally occurring mutant with a

point mutation in the peripheral myelin protein-22 gene causing

severe peripheral nerve demyelination. It is a genetically

homologous murine model for Charcot-Marie-Tooth disease type 1A (CMT

1A).

Our prior pilot studies using stimulated single-fiber needle

electromyograpy (SSFEMG) showed increased jitter in 60-day-old Tr-j

mice compared to age-matched, wildtype animals. The aim of this

study was to better elucidate the etiology of increased jitter in Tr-

j mice and test the following hypotheses: (1) the increased jitter

in Tr-j mice is due to turnover of endplates secondary to axonal

degeneration with reinnervation and not to conduction block

secondary to demyelination of motor nerve axons; and (2) aging Tr-j

mice demonstrate increased jitter and fiber density compared with

younger mutant mice due to progressive motor axon loss.

SSFEMG studies performed on 60- and 140-day-old mice indicated that

average mean consecutive difference (MCD) and fiber density

estimates (FDE) were significantly increased in Tr-j mice at both

ages compared to age-matched wildtypes. FDE also increased

substantially in older mutant mice.

Intraperitoneal neostigmine injections produced significant

reductions in average MCD in Tr-j mice, suggesting that impaired

neuromuscular transmission is an early pathologic feature in these

mice and likely reflects distal axonal degeneration.

Our findings corroborate our prior pilot study, although in a much

larger number of animals across a wider age span. Our study also

indicates that SSFEMG, performed in a serial fashion, is a useful,

noninvasive method of detecting progressive axon loss in this murine

model of CMT 1A.

This technique may be a valuable tool to study the affects of

genetic or pharmaceutical interventions in murine models of

peripheral neuropathy.