Early CMT 1A abnormalities in sciatic nerve function & structure in rat model

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Abstract from Exp Neurol. 2004 Nov;190(1):213-223.

Early abnormalities in sciatic nerve function and structure in a rat

model of Charcot-Marie-Tooth type 1A disease.

Grandis M, Leandri M, Vigo T, Cilli M, Sereda MW, Gherardi G, Benedetti

L, Mancardi G, Abbruzzese M, Nave KA, Nobbio L, Schenone A.

Department of Neuroscience, Ophthalmology and Genetics, University of

Genova, 16132 Genova, Italy.

We investigated early peripheral nervous system impairment in

PMP22-transgenic rats ( " CMT rat " ), an established animal model for

Charcot-Marie-Tooth disease 1A, at postnatal day 30 (P30), when the

clinical phenotype is not yet apparent. Hemizygous CMT1A rats and

wildtype littermates were studied by means of behavioral examination,

electrophysiology, molecular biology, and light microscopy analysis.

Behavioral studies only showed, a mild, but significant, decrease in toe

spread 1-5, suggesting a weakness of distal foot muscles in CMT1A rats

compared with normal littermates. Nerve conduction studies disclosed a

severe slowing in motor conduction velocity, a temporal dispersion and a

dramatic decrease of amplitude of motor waves in P30 transgenic animals.

Coherently with a demyelinating process, affected nerves showed a

significant thinning of myelin. Interestingly, axonal diameter and area

were unchanged, but expression of non-phosphorylated neurofilaments was

increased in CMT1A rats compared with normal controls. Our results

confirm the fidelity of this animal model to human disease. Similarly,

in young CMT1A patients, the MCV is significantly reduced and the muscle

weakness is confined to distal segments, whereas morphological and

morphometrical signs of axonal atrophy are absent. However, the presence

of a molecular and functional damage of the axons suggests that this may

be the correct moment to start neuroprotective therapies.