CMT 1A: Antiprogesterone therapy uncouples axonal loss from demyelination in a t

[Guest guest]

Ann Neurol. 2007 Jan 29;61(1):61-72

Antiprogesterone therapy uncouples axonal loss from demyelination in

a transgenic rat model of CMT1A neuropathy.

Meyer Zu Horste G, Prukop T, Liebetanz D, Mobius W, Nave KA, Sereda

MW.

Department of Neurogenetics, Max-Planck-Institute of Experimental

Medicine, University of Gottingen, Gottingen, Germany.

OBJECTIVE: Charcot-Marie-Tooth disease (CMT) is the most common

inherited neuropathy, and a duplication of the Pmp22 gene causes the

most frequent subform CMT1A. Using a transgenic rat model of CMT1A,

we tested the hypothesis that long-term treatment with anti-

progesterone (Onapristone) reduces Pmp22 overexpression and improves

CMT disease phenotype of older animals, thereby extending a previous

proof-of-concept observation in a more clinically relevant setting.

METHODS: We applied placebo-controlled progesterone-antagonist

therapy to CMT rats for 5 months and performed grip-strength

analysis to assess the motor phenotype. Quantitative Pmp22 RT-PCR

and complete histological analysis of peripheral nerves and skin

biopsies were performed.

RESULTS: Anti-progesterone therapy significantly increased muscle

strength and muscle mass of CMT rats and reduced the performance

difference to wildtype rats by about 50%. Physical improvements can

be explained by the prevention of axon loss. Surprisingly, the

effects of anti-progesterone were not reflected by improved myelin

sheath thickness. Electrophysiology confirmed unaltered NCV, but

less reduced CMAP recordings in the treatment group. Moreover, the

reduction of Pmp22 mRNA, as quantified in cutaneous nerves,

correlated with the clinical phenotype at later stages.

INTERPRETATION: Progesterone-antagonist treatment. Pmp22

overexpression to a degree at which the axonal support function of

Schwann cells is better maintained than myelination. This suggests

that axonal loss in CMT1A is not caused by demyelination, but rather

by a Schwann cell defect that has been partially uncoupled by anti-

progesterone treatment. Pmp22 expression analysis in skin may

provide a prognostic marker for disease severity and for monitoring

future clinical trials.