Distal axonopathy in peripheral nerves of PMP22-mutant mice

A partial duplication of chromosome 17 is associated with Charcot-Marie-Too th disease type 1A (CMT1A), a demyelinating peripheral neuropathy that caus es progressive distal muscle atrophy and sensory impairment. Trisomic expre ssion of peripheral myelin protein 22 (PMP22) whose gene is contained withi n the duplicated region is considered to be responsible for the disease. By using recombinant gene technology in rodents, we had demonstrated previous ly that PMP22 is sensitive to gene dosage, Homozygous PMP22 knockout (PMP22 (0/0)) mice and transgenic animals carrying additional copies of the PMP22 gene develop distinct peripheral polyneuropathies. We have now performed a detailed morphometrical analysis of the L3 roots, quadriceps and saphenous nerves of these PMP22-mutant mice to study whether the myelin and potential axonal deficits are evenly distributed. The L3 roots and the peripheral ne rves were chosen as representatives of the proximal and distal segments of the peripheral nervous system. When the roots were compared with the periph eral nerves, myelin deficiencies appeared more severe at the radicular leve ls, in particular the ventral roots. Decreased numbers of large calibre axo ns were a prominent feature in the motor branches of both strains of PMP22- mutant mice, and these axonal deficits were more severe distally, Active ax onal damage was only observed in the nerves of PMP22(0/0) mice. Despite the distinct effects on myelination and the Schwann cell phenotype that charac terize the neuropathies of PMP22-mutant mice, both strains develop a distal ly accentuated axonopathy as a common disease mechanism which is likely to be responsible for the neurological deficits.