Evidence of axonal damage has been recently found in both PMD and its animal models, a finding that is important for future understanding of the pathogenesis of demyelinating disease and its treatment. In his original description of the neuropathological features of PMD, Merzbacher2
noted: Es stellt sich nämlich heraus: daß dort, wo die Markscheiden fehlen, auch keine Achsencylinder nachweisbar sind
(It is evident that there are no axons demonstrated where the myelin sheaths are absent). Merzbacher, however, was not convinced that there was axonal damage, and he subsequently concluded that axons were much thinner and did not stain well with axonal stains. Conclusive evidence for axonal damage in PMD, however, has been found in several rodent models, including those caused by PLPpoint mutations, increased PLPgene dosage, or PLPnull mutation.9,13,15,17Consistent with this interpretation, we have found a significant decrease in the N-acetyl aspartate/creatine ratio using magnetic resonance spectroscopy both in mice overexpressing PLP due to increased gene dosage and in patients with PMD (J.G., J.K., and Gregory Moore, PhD, unpublished data, 1998). In animals carrying a PLPnull mutation, this axonal injury is not caused by demyelination, since myelin in these animals is intact, or by oligodendrocyte cell death, since these cells appear healthy and ensheathe axons. Also, the extent of axonal injury increases with the age of the animal, and probably accounts for the onset of its neurological signs and symptoms.9These data thus demonstrate that progressive axonal damage is a common feature of the pathogenesis of PMD and that it is clinically relevant. Furthermore, they suggest that axonal damage is caused by abnormalities of oligodendrocyte-axon interactions that are, at least in part, mediated by PLP or DM20.