Myelin mosaicism and brain plasticity in heterozygous females of a canine X-linked trait.

The shaking (sh) pup, an animal model of Pelizaeus-Merzbacher disease, is characterized by severe central nervous system dysmyelination in affected males, and myelin mosaicism in some female heterozygotes as a result of X-linked inactivation. Heterozygous females develop a tremor of varying severity that usually disappears at 4 to 6 weeks, whereas male hemizygotes have severe, generalized tremor that persists throughout life. We have used these two myelin-deficient models to study the potential for recovery with time as reflected by brainstem auditory evoked responses (BAERs). At set time points, the state of myelination in the trapezoid body was studied microscopically. Sequential BAERs demonstrated consistently prolonged interpeak latencies during the period of gross tremor in heterozygotes, with the trend continuing to a lesser extent after tremor cessation. The random nature of X-linked inactivation resulted in variable myelin mosaicism that was reflected in variations in BAER changes within animals in the same litter. In most heterozygotes, the tremor resolved with time, the BAERs returned to near normal, and myelin mosaicism was lost. In contrast, in the affected males, the severity of tremor and lack of recovery was demonstrated by consistent abnormalities in BAER waves at all times studied, and severe and persistent myelin deficiency in the trapezoid body. These findings show that despite the normal tightly programmed temporal development of myelin in the brain in the heterozygous mosaic state, sufficient plasticity persists during the neonatal period for late-stage myelination to occur.