Neuropathologic study in the heterozygotes of X-linked brindled mutant mouse

The clinical and morphological features were studied in female heterozygotes of the sex-linked brindled mutant mice, which are an appropriate animal model for human Menkes' kinky hair disease (MKHD). Clinically, female heterozygotes presented phenotypical variety. In these heterozygotes, we distinguished the unique group of mice, which showed mottled white and dark brown fur and curly whiskers. We designated this unique group "heterozygote, variant type", in contrast to the remaining group--"heterozygote, usual type"--, of which the fur was mottled dark and light brown, and the whiskers were straight. Ultrastructurally, various degrees of mitochondrial changes, from an almost normal appearance of the mitochondria to similar to those of the hemizygotes, were observed. Furthermore we noticed that, in the heterozygotes, there were positive correlations between this morphological spectrum and those phenotypical varieties. These findings were interpreted as a possible subclinical copper deficiency in the heterozygotes, and the morphological alterations in heterozygotes were probably due to X-chromosome inactivation according to Lyon's hypothesis. The presence, however, of clinical and morphological varieties in the heterozygotes leads us to the hypothesis that the inactivation rate is not necessarily the same for all carriers. Moreover, it can be speculated that pathologic changes similar to those in heterozygotes may be present in the female carriers of human MKHD.