Dramatic phenotypic improvement during pregnancy in a genetic leukodystrophy: estrogen appears to be a critical factor.

Globoid cell leukodystrophy is one of the classical genetic leukodystrophies in humans. The typical infantile disease in man (Krabbe disease) is caused by deficiency of lysosomal galactosylceramidase. We recently generated a new mouse model of a late-onset, chronic form of the disease by inactivating saposin A, the essential activator of galactosylceramidase. The phenotypic features of saposin A(-/-) mice are qualitatively identical but milder than those of twitcher mice, which is caused by genetic galactosylceramidase deficiency. During intercrossing of saposin A(-/-) mice, we observed that affected females that are continually pregnant showed greatly improved neurological symptoms compared to affected females that do not experience pregnancy, or affected males. The pathological hallmark of globoid cell leukodystrophy, demyelination with infiltration of globoid cells, largely disappeared. The immune-related gene expression (MCP-1, TNF-alpha) was significantly down-regulated in the brain of pregnant saposin A(-/-) mice. In addition, we found intense expression of the estrogen receptors (ER alpha and ER beta) on the globoid cells, activated astrocytes and microglia in the demyelinating area of saposin A(-/-) mice. When saposin A(-/-) mice were subcutaneously implanted with time-release 17 beta-estradiol (E2) pellets from 30 to 90 days, the pathology was vastly improved. These findings suggest that a higher level of estrogen during pregnancy is one of the important factors in the protective effect of pregnancy. While we should be cautious in extrapolating these observations in the mouse to human disease, the phenomenon is spectacularly dramatic and estrogen administration might be worth a consideration as a supplementary treatment for some chronic genetic leukodystrophies.