Complete loss of the X-linked gene causes severe cerebellar degeneration.

Background: Heterozygous loss of X-linked genes like and MeCP2 (Rett syndrome) causes developmental delay in girls, while in boys, loss of the only allele of these genes leads to epileptic encephalopathy. The mechanism for these disorders remains unknown. -linked cerebellar hypoplasia is presumed to result from defects in Tbr1-reelin-mediated neuronal migration.

Method: Here we report clinical and histopathological analyses of a deceased 2-month-old boy with a -null mutation. We next generated a mouse line where is completely deleted (hemizygous and homozygous) from postmigratory neurons in the cerebellum.

Result: The -null human brain was smaller in size but exhibited normal lamination without defective neuronal differentiation, migration or axonal guidance. The hypoplastic cerebellum instead displayed astrogliosis and microgliosis, which are markers for neuronal loss. We therefore hypothesise that loss-induced cerebellar hypoplasia is the result of early neurodegeneration. Data from the murine model confirmed that in CASK loss, a small cerebellum results from postdevelopmental degeneration of cerebellar granule neurons. Furthermore, at least in the cerebellum, functional loss from deletion is secondary to degeneration of granule cells and not due to an acute molecular functional loss of . Intriguingly, female mice with heterozygous deletion of in the cerebellum do not display neurodegeneration.

Conclusion: We suggest that X-linked neurodevelopmental disorders like mutation and Rett syndrome are pathologically neurodegenerative; random X-chromosome inactivation in heterozygous mutant girls, however, results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy.