Figure 6. Model describing zygosity-based mechanism of a neurodevelopmental versus neurodegenerative clinical course of CASK-linked phenotype based on random X-chromosome inactivation.

CASK is an X-linked gene critical for maintenance of cerebellar neurons. Heterozygous mutation in CASK produces CASK loss-of-function in only 50% of neurons (red). In the heterozygous condition (red and gray), neurodegeneration thus plateaus (bottom middle), causing an apparent neurodevelopmental disorder, whereas hemizygous CASK mutations (red and purple) in male mice or homozygous CASK mutation (two reds) in female mice produce a progressive phenotype typical of neurodegeneration with severe ataxia (bottom right).