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

J Med Genet. 2022 Nov;59(11):1044-1057. doi: 10.1136/jmedgenet-2021-108115. Epub 2022 Feb 11.


Background: Heterozygous loss of X-linked genes like CASK 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. CASK-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 CASK-null mutation. We next generated a mouse line where CASK is completely deleted (hemizygous and homozygous) from postmigratory neurons in the cerebellum.

Result: The CASK-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 CASK 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 CASK deletion is secondary to degeneration of granule cells and not due to an acute molecular functional loss of CASK. Intriguingly, female mice with heterozygous deletion of CASK in the cerebellum do not display neurodegeneration.

Conclusion: We suggest that X-linked neurodevelopmental disorders like CASK 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.

Keywords: central nervous system diseases; congenital; hereditary; neonatal diseases and abnormalities; nervous system diseases; paediatrics; pathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebellar Diseases* / genetics
  • Female
  • Genes, X-Linked / genetics
  • Guanylate Kinases / genetics
  • Humans
  • Infant
  • Male
  • Mice
  • Neurodegenerative Diseases* / genetics
  • Rett Syndrome* / genetics


  • Guanylate Kinases

Supplementary concepts

  • Cerebellar Hypoplasia