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The phenotypic spectrum among girls with heterozygous mutations in the X-linked intellectual disability (XLID) gene  CASK  (calcium/calmodulin-dependent serine protein kinase) includes postnatal microcephaly, ponto-cerebellar hypoplasia, seizures, optic nerve hypoplasia, growth retardation and hypotonia. Although  CASK  knockout mice were previously reported to exhibit perinatal lethality and a 3-fold increased apoptotic rate in the brain,  CASK  deletion was not found to affect neuronal physiology and their electrical properties. The pathogenesis of  CASK  associated disorders and the potential function of  CASK  therefore remains unknown. Here, using Cre-LoxP mediated gene excision experiments; we demonstrate that deleting  CASK  specifically from mouse cerebellar neurons does not alter the cerebellar architecture or function. We demonstrate that the neuron-specific deletion of  CASK  in mice does not cause perinatal lethality but induces severe recurrent epileptic seizures and growth retardation before the onset of adulthood. Furthermore, we demonstrate that although neuron-specific haploinsufficiency of  CASK  is inconsequential, the  CASK  mutation associated human phenotypes are replicated with high fidelity in  CASK  heterozygous knockout female mice ( CASK  (+/-) ). These data suggest that  CASK -related phenotypes are not purely neuronal in origin. Surprisingly, the observed microcephaly in  CASK  (+/-)  animals is not associated with a specific loss of  CASK  null brain cells indicating that  CASK  regulates postnatal brain growth in a non-cell autonomous manner. Using biochemical assay, we also demonstrate that CASK can interact with metabolic proteins.  CASK  knockdown in human cell lines cause reduced cellular respiration and  CASK  (+/-)  mice display abnormalities in muscle and brain oxidative metabolism, suggesting a novel function of CASK in metabolism. Our data implies that some phenotypic components of  CASK  heterozygous deletion mutation associated disorders represent systemic manifestation of metabolic stress and therefore amenable to therapeutic intervention.   Electronic supplementary material  The online version of this article (doi:10.1186/s40478-016-0295-6) contains supplementary material, which is available to authorized users.

X-linked intellectual disability gene CASK regulates postnatal brain growth in a non-cell autonomous manner