Insights on Rare MICPCH Syndrome Could Help with Autism, Epilepsy

A study led by investigators from Shinshu University in Nagano, Japan, has made a key discovery about the mechanism that causes microcephaly with pontine and cerebellar hypoplasia (MICPCH), a rare genetic disorder affecting brain development.

One of 2 CASK-related intellectual disabilities, MICPCH is a rare condition, with only 53 cases in females and 7 cases in males to date described in literature. Symptoms of the disorder include an unusually small head at birth that does not grow at the same rate as the body, severe intellectual disability, underdevelopment in the brain’s cerebellum and pons, seizures, sleep disturbances, vision and hearing loss, and decreased muscle tone. MICPCH is caused by mutations in the gene providing instructions for making a protein called calcium/calmodulin-dependent serine protein kinase (CASK), and the CASK gene is located on the X chromosome. The protein is mostly found in neurons and helps control the expression of genes that are important to brain development.

In the recent study published in the journal Molecular Psychiatry, investigators overcame obstacles to studying CASK-deficiency in mice by using X-chromosome inactivation in female mice, shutting off the CASK gene without killing the mice. They then examined the synaptic functions of CASK-knockout neurons in acute brain slices of heterozygous female mice, and examined CASK-knockdown neurons in acute brain slices generated by in utero electroporation.

“Unlike most of the genetic disorders in which all of the cells in the body have same mutant genotype, our disease model possesses normal and morbid cells in the body as a result of X-chromosome inactivation,” explained study author Katsuhiko Tabuchi, MD, PhD, in an interview with Rare Disease Report. The study examined the role of CASK in maintaining the balance of the excitatory neurons and inhibitory neurons in the brain that work to increase and decrease brain activity, and how mutations in the gene and an imbalance in this mechanism lead to neurological disorders.

“In our study, we found an increase in the excitatory synaptic function and decrease in the inhibitory synaptic function only in CASK mutant neurons, but not in wild-type neurons in the same brain,” added Tabuchi.

The study team found that the imbalance is caused by a decrease in concentration of a specific receptor on the membrane that receives signals from other neurons, and increasing the concentration restored balance. The findings, said Tabuchi, may have important implications for other mental disorders such as autism or epilepsy.

“Although the number of patients of MICPCH syndrome is not that many, I believe the basic idea in our study would be applicable, at least, to the other x-linked female neurodevelopmental disorders, such as Rett syndrome, of which pathophysiology is affected by x-chromosome inactivation,” he explained.

Tabuchi said the findings may help with research on the epilepsy drug diazepam, an enhancer of inhibitory synaptic transmission. “It may be harmful if it affects normal cells in the patients with those disorders,” he said. “Our model mice can provide the answer by testing those drugs. For the next step of our work, we aim to study how skewness of the distribution of 2 different genotype of cells affects the symptoms of disorders. We also want to study whether normal and mutant neurons constitute neural circuit separately or cooperatively.”

The study, “Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B,” was published in Molecular Psychiatry.