Medical research drives a huge amount of our understanding around rare diseases. Recently, researchers from Brown University performed a study to deepen their understanding of a rare, X-linked genetic disorder called Christianson syndrome. According to news shared by Brown University, a new study lead by one of the school’s research teams highlighted some of the cellular mechanisms which drive Christianson syndrome. Ultimately, understanding these mechanisms could help to develop future treatment options for patients. Check out the full study findings published in the Journal of Neuroscience. 

Christianson Syndrome

To begin, let’s first fill you in on what exactly Christianson syndrome is. SLC9A6 gene mutations cause Christianson syndrome, a genetic disorder which affects brain development. As described by the Christianson Syndrome Association (CSA):

The SLC9A6 gene codes for the NHE6 protein, …part of a family of proteins that are sodium/hydrogen exchangers. The NHE6 protein is found in endosome, which take up molecules to be destroyed or recycled for other processes in our body.

But these mutations prevent this protein from working correctly. As a result, NHE6 cannot perform the proper processes in the endosome, such as releasing hydrogen and regulating protein turnover. Researchers believe this causes the endosome to become overly acidic. 

Because the syndrome is X-linked, it predominantly affects males. Females are more often carriers, though they may present with some intellectual disability. Symptoms in males include:

• Microcephaly (abnormally small head size)
• Low muscle tone
• Happy demeanor and unprovoked laughter
• Poor movement and balance
• Eye movement issues, such as strabismus
• Absent speech
• Cerebellar atrophy
• Gastrointestinal difficulties
• Low height and weight
• Intellectual disability
• Developmental regression
• Autism
• Epilepsy

The Research 

As described above, researchers knew that the endosome might become over-acidified. But how does this affect patients? You see, endosomes fuse with lysosomes to manage cellular waste. However, the over-acidification could cause issues. To further explore the exact impact, researchers used mice models of SLC9A6 mutations. 

First, researchers utilized a microscopic marker to track brain cell activity within these mice models. Through this, researchers saw how endosomes and lysosomes fused, as well as how endosomes released the “cargo” they were carrying. Findings from the study include:

• Endosome expulsion was much higher in cells associated with Christianson syndrome.
• Within patients with Christianson syndrome, lysosomes do not function properly. Researchers believe this could mean that Christianson syndrome is functionally similar to other conditions, such as Niemann-Pick disease or Tay-Sachs disease.
• Because of this, researchers believe that gene therapy could be a potentially promising treatment for patients with Christianson syndrome. 
• Within this condition, the endosome does not mature properly, thus creating fusion difficulties. As a result, endosomes were dropping “cargo” into the cell’s plasma membrane rather than where the cargo should be dropped. Researchers believe this could be a cellular attempt to get rid of waste without having to drop the waste into a non-functional lysosome. 

So what does this mean? In short, it means that while over-acidification does play a role, there are also other cellular mechanisms occurring which cause neurodegeneration. For example, non-functional endosome trafficking prompts other neurodegenerative processes. In the future, hopefully, this knowledge can be used to improve patient outcomes.