by Dr. Eric Morrow
Christianson syndrome is a genetic disorder that affects brain development. It is an “X – linked” disorder (see “Why is CS found only in boys?” section for a description of what X – linked means). Symptoms of CS usually appear in infancy and include epilepsy and intellectual disability. Although the exact prevalence of Christianson syndrome is unknown, a genetic study by Tarpey and colleagues identified Christianson Syndrome in 2 of about 200 families (about 1% of families with apparent X – linked developmental disabilities). This was among the most common genetic change in X – linked forms of intellectual disability.
What are the causes of Christianson syndrome?
Christianson syndrome is caused by changes in the gene, SLC9A6. Genes are important because they code for proteins, which carry out essential processes in the cells of our bodies. The SLC9A6 gene codes for the NHE6 protein. NHE6 is part of a family of proteins that are sodium (NA+)/hydrogen (H+) exchangers. The NHE6 protein is found in endosomes, which take up molecules to be destroyed or recycled for other processes in our body. NHE6 makes sure that these endosomes have the correct intra-endosomal acid level by letting Na into the endosome and getting rid of hydrogen, which is the acid molecule. The acid level regulates protein turnover. An analogy is our stomach acid, the acidity in endosomes helps degrade cellular proteins.
These genetic changes in SLC9A6 cause the NHE6 protein to not work properly. You may have heard words such as “loss-of-function,” “truncation” or “frame-shift,” which describe how the NHE6 protein cannot be made in the cells to carry out these processes in the endosome. In a recent study from the Morrow lab, researchers showed that in the absence of NHE6 function in the endosomes, the endosomes become overly-acidic and they may become prone to over-degrade proteins. More research is needed to understand this mechanism further.
What are the symptoms of Christianson syndrome?
As we all know, children diagnosed with Christianson syndrome are special and unique in their own way. The “core” symptoms, ie those present in the majority of boys with CS, are intellectual disability, epilepsy, ataxia (movement/balance problems), lack of speech, eye movement problems (such as strabismus), microcephaly (small head size) and hyperkinesis (constantly moving). Other symptoms that may not be present in all boys but are present in some include hypotonia (low muscle tone), gastrointestinal problems (such as GERD), regressions (loss of previously learned skills like walking), symptoms of Angelman syndrome (such as happy demeanor and unprovoked laughter) and autism, low weight/height, and cerebellar atrophy (meaning the cerebellum does not grow and/or gets smaller).
Why is Christianson syndrome only found in boys?
We usually have 2 copies of each gene (1 copy from mothers and 1 copy from fathers). This is the case for chromosomes 1-22 or “autosomal” chromosomes. But we also have “sex” chromosomes where females have 2 copies of the X chromosome and males have only 1 copy of the X chromosome and 1 copy of the Y chromosome. The SLC9A6 gene is found on the X chromosome. This means that if there are changes in 1 copy of the SLC9A6 gene in females, there is a copy of the SCL9A6 gene in the other X chromosome that can function and make the NHE6 protein. But in males who have only 1 copy of the X chromosome, a change in the SLC9A6 gene means that the NHE6 protein cannot be made (because males only have that 1 copy of the X chromosome). This is why you may have heard that this is an X-linked disorder that affects boys.
What is the prognosis of Christianson syndrome?
Because this is a newly recognized genetic disorder and a relatively small number of boys have been diagnosed, we cannot fully predict the prognosis. These symptoms usually continue as the boys age, but epilepsy treatments (such as anti-epileptic medication) may be able to make the seizures less severe and decrease the number of seizures. Currently, there are no treatments available to fully treat boys diagnosed with CS. We believe that by continuing to study CS, we will have a better idea of what CS is and how to treat CS in the future. The challenges for research are substantial but we know a lot more in just the last year than we did previously, so we hope that research will continue to advance at a fast pace.
Are there any new studies about NHE6?
Dr. Eric Morrow’s lab recently published a study in the widely-read journal Neuron investigating NHE6 and its role in brain development. The results showed loss of NHE6 protein causes endosomes to be too acidic. Neurons with no NHE6 protein (in mice) had less branching (or connections) in dendrites (the part of the neuron that receives information) and axons (the part of the neuron that sends information). Because endosomes are too acidic, the protein TrkB, a receptor for a brain growth factor BDNF, is broken down excessively causing neurons to not branch or make as many connections. Finally, by adding the neuronal growth factor BDNF back to cells in excess, neurons lacking NHE6 were able to grow more branches, looking more like neurons that had NHE6. Much more research needs to be done to develop a fuller explanation for the symptoms in CS and to develop treatments. We don’t know if a BDNF-like molecule could be used for treatment and/or another molecule. While there remain a good number of important studies that need to be done prior to treatment trials, these initial results are very hopeful as they provide important information about different directions that scientists like Dr. Morrow and colleagues may take in the future in order to develop a treatment.
Dr. Eric Morrow is a graduate of Harvard Medical School. He is Board certified with the American Board of Neurology and Psychiatry. Dr. Morrow is now at Brown University in Providence, Rhode Island, where he is Associate Professor and the founding director of the Developmental Disorders Genetics Research Program (DDGRP) at the Emma Pendleton Bradley Hospital. His research group is devoted to the study of Christianson Syndrome and related neurodevelopmental conditions.