KLS research update in laboratory of Dr. Mignot, Stanford University (Oct 2018)

Exciting time in Kleine Levin Syndrome (KLS) research and a postdoctoral fellow opportunity

2018 has been a very productive year in KLS research!  Multiple directions of research, both clinical and basic research, have expanded. To pursue these areas, we need a motivated student interested in data analysis and statistics, as well as excellent communication skills, especially bedside manner. We have advertised locally and have not yet been successful in identifying a suitable person. It is our hope to find a candidate who may be associated with the KLS community in some form, whether it is personal interest and/or familial connection to the disease. Either way, we are seeking an intrigued individual who is finishing their PhD this year to join our lab and lead this effort. Below is a more detailed description of the work of our lab and what we’ve discovered.

 KLS research over the past few years has been extremely exciting!  We have been able to open the black box of this enigmatic illness using samples collected from individuals with KLS from around the world. We have used two complementary laboratory research approaches based on (1) genomics and (2) proteomics. Results have recently been presented at the 2018 European Sleep Research Society conference as described in two published abstracts (Ambati et al. 2018; Hillary et al., 2018, attached).

  1. In the first research so called ‘genomic’ approach, we completed a genetic study (‘GWAS’, genomic wide association study) of approximately 700 individuals with KLS versus matched healthy control individuals. The most salient discovery was a very strong GWA-significant association (a 50% increased risk, expressed as OR=1.5) with genetic polymorphisms located in a gene called TRANK1. A ‘genetic polymorphism’ is a change in the DNA in a genomic region in an individual as compared to healthy controls.

There are several implications of this finding. Strikingly, the exact same alleles of these TRANK1 polymorphisms have also been found in other GWAS studies to be associated with bipolar disorder (OR=1.23) and more weakly with schizophrenia (OR=1.08). It is important to note that the effect is much stronger in KLS versus these other diseases. It should be further noted that in the reported GWAS studies in bipolar disorder and schizophrenia, over 100 polymorphisms in other genes were also identified, but the commonality with the TRANK1 polymorphism provides a potentially important clue to understand KLS. The TRANK1 association may also explain the recent report of response to the drug lithium in a subset of KLS patients (when used in severe cases), as lithium is a common treatment for bipolar disorder.

KLS individuals with the TRANK1 polymorphism where further analyzed based on their clinical histories as reported in the KLS patient questionnaires. It is notable that individuals with KLS and with the TRANK1 polymorphisms did not report much more depression but did report a 2- fold increase in past history of perinatal problems or difficult birth. As increased perinatal problems have been reported in KLS, TRANK1-associated polymorphisms may mediate this effect, for example making birth more difficult and affecting brain function as a result. Furthermore, soon after we discovered the TRANK1 association, a publication in Nature Medicine found that bipolar and schizophrenia-associated polymorphisms (that include TRANK1) are associated with difficult birth in this population as well, an effect that the authors of the study suggest is explained by expression of many of the associated genes in the placenta. The combination of all these findings makes it likely that bipolar and KLS are related pathophysiologically, although it is unclear if some of the genetic effects are causing difficult birth that causes KLS later, or it is a mere co-association.

Using the KLS GWAS results, we also did what is known as a ‘gene pathway analysis.’ This can identify related biological pathways in such a large dataset and biological causes can be explored. This analysis revealed that, in addition to TRANK1, many other polymorphisms participate to the regulation of rhythmic behavior or circadian rhythms. This suggests that KLS may result from the conjunction of a bipolar-like predisposition and circadian regulation vulnerability.

These findings have been submitted for publication, but the editors asked us to independently replicate the TRANK1 finding in separate, new sample. Accordingly, we decided to collect an additional 100 KLS samples to replicate the finding. I am happy to announce that we have reached our goal, and will be sending these replication samples for genetic testing in a few weeks. I want to thank the KLS Foundation as many new samples came from our last meeting in San Francisco and also to researchers in France, Sweden, England, Germany, Italy, Taiwan, and Spain for sending additional samples to achieve this goal so rapidly.

These findings have two immediate clinical applications. First, considering the TRANK1 association, it may be logical to attempt treatment (under proper physician oversight) of patients in KLS episodes with the drug ketamine, a new treatment that has been shown to be effective in treatment-resistant depression and depressive bipolar episodes. One feature of ketamine is that it has immediate effects and the effects are short lasting (a few days to a week), which is a formidable issue for chronic depression but possibly an advantage for KLS episodes that only last 1-2 weeks. In KLS, it may thus be possible to administer ketamine only a couple of times during episodes at home and this could abort the episode altogether. Second, the fact that circadian and rhythmic genes are showing up in our GWAS results suggest that stabilizing circadian rhythms, such as with using light and melatonin, with careful monitoring of patients’ activity using an actigraph, could also prevent or reduce episodes.

We are hoping to find a KLS researcher finishing his/her PhD who would be interested in organizing such a study and to do other postdoctoral research at Stanford in this area.

2. In a second research approach, in parallel with the above, we also conducted very promising pilot proteomic experiments studying the blood and cerebrospinal fluid of patients with KLS, both in and out of KLS episodes (see Ambati et al., 2018). These experiments use a very new research technique (SomaScanTM) that can for the first time simultaneously measure the amount of 5,500 different proteins in a few drops of plasma and serum. Using an early released version of the technology, which enabled studying 1,100 proteins, we found very striking changes in protein levels during episodes that suggest activation of white blood cells known as monocytes. This was a surprise and suggests that some unusual type of immune activation occurs during KLS episodes. We now want to include more KLS patient samples to reproduce this finding. We will compare baseline levels of these same protein in patients out of episodes versus controls and study these in relation to our genetic findings. This is possible, as we have a database of thousands of SomaScanTM tested samples from other studies which has revealed genetic changes that modulate the levels of some of the altered proteins. In parallel, we could also examine if the DNA polymorphisms that change the levels of these proteins are associated genetically with KLS in our GWAS study. These experiments necessitate statistical, programming and genetic analytical skills, and for this reason, we are seeking a researcher with these skills or willing/able to learn, to join the laboratory.

In summary, there are very exciting things happening in the KLS research world.  As stated we are in search of the right individual, to join our team and help us get even closer to finding the cause and cure for KLS.  Please share this Ad with individuals you feel may fit the criteria we are looking for.  We are open to any and all suggestions and we look forward to hearing from you.  Thank you for your support and assistance in our search.

If you are interested in applying, please reach out to Briana Gomez, Executive Assistant to Dr. Emmanuel Mignot, Stanford University School of Medicine at: brianag@stanford.edu

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