Originally posted 4 July 2021. Updated 28 May 2023.
David loves to walk. He has a strange cycle of activity and there are periods where he just cannot sit still. So, he walks and walks to burn off the need to have activity. Getting him to walk was a major undertaking. It took 6 years of hard work with the physical therapist and his family at home until walking emerged. His gait is clunky. He walks as if he has weights in his shoes. But, he walks and walks when he needs to. Walking is so important for David in so many ways.
David might not be able to walk if he had serious lymphedema. David has peers with 22q13.3 deletion syndrome (Phelan-McDermid syndrome, PMS) who suffer from lymphedema. Lymphedema is seen much more often in cases of large terminal deletions. Undoubtedly, there is a gene somewhere in the list of PMS genes that causes lymphedema (see How do I know which genes are missing?). A group of medical researchers in China who study lymphatic surgery and pediatrics teamed up to treat a 20-year-old woman with lymphedema due to PMS. After careful examination of the woman, her genetics and the pathological mechanisms that can lead to lymphedema, the research group has come up with a very plausible explanation. Subsequent work has verified the gene involved.
The key to this investigation is that the young woman suffers not only from lymphedema, but also from protein-losing enteropathy (PLE). PLE is a condition where the body has an insufficient amount of protein. PLE is related to lymphedema when problems with the lymph vessels supplying the lining of the intestine cause poor absorption of nutrients. When improperly formed intestinal lymph vessels or blockage of lymph flow from the intestines (called lymphangiectasia) occurs, you can have insufficient protein absorption. In 2013 it was shown that loss of the gene celsr1 in mice leads to improperly patterned lymph vessels and lymph valves. In 2016 it was shown that an error in the CELSR1 gene in several generations of a family caused inherited lymphedema in their legs (Gonzalez-Garay et al 2016). Through this understanding, Xia and colleagues have provided a strong case for human CELSR1 as the causal gene for lymphedema in PMS (Xia et al 2021 Lymphedema complicated by protein-losing enteropathy with a 22q13.3 deletion and the potential role of CELSR1).
The researchers were not able to specifically demonstrate GI lymph flow was disrupted in their clinical case, partly because the young woman was not a candidate for lymphography and there was no clinical justification for sampling with endoscopy. Still, the lymphedema was quite clear in this patient and likely the cause of PLE. More importantly, the patterning gene CELSR1 can explain both lymphedema and PLE.
So far as seen the in literature, PLE seems to be very uncommon in PMS. Maybe it showed up in this case because of a diet less protein-rich than in many Western countries. Would we have discovered this sooner if we had more low-income or otherwise disadvantaged people in our community? Diversity and inclusion is not just an ethical concern. It is at the heart of scientific understanding.
A new study was published in May 2023 confirming CELSR1 as the central gene for lymphedema (https://pubmed.ncbi.nlm.nih.gov/37232218/). In this study, the authors reviewed 404 cases from the PMS Foundation Data Hub and showed that the likelihood of lymphedema is greatest when CELSR1 is missing.
Perhaps it is time to look more closely at protein absorption in people with PMS. Are there subclinical cases of malabsorption? Since CELSR1 is the central gene for lymphedema, people with PMS terminal deletions of sizes greater than 4.3 Mb are at risk for lymphedema and (perhaps) PLE. In both cases, the penetrance is incomplete: the deletion of one copy of CELSR1 makes someone more prone to these problems. We should not dismiss the importance of this work even if the problems are not expressed in every case.
I see an additional take home message from this research. It is clear that helping people with PMS requires understanding and considering all the genes lost when a deletion occurs. This requires input from many different medical and research fields. As parents of children with PMS, it is our job to encourage and reward novel and valuable contributions. In science, one way to acknowledge the contribution of a fellow scientist is to cite his/her work. This blog serves as a thank-you to Song Xia, Wenbin Shen and colleagues. This blog is not the first time I have acknowledged the work of Gonzalez-Garay et al in the Sevick-Muraca laboratory. The mouse work on the Celsr1 protein was done in the Makinen laboratory in the UK and the mouse model was developed by Fadel Tissir in Belgium. Fadel Tissir has studied Celsr1 over many years. All of these people deserve recognition for their contributions. I have personally emailed Dr. Tissir to thank him for his contributions to PMS. Letters of encouragement are a powerful and largely untapped tool we parents have to accelerate the discovery of new treatments for our children. I think we miss an opportunity each time a relevant paper gets published without thank-you notes from our community.