MWSF Newsletter April 2023 : simplebooklet.com

Dr. Margaret L. P. Adamexplains the importanceof a registry in this way.“For health care providers who care for peoplewith MWS, it is important to understand whatmedical issues can occur and when they mightdevelop. This information is currentlyincomplete. Some medical and health issuesmay be specific to the specific genetic cause ofMWS in each person. Therefore, we are re-launching a new MWS Patient Registry to helpcollect clinical and laboratory data on MWSfrom people around the world. It is veryimportant for both clinicians and clinicalresearchers to understand a person’s medicaland developmental history in the context oftheir genetic testing result. For those familieswho are interested in enrolling in futureresearch studies, knowing the specific geneticchange causing MWS in an individual person isvery important. We are asking participants toprovide genetic testing information inaddition to clinical information, as they feelcomfortable. You can still participate in theregistry even if you don’t have genetic testresults or choose not to share them. We hopethat you will consider participating!” LEARN MORE

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Epilepsy is common in Mowat-Wilson Syndrome (MWS), present in over 70%,with about one in four intractable to anti-seizure medications. Seizures oftenbegin in late infancy or early childhood. About one-third with MWS haveessentially continuous abnormal EEG activity during sleep, a finding calledelectrical status epilepticus of sleep, or ESES. This continuous “epileptiform”activity may affect a child’s development. Our study aims to track theoccurrence of ESES and seizures in patients with MWS according to age,examine developmental outcomes, and explore associations between ESESand seizures, development, and response to therapy. Reports on MWSF Funded ResearchDr. John SchreiberDr. Rebekah CharneyThe objective of this project is to establish a brain organoid system for thestudy of neurological disability in Mowat-Wilson syndrome. Humanpluripotent stem cells can form any cell type in the body when exposed tothe correct cues and are a powerful system to examine human developmentand birth defects in the laboratory. Recently, researchers have developedexciting ways to use stem cells to assemble 3-dimensional “miniatureorgans” in a dish that are known as organoids. Organoids have beendeveloped for many organ systems and allow researchers to examinehuman developmental events that are otherwise inaccessible. Importantly,organoids represent enormous potential for disease modeling and drugdiscovery.The wide range of neurological disability seen in patients withMowat-Wilson syndrome highlight the crucial role that the ZEB2 gene playsduring the development of the central nervous system. In the first six months, we created the research protocol and obtained study approval from ourinstitutional review board. We identified and trained a clinical research coordinator, Taylor Haughton,who has a master’s degree in Psychology, to assist with the project. To facilitate remote study visits,we also made an electronic consent form. We created a study-specific database and electronic surveyto collect data on seizures, development, and other medical history. With our IRB and IT departments,we developed a process for secure data transfer from participants and secure data storage. We arenow pre-screening and consenting subjects for participation, obtaining medical records, history, andEEG, and collecting data. In the time remaining, we plan to enroll and collect data in 40 participants.We will complete developmental assessments, EEG review, and data collection and begin to analyzethe results. After the conclusion of the study, we will submit our findings as a manuscript in a peer-reviewed journal and seek additional outside funding for future projects stemming from this work

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With this project, I aim to examine the changes that occur during brain development in Mowat-Wilsonsyndrome by using patient-derived induced pluripotent stem cells to generate brain organoids. Towards the establishment of this model, it is important to examine the molecular changes in earlycentral nervous system formation in Mowat-Wilson syndrome. To accomplish this, I have been workingon validating the differentiation of human embryonic stem cells towards the neural lineage. Formation ofthis cell fate is being examined through changes in gene (mRNA) and protein expression. The use ofhuman embryonic stem cells allows me to confirm proper neural differentiation compared to previousreports using these same cell lines. This protocol will then be used with MWS induced pluripotent stemcells to examine changes in neuroectoderm formation. Next, as I initiate the brain organoid model, thesedata will be crucial in examining the molecular changes in MWS.As I establish my own independent research group, the Maci Whisner Research Grant from the Mowat-Wilson Syndrome Foundation is allowing me to establish the brain organoid model in my laboratory andgenerate novel data on how mutations in ZEB2 result in changes in human brain development. I hopethat this pilot project will pave the way for strong collaborations with the Mowat-Wilson syndromecommunity to use pluripotent stem cells to better understand and treat the clinical features of Mowat-Wilson syndrome.This study aims to understand the genetic basis of the changes observed in children with Mowat-Wilson syndrome (MWS) who also have Hirschsprung disease (HSCR) and other digestive issues. Weare sequencing the whole genomes for 2 kinds of families (Father, Mother, affected child): 1) wherethe child only has MWS and 2) where the child has both MWS and HSCR. Simultaneously we are alsogenerating the neurons and glia’s of the enteric nervous system (the cells affected in HSCR) in the labto study how specific Zeb2 mutations affect the formation of these cells and if these cells lose theirability to move, which is the major change in HSCR.We have within the first 6 months performed whole genome sequencing on 2 trios; one with a childwith only MWS and another family with child with both MWS and long segment HSCR. The DNA fromthese individuals were provided by Dr. David Mowat from Sydney Children’s Hospital. Dr. Mowat hasIRB approval for these sequencing studies. We were only provided deidentified DNA and were toldthe sex of the patient and if they had only MWS or MWS+HSCR.Our sequencing identified the specific mutations in ZEB2 for both the patients. Additionally, we alsodetected a large region of the genome duplicated near the gene EDNRB in the patient who had bothMWS and HSCR (Figure 1). EDNRB is a gene, mutations in which can lead to HSCR. Thus, it is highlyprobable that this disruption near the EDNRB gene leads to HSCR in this patient. In the next 6 monthswe hope to sequence 5 additional families.We have also now generated both neurons and glia of the enteric nervous system (nerves of thegastrointestinal system) from human embryonic stem cells. We are still in the process of making thespecific ZEB2 mutations to understand the cellular changes in the ENS due to these specificmutations, which we aim to finish in the next 6 months.Genetic and cellular interactions in Mowat-Wilson Syndrome patients with and withoutHirschsprung diseaseDr. Sumantra Chatterjee

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by Melissa (Harper's mom)Our daughter, Harper, is a perfect 7-year-old kid. She is happy, hilarious, smart,hardworking, kind, stubborn, she loves her sister and tolerates our dog, she LOVES herfriends and Roblox, and she has Mowat-Wilson syndrome.My husband, Adam, and I were so excited to get married and start our family in 2013. Whenwe found out in 2015 that we were expecting our first child, we had all the overwhelmingjoy, fear, and hope that all expectant parents experience. My pregnancy seemed typical.The 20-week anatomy scan was normal, and, as far as we knew, we were to have a healthy,typical baby.Harper came into the world in a blaze of glory. After 22 hours of grueling labor followed by an emergency C-section, she needed some assistance to start breathing. I think part of me knew from the beginning that she was different. She looked a bit different (striking really)and seemed to behave a little differently than other newborns...Meet the Batchelor Family and Harper's StoryREAD ON

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DONATE & SUPPORTFUNDRAISER EFFORTS1,000 FREE THROWS FOR MWSFGet ready for a slam dunk of a good time because Logan's family and the Woodstock,GA community are teaming up for Free Throws for Logan - an event you won't wantto miss! Jackie Arnold, Logan's mom, is the driving force behind this exciting event.Before COVID even hit, Jackie had a brilliant idea to put her unique skills to good use.Logan is a huge fan of basketball and baseball, he loves nothing more than watchinghis mom swish shot after shot as she practices for the event.Jackie has been working hard to perfect her free throws, and her goal is to get hershooting percentage as close to 90% as possible - just like she did in high school!She's already at 88%, which beats out 90% of college and pro basketball players.Impressive, right?Logan is 13 years old and will be starting at Woodstock Middle School this fall. FreeThrows for Logan is not only a fantastic way to introduce him to the community, but italso benefits both the Mowat Wilson Syndrome Foundation and Woodstock MiddleSchool's Special Education Department. It's a win-win situation!The event takes place on April 15th, and Jackie has set an ambitious goal of making1000 free throws in just five hours! From 11am to 2pm, attendees can show off theirskills in the "Beat the Mom" free throw contest. Then, from 2pm to 3pm, Jackie willmake her 1000th free throw, and the entire Mowat Wilson Syndrome Foundation willbe cheering her on!

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The MWS Foundation is looking for members forour Community Advisory Board. The Community Advisory Board provides the foundation with input and feedbackon the issues facing families. This is mainly done by interacting with your ownnetwork within the MWS community to gain information that can be shared withthe foundation. We meet quarterly, via Zoom. Meeting times vary to try to workwithin everyone's schedule. You will also be asked to participate in surveys and toencourage others to participate. It is a 2-year commitment. If you are interested,contact Deborah Curry at debyc@mowat-wilson.orgDONATEThe mission of the Mowat-Wilson Syndrome Foundation is to enhance the lives of people affected by Mowat-Wilson Syndrome by providing family support, raising awareness, and supporting research and education. Because we don't know what's possible.RESEARCH. SUPPORT. HOPE

MWSF Newsletter April 2023

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