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In this issue: What are experts saying about the importance of genetic testing in individuals with bone marrow failure? Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you! The Importance of Germline Genetic Testing for Patients with Bone Marrow Failure and Related Disorders Between March 21-22, 2024, the Aplastic Anemia and Myelodysplastic Syndrome International Foundation (AAMDSIF) hosted the 9th International Bone Marrow Failure Disease Scientific Symposium in Bethesda, MD, USA. This meeting brought together experts from around the world to discuss the latest advances in both the science and patient care for these disorders. The first session at the Scientific Symposium highlighted the role of genetic testing for persons with bone marrow failure, and led to a lively discussion on when, whom, and what genetic testing should be offered. We reached out to Dr. Lisa J. McReynolds, a leading physician-scientist studying inherited bone marrow failure syndromes (including Shwachman-Diamond Syndrome!) and the first speaker at this Scientific Symposium, to bring you an exclusive summary of their thoughts on the importance of genetic testing for individuals with bone marrow failure. Here is what they shared: Shwachman-Diamond Syndrome (SDS) is part of a group of disorders that are often collectively called “inherited bone marrow failure syndromes (IBMFS).” This is because what unites all IBMFS is that they can be genetic (or inherited, passed from parent to child in the genes) and can cause a person’s bone marrow to “fail”, stop working, or malfunction. It can be very difficult to sort out which form of bone marrow failure a person has. This problem is made worse by the fact that other disorders that are not genetic can look a lot like an IBMFS. Two of these disorders are aplastic anemia (AA) and myelodysplastic syndrome (MDS). AA is caused by an immune attack on the person’s bone marrow leading to it to not function. MDS is a form of blood cancer that under the microscope can look like an IBMFS. There are some laboratory tests that can help sort out IBMFS (and which specific type) versus AA versus MDS, but they can be insufficient to get a final diagnosis. One of the best tools healthcare providers have to reach an accurate diagnosis is genetic testing. This SDS & Science Snapshot published last fall helps explain the role of genes in developing diseases such as AA or MDS and the difference between somatic and germline mutations. Additionally, the SDS Science Spotlight YouTube video below also explains how individuals with SDS are at-risk of developing bone marrow failure or leukemia and how this relates to the genetics of SDS. So, why should people with bone marrow failure, such as individuals with SDS, have genetic testing? The signs of a genetic disorder can be subtle or absent when a person comes to the attention of a healthcare provider, and there is often no family history of a genetic disease. About 5% of all patients with bone marrow failure have a genetic reason for their disease. This number is critical since many professional societies recommend genetic testing for diseases with a greater than 5% chance of being genetic. Uncovering a genetic cause for the person with bone marrow failure can lead to changes in treatment planning and screening recommendations moving forward. Genetic testing results may also change who is chosen as a donor if the person plans to have a bone marrow transplant. Genetic testing results can also help guide potential genetic testing of other family members. There are several different types of genetic testing that can be done for SDS and other bone marrow failure diseases, such as panel testing or exome sequencing (this SDS & Science Snapshot published a few weeks ago reviews genetic testing for SDS in more detail). The choice of testing is best determined by your genetic counselor and physician. However, getting genetic testing can be challenging for some patients. One of the biggest challenges many patients face is insurance coverage. Many insurance companies do not cover the testing and if it is covered it can be insufficient or come with large out-of-pocket costs. This has unfortunately led to inequities across our bone marrow failure community with some patients being able to access genetic testing and others not. Healthcare providers need to advocate for all bone marrow failure patients to receive genetic testing as recommended. To help address these inequities, Shwachman-Diamond Syndrome Alliance is committed to increasing access to no-cost clinical genetic testing for individuals suspected of having SDS and providing opportunities to participate in research for those with previous negative or uninformative genetic testing results. Stay tuned to our SDS & Science Snapshot series this Spring to learn more about genetic testing resources that may be helpful for your family! Or, reach out to us directly via email at genetics@SDSAlliance.org. We are here to help! The team at SDS Alliance would like to extend a warm message of appreciation to Dr. Lisa J. McReynolds for their contributions to this SDS & Science Snapshot and, more importantly, for leading critical research efforts for individuals with IBMFS such as SDS! AAMDSIF Resources: The AAMDSIF has published several Patient Guides and Fact Sheets (available in multiple languages including Italian, French, German, Spanish, and Portuguese!) for understanding acute myeloid leukemia (AML), MDS, and AA on their website! These toolkits published by AAMDSIF answer some of your most important questions about Aplastic Anemia and Myelodysplastic Syndrome! AAMDSIF also hosts Patient and Family Conferences for individuals who have been diagnosed with and/or survived AA, MDS, AML - visit their website for a list of these events happening this year across the United States in Los Angeles, Seattle, Philadelphia, Chicago, and Tampa. Disclaimer: The views and opinions expressed in this SDS & Science Snapshot only reflect those of Lisa J. McReynolds, MD, PhD. Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

In this issue: How are advances in genetic testing technology changing newborn screening and the course of the diagnostic odyssey in rare disease? Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you! BeginNGS: Newborn Genomic Sequencing to End the Diagnostic Odyssey Two weeks ago, a new podcast episode of Once Upon a Gene was released highlighting BeginNGS, a ground-breaking initiative at Rady Children’s Institute for Genomic Medicine (RCIGM) that is helping to rewrite the story for infants with rare diseases (including Shwachman-Diamond Syndrome!). We reached out to Dr. Jennifer Schleit, Laboratory Director at RCIGM, to bring you an exclusive summary on how advances in genetic testing technology are changing newborn screening methods and the course of the diagnostic odyssey in rare disease. Here is what they shared: Newborn screening (NBS) is a public health program aimed at testing babies for genetic conditions that are treatable, but may not be apparent at birth. Through early diagnosis, affected children can receive appropriate monitoring and treatments to reduce the negative impacts of these disorders and improve survival rates. (For more information about the economic impact of a delayed diagnosis, you can read this recent SDS & Science Snapshot). Currently, NBS programs are active in all 50 states and it is estimated that approximately 98% of babies born in the United States will be tested in the first two days of life. An interactive timeline showing the evolution of newborn screening methods is published on the BeginNGS website. For more information about traditional newborn screening and what conditions are screened for across the United States, you can visit this website, Baby’s First Test. How are advances in genetic testing technology changing newborn screening? Current NBS programs primarily use laboratory methods such as mass spectrometry or enzyme activity to perform the screening in babies These methods have been successful, however they limit the number of disorders that can be tested, as only those disorders that can be detected with these testing methods can be included in current screening programs. Recent advances in genome sequencing, including reduced sequencing costs and faster sequencing time, have led to this technology being considered as a new testing method in NBS. Genome sequencing allows for more disorders to be tested simultaneously. The SDS & Science Snapshot published a few weeks ago helps explain why genetic testing for SDS is important and how you can access it. What is BeginNGS? BeginNGS is a pilot project based out of Rady Children’s Institute for Genomic Medicine (RCIGM) to use genome sequencing to screen newborns for over 400 early onset, actionable disorders (including Shwachman-Diamond Syndrome!). RCIGM is a world leader in ultra-rapid and rapid genome testing, making it uniquely positioned to deliver NBS results in a timely manner. This project is currently based at Rady’s Children’s Hospital in San Diego, California. The BeginNGS team is actively planning to expand this trial to include additional health systems to enable participation from more geographic areas. How are disorders selected or BeginNGS? Candidate disorders were identified by reviewing clinical diagnostic testing of over 4000 critically ill newborns and children at RCIGM, by reviewing lists of expanded NBS disorder lists developed by other groups, and by evaluating publications which reported interventions for these disorders. Selected disorders were then evaluated by a team of medical and genetics professionals. Disorders included in BeginNGS met the following criteria: They had acute, childhood admission that were likely to lead to hospital admission A treatment was available for the disorder It is a single-locus genetic disorder, inherited defects in a single gene can cause disease There is a high likelihood of rapid disease progression without treatment The disorder can be diagnosed by genome sequencing Additional disorders could be added to BeginNGS as they are discovered and/or new treatments become available. The team at SDS Alliance would like to extend a warm message of appreciation to Dr. Jennifer Schleit and the BeginNGS team for blazing trails in the newborn genomic sequencing space, shortening the diagnostic odyssey for individuals and families in the SDS community. SDS Alliance looks forward to sharing the results of the BeginNGS initiative with the SDS community in future SDS & Science Snapshots. For more detailed information about how Rady Children’s Institute for Genomic Medicine plans to change the landscape of newborn screening with whole genome sequencing, you can read their manuscript published in the American Journal of Medical Genetics. Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

In this issue: Three different case reports about various aspects of SDS, and the affected SDS patients' unique experiences. Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you! The last few weeks have brought us three different case reports published in the biomedical literature, each highlighting a different aspect of the disease. A case report of a young patient with SDS whose diagnosis was nearly missed This case report shares the story of a young patient with SDS whose diagnosis was nearly missed due to inconsistent genetic test results and liver issues not always recognized as typical for SDS. Initially, the patient was thought to have a rare, genetic liver disease or mitochondrial disease. The authors describe in great detail their findings regarding the liver of the patient, such as electron microscopy imaging of the inside structure of liver cells, including mitochondria. Note, that the ribosomes in the mitochondria (a.k.a. mitoribosomes) are structurally different and responsible for translating genetic information encoded in mitochondrial DNA. These ribosomes are NOT involved in SDS, but can cause mitochondrial diseases if there is a defect. Mitochondria are organelles responsible for converting energy from food into ATP, the chemical energy our cells need to live and thrive. Check out our blog post on ribosomes and mitochondria, here. The authors report: "Ultrastructural analysis of SDS-related hepatic pathology has not been previously reported. In our patient, EM on liver biopsy specimens was notable for numerous small mitochondria that were densely packed within the cytoplasm, reminiscent of “oncocytic transformation” usually seen with the primary mitochondrial condition, mitochondrial DNA depletion syndrome." As we all know, SDS is a rare genetic syndrome characterized by multiorgan dysfunction with typical presenting features that include exocrine pancreatic, hematologic, and skeletal abnormalities. It is now also established that the liver is often affected. However, the long-term implications are not known, and there is no treatment available for the frequently reported highly elevated liver enzymes (transaminases) in young children. We know from the SDS patient community that many patients undergo liver biopsy before being diagnosed with SDS, with no clinically actionable outcomes. For most patients, the liver enzyme levels go back down into (or close to) normal levels within the first 5 years of life. The authors report: "SDS-related liver disease has an overall good prognosis, as the elevates transaminases, hepatosteatosis, and fibrosis tend to normalize around 5 years of age. Adult patients with SDS usually have no evidence of clinical liver disease, with few rare exceptions." We believe that this assumption warrants further investigation, as there is very little data available about adult SDS patients' overall health. Despite the high prevalence of highly elevated liver enzymes in early childhood, very little is known about the condition. There is a high need for research in this area. The genetic workup of the child has not been straightforward, either. Whole exome sequencing (WES) initially missed the diagnosis. The authors looked into why. They think that it is either because not all the relevant symptoms were listed in the WES test request, and therefore the SDS genes may not have received the proper attention at the data interpretation step by the testing company, or perhaps there was a problem with the test analytics due to the SBDS pseudogene SBDSP1. Check out our blog post on pseudogenes to learn more. The authors report: "Interestingly, the SBDS gene variants that were ultimately identified on the patients WGS were within genetic regions that could have been identified on WES, with one variant within exon 2 (c.183_184delTAinsCT), and the other a 5′ donor splice-site mutation between exons 2 and 3 (c.258 + 2T > C). This is significant because c.183_184delTAinsCT and c.258 + 2T > C are two of the most common pathogenic variants in SBDS." The full article is available here: A success story of treating an SDS patient with AML in China One of the biggest concerns we face as SDS patients and caregivers is the risk of developing leukemia, specifically acute myeloid leukemia, or AML for short. The risk is estimated to be around 30% by age 30, which keeps on going up after that. AML develops when the blood-forming stem cells in the bone marrow accumulate new mutations (also known as somatic mutations) that allow them to grow out of control. We have covered the mechanism of this in an educational video, here. To make matters worse, AML in SDS patients often contains p53 mutations, which makes its treatment even harder than it already is. Combined with the increased sensitivity to chemotherapy that would be needed to get rid of AML, there are very few success stories of a positive outcome. The medical and scientific community is hard at work trying to find better treatment options for AML, for both the general population and for SDS patients, as highlighted at many scientific conferences, including the AA-MDS Symposium which our team attended just last week. More about that soon. Today, we want to highlight a brand new case report from Beijing, China, in which the authors report success in treating one SDS patient who developed AML. The approach was to treat the AML first to reduce the number of AML cells, in order to increase the likelihood of success for hematopoietic stem cell transplant. This is not a new approach, and many groups are looking for a good combination of chemotherapeutic drugs that can work for SDS. It seems that for this particular patient, they found something that worked. The authors report: "At present, pre-transplant bridging therapy has emerged as one of the important options with improved efficacy, reduced tumor burden, and less treatment-related toxicity. Here we reported azacitidine combined with venetoclax was used as pre-transplant bridging regimen in a TP53-mutant AML-MR case developed from SDS. He achieved complete remission with incomplete recovery and proceeded to Allo-HSCT. We hope to provide some evidence and insight for in-depth research and clinical treatment by presenting this case." At the time of this article, the patient has been 6 months post-transplant and well. We wish the 15 year-old-patient continued health and recovery. We have reached out to the authors to learn more and will update this blog post if new information becomes available. Azacitidine combined with venetoclax alleviates AML-MR with TP53 mutation in SDS: a case report and literature review. Ma C, Lang H, Chen Y, Yang L, Wang C, Han L, Chen X, Ma W.Anticancer Drugs. 2024 Mar 15. doi: 10.1097/CAD.0000000000001594. Online ahead of print.PMID: 38502829 A case of a severe, zoonic infection of a 17-year-old patient with SDS In this recent case report, the authors share the case of a 17-year-old patient who was diagnosed with SDS as a child and treated with GCSF and PERT but lost to follow-up for several years. She came to the emergency room very ill with an acute infection, which developed into sepsis. The primary infection was identified as rat-bite fever (RBF), an important bacterial zoonosis primarily caused by Streptobacillus moniliformis in North America, but the pathogenesis is understudied. "She reported exposure to pet rats, dogs, cats, chickens, guinea pigs, sugar gliders, and a snake." From the information available to us about the article, it is unclear whether the patient made a full recovery or not. We have reached out to the authors to request more information and will update this blog post as we learn more. If you or your child has SDS, please discuss with your healthcare team whether pets are safe for your household, and/or what special precautions should be taken around them. Frequent recommendations from the SDS community include being extra careful around cat litter and avoiding handing cat litter to SDS patients and any people who may be immune-compromised (such as pregnant people) to reduce the risks of toxoplasmosis. Warning: there are disturbing images included in the original article. Viewer discretion is advised. Oh rats! Intracellular rod-like inclusions in an adolescent with Shwachman-Diamond syndrome. Mayhew J, Luttrell H, Barros K, Blazin L, Nichols C, Avashia-Khemka N, Lavik JP, Relich RF, Skinner D, Zhou J, Saraf A, Khaitan A.Pediatr Blood Cancer. 2024 May;71(5):e30918. doi: 10.1002/pbc.30918. Epub 2024 Feb 23.PMID: 38391125 No abstract available. Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

In this issue: Why is genetic testing for SDS important and how do I access it? Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you! Spring into Action: Genes and Genetic Testing for SDS On Rare Disease Day two weeks ago, we launched our "Spring into Action" campaign, with which we amplify the patient voice in SDS in order to improve patients' lives, be it through more focused, impactful research, community support, or advocacy. Over the next few weeks and months, we will highlight multiple efforts, resources, and learning opportunities. Today, we bring you a summary of genes, genetic testing, and the importance of both in SDS. What are genes? Our bodies are composed of trillions of cells that have many different roles – to help us grow, digest food, protect us against infections, and more. These different tasks are controlled by a set of instructions known as genes. (We even have genes whose purpose is to protect us against cancer!) Genes are made up of DNA, which you inherit from your parents, and they determine things like your eye color, height, and even your risk for certain health conditions. What are genetic mutations (i.e., variants)? Sometimes there are mistakes in our genes, like a typo or error in an instruction manual or recipe book. These genetic mistakes are called mutations or variants. Shwachman-Diamond Syndrome (SDS) happens because of these genetic mistakes in certain genes including SBDS, EFL1, DNAJC21, and SRP54. These genetic mistakes are passed down from parents to kids and cause SDS. Imagine if a sentence in a recipe book had a mistake, like telling you to turn off the oven to bake cookies. Then the cookies wouldn’t bake properly! Our cells work the same way. If there's a mistake in the genes that tell our cells what to do, our cells may have a difficult time functioning properly. You can also watch our SDS Science Spotlight video on the Genetics of SDS to hear more about how these genetic mistakes (or mutations) contribute to the development of SDS. What is genetic testing? Genetic testing is the process of analyzing a gene (or more commonly, a set of genes) for these genetic mistakes that would result in SDS. Genetic testing is comparable to reading an instruction manual or recipe book very closely to identify any errors made during the writing process. Why is genetic testing for SDS important? Genetic testing for SDS helps your care team confirm a diagnosis of SDS and provide a clearer understanding of why you may be experiencing certain health issues. A genetic diagnosis of SDS can help guide your care team in making and following personalized treatment plans and surveillance guidelines to help you stay healthy! What types of genetic testing are recommended for individuals with symptoms of SDS? There are different kinds of genetic testing available for individuals who have a suspicion for SDS based on symptoms or health issues and/or a family history of SDS. If we return to the instruction manual analogy when considering the different types of genetic testing, there are some genetic tests that only look for errors in specific sections of the instruction manual known to be associated with SDS. This type of genetic testing only looks at one or all of the known SDS/SDS-like genes, including SBDS, EFL1, DNAJC21, and/or SRP54. There are other more thorough types of genetic testing that look for errors in the entire instruction manual, meaning all of the genes in your cells (over 20,000!) are analyzed. This kind of genetic testing can be costly and time-consuming but may provide an answer for some families as we learn more about the genetic cause(s) of SDS. My care team has mentioned their concern for SDS, how do I access genetic testing? If your care team has mentioned a concern for SDS, we encourage you to talk with them about your options for genetic counseling and testing. Genetic testing can be ordered by a healthcare provider such as a doctor or a genetic counselor. In the SDS community, physicians who order genetic testing for SDS frequently include primary care physicians, pediatricians, gastroenterologists, hematologists, oncologists, and many others. For individuals in the United States, The National Society of Genetic Counselors has a Find a Genetic Counselor Tool available on their website to search for a genetic counselor local to you. We encourage you to choose the specialties of Cancer, Hematology, and/or Pediatrics to help you narrow your search for a genetic counselor. If I have SDS myself, and my partner doesn't, can our kids get SDS? The odds of your children getting SDS depends on your and your partner's genetic makeup. For example, let's consider SDS caused by mutations in the SBDS gene, which typically is inherited in an autosomal recessive pattern. A partner who doesn't have symptoms of SDS may be a carrier of one mutation in a gene that causes SDS or have no mutation at all. The partner with SDS will have two mutated versions of the gene, and no healthy copy. The odds of the children getting SDS will depends on all these factors and more, such as rare genetic events related to pseudogenes, for example. Check out the video embedded above. We covered the concept of pseudogenes in an earlier edition of the snapshots, and these may factor into the odds as well. If you have a diagnosis of SDS and/or a family history of SDS, and are planning a pregnancy, you may also find it helpful to speak with a Prenatal Genetic Counselor to discuss what genetic testing might be available to help inform you and your partner on the chances of having a baby who also has SDS. For individuals in the United States, The National Society of Genetic Counselors has a Find a Genetic Counselor Tool available on their website to search for a genetic counselor local to you. Stay tuned to our Science Snapshot series this Spring to learn more about genetic testing resources that may be helpful for your family! __________________________________________________________________________________ Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

In this issue: Q&A with an SDS Advocate: What were they doing on Rare Disease Day? (¡También disponible en español!) Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you! Spring into Action: Joyce's Rare Disease Day Experience Every year, on the last day of February, the international Rare Disease Community comes together to raise awareness about important policy and other issues related to rare disease. For us, every day is Rare Disease Day. Check out our updated Rare Disease Day website. Rare Disease Day, for us, is a launch pad for our "Spring into Action" campaign, with which we amplify the patient voice in SDS in order to improve patients' lives, be it through more focused, impactful research, community support, or advocacy. Over the next few weeks and months, we will highlight multiple efforts on how the SDS community springs into action, starting with how our community leveraged Rare Disease Day events to learn and make progress. Today, we bring you an interview with Joyce, a young advocate living with SDS, highlighting her Rare Disease Day experience. You can learn more about Joyce’s story of living with SDS on the Rare Disease Day website where she is featured as a hero or in this 60 Seconds of RARE video published by the RARE Revolutions Magazine. What event(s) did you participate in for Rare Disease Day and what was your motivation to participate? Joyce: On Rare Disease Day in 2024, I participated in the Rare Disease Legislative Advocates’ Annual Rare Disease Week on Capitol Hill. Over four days we attended conferences, caucus briefings, and discussions. On February 27th, everyone had meetings with their state senate offices and representatives to share their story and introduce legislation to help them in their journey. I was motivated to participate in this event not only because of my advocacy experience and public speaking skills, but also because I wanted to share my story to help assist and guide the government into making decisions that would benefit the rare disease community. I used my experiences and knowledge to my advantage to guide the minds of those in Congress to sign-off on key legislation that would impact the rare disease community. What was your most memorable moment from Rare Disease Day? My most memorable moment from Rare Disease Week was meeting others with rare diseases or connecting with rare diseases and advocating together. It was such an empowering moment to be able to connect with others who have experienced similar journeys – being together in one room to advocate for similar goals. We all were encouraging and standing with each other during our meetings and events to motivate ourselves and the people around us. I very much enjoyed being able to speak up about some issues involving the rare disease community and some possible legislation that would impact the SDS community. Did you learn anything new or gain any insights from your participation in Rare Disease Day events? I learned a lot this year on Rare Disease Week. I learned how to gain a stronger understanding of how to tell my story, and what details to share when speaking with government officials. I learned how I can incorporate my experience and journey with SDS into advocating for certain bills for the rare disease community as a whole. I gained insight from fellow peers, advocates, and leaders in the rare disease community about the diagnostic odyssey of rare disease patients and what each individual is doing to help us as a community. I learned how to transform my public speaking skills into a motivational day full of business and fun. Plus a fun little perk of attending this event is that I learned how to navigate my way through the US House of Representatives and Senate buildings through underground tunnels. How do you plan to continue advocating for SDS and other rare diseases beyond Rare Disease Day? I plan to continue to be an active member of the Rare Disease Legislative Advocates this year, speaking out for legislation for the rare disease community. This year I plan to be an active Young Adult Rare Representative as I enter my 16th year of life. I plan to continue to use my experience of living with a rare genetic disorder to further expand the knowledge of those around me about SDS and the problems surrounding our community. By using my story, I can have solid backing for my proposals to the congressmen and women, giving them a personal connection to the legislation. I also plan to continue to post on my SDS Instagram account @cure.sds, to provide information on the disease and what daily life looks like. What advice would you give to others who are interested in getting involved in advocacy efforts for Rare Disease? The advice I give to others is always to use their past experiences and traumas to their advantage in the field of advocacy. Use your insight and knowledge of living with or caring for someone with a rare condition to be able to speak up against the issues in the rare disease community. I always tell people they should not fear their disease and instead make it a part of them. In advocacy work, it is key to embrace your disorder to truly be able to speak out and stand up for what is right. By using your story, you can catch the eyes of people who may have never heard of your disorder and are willing to help. If you are just entering into the advocacy space, I recommend starting small, creating a social media platform to raise awareness and give insight into the common problems and daily life of living with a rare disorder. Never stop because something goes wrong, use that negative event as further inspiration to keep thriving as an advocate and as a human being. Not everything is going to go your way all the time, there will be some bumps in the road, so turn that negativity into strength. On behalf of our team at SDS Alliance - Joyce, we thank you for your hard work, dedication, and passionate advocacy for the SDS community on Rare Disease Day and everyday! We are grateful to have you as a member of our community and can't wait to see how you transform the lives of so many living with a rare disease. __________________________________________________________________________________ Check out our new SDS infographics (available in English and Spanish/Español)! __________________________________________________________________________________ If you’re interested in viewing some of this year’s Rare Disease Day events, many of them were recorded and are now available to stream online: The White House: Rare Disease Forum Broad Institute of MIT and Harvard: Rare Disease Day 2024: Climbing Ladders to Cures in Rare Disease Research National Institutes of Health (NIH): Rare Disease Day Event US Food and Drug Administration (FDA): FDA's Rare Disease Day 2024—Dedicated to Patients and Providers __________________________________________________________________________________ Actúe: la experiencia del Día de las Enfermedades Raras de Joyce En este número: Preguntas y respuestas con un defensor de SDS: ¿Qué estaban haciendo el Día de las Enfermedades Raras? Cada año, en el último día de febrero, la comunidad internacional de enfermedades raras se reúne para crear conciencia sobre políticas importantes y otras cuestiones relacionadas con las enfermedades raras. Para nosotros, cada día es un día de Enfermedad Rara. Para nosotros, el Día de las Enfermedades Raras es una plataforma de lanzamiento para nuestra campaña "Actúe en primavera", con la que amplificamos la voz de los pacientes en SDS para mejorar sus vidas, ya sea a través de investigaciones más enfocadas e impactantes, apoyo comunitario o abogacía. Durante las próximas semanas y meses, destacaremos múltiples esfuerzos. Hoy les traemos un resumen de cómo nuestro equipo aprovechó los eventos del Día de las Enfermedades Raras para aprender y progresar. Le preguntamos a Joyce, una joven defensora que vive con SDS, sobre su experiencia en el Día de las Enfermedades Raras. Puede obtener más información sobre la historia de Joyce sobre cómo vivir con SDS en el sitio web del Día de las Enfermedades Raras, donde aparece como una heroína o en este video de 60 Seconds of RARE publicado por la revista RARE Revolutions. ¿En qué eventos participó para el Día de las Enfermedades Raras y cuál fue su motivación para participar? Joyce: En el Día de las Enfermedades Raras de 2024, participé en la Semana Anual de Enfermedades Raras de los Defensores Legislativos de Enfermedades Raras en Capitol Hill. Durante cuatro días asistimos a conferencias, reuniones informativas y discusiones. El 27 de febrero, todos se reunieron con las oficinas y representantes del senado estatal para compartir su historia y presentar legislación que los ayude en su viaje. Me motivó a participar en este evento no solo por mi experiencia en defensa de derechos y mis habilidades para hablar en público, sino también porque quería compartir mi historia para ayudar y guiar al gobierno en la toma de decisiones que beneficiarían a la comunidad de enfermedades raras. Utilicé mis experiencias y conocimientos a mi favor para guiar las mentes de los miembros del Congreso para aprobar una legislación clave que afectaría a la comunidad de enfermedades raras. ¿Cuál fue tu momento más memorable del Día de las Enfermedades Raras? Mi momento más memorable de la Semana de las Enfermedades Raras fue conocer a otras personas con enfermedades raras o conectarme con enfermedades raras y abogar juntos. Fue un momento muy enriquecedor poder conectarme con otras personas que han experimentado viajes similares: estar juntos en una sala para abogar por objetivos similares. Todos nos animamos y nos apoyamos unos a otros durante nuestras reuniones y eventos para motivarnos a nosotros mismos y a las personas que nos rodean. Disfruté mucho poder hablar sobre algunos temas que involucran a la comunidad de enfermedades raras y algunas posibles leyes que afectarían a la comunidad SDS. ¿Aprendió algo nuevo u obtuvo alguna información a partir de su participación en los eventos del Día de las Enfermedades Raras? Aprendí mucho este año en la Semana de las Enfermedades Raras. Aprendí a comprender mejor cómo contar mi historia y qué detalles compartir al hablar con funcionarios del gobierno. Aprendí cómo puedo incorporar mi experiencia y mi trayectoria con SDS para defender ciertos proyectos de ley para la comunidad de enfermedades raras en su conjunto. Obtuve información de colegas, defensores y líderes de la comunidad de enfermedades raras sobre la odisea diagnóstica de los pacientes con enfermedades raras y lo que cada individuo está haciendo para ayudarnos como comunidad. Aprendí cómo transformar mis habilidades para hablar en público en un día motivador lleno de negocios y diversión. Además, una pequeña ventaja divertida de asistir a este evento es que aprendí a navegar a través de los edificios de la Cámara de Representantes y del Senado de los Estados Unidos a través de túneles subterráneos. ¿Cómo planea continuar abogando por el SDS y otras enfermedades raras más allá del Día de las Enfermedades Raras? Planeo seguir siendo un miembro activo de los Defensores Legislativos de Enfermedades Raras este año, defendiendo la legislación para la comunidad de enfermedades raras. Este año planeo ser un Representante Raro de Adultos Jóvenes activa al cumplir 16 años de vida. Planeo seguir utilizando mi experiencia de vivir con un trastorno genético poco común para ampliar aún más el conocimiento de quienes me rodean sobre el SDS y los problemas que rodean a nuestra comunidad. Al utilizar mi historia, puedo tener un respaldo sólido para mis propuestas a los congresistas, brindándoles una conexión personal con la legislación. También planeo seguir publicando en mi cuenta de Instagram de SDS @cure.sds, para brindar información sobre la enfermedad y cómo es la vida diaria. ¿Qué consejo le daría a otras personas interesadas en participar en esfuerzos de defensa de las enfermedades raras? El consejo que doy a los demás es siempre que utilicen sus experiencias y traumas pasados ​​a su favor en el campo de la defensa. Utilice su visión y conocimiento sobre cómo vivir con alguien con una enfermedad rara o cuidar de ella para poder hablar en contra de los problemas de la comunidad de enfermedades raras. Siempre les digo a las personas que no deben temer a su enfermedad y, en cambio, hacerla parte de ellos. En el trabajo de promoción, es clave aceptar su trastorno para poder verdaderamente hablar y defender lo que es correcto. Al utilizar su historia, puede captar la atención de personas que tal vez nunca hayan oído hablar de su trastorno y estén dispuestas a ayudar. Si recién está ingresando al espacio de la defensa, le recomiendo comenzar poco a poco, creando una plataforma de redes sociales para crear conciencia y brindar información sobre los problemas comunes y la vida diaria de vivir con una enfermedad rara. Nunca te detengas porque algo sale mal, utiliza ese evento negativo como inspiración adicional para seguir prosperando como defensor y como ser humano. No todo va a salir como quieres todo el tiempo, habrá algunos obstáculos en el camino, así que convierte esa negatividad en fuerza. En nombre de nuestro equipo en SDS Alliance - Joyce, le agradecemos su arduo trabajo, dedicación y defensa apasionada de la comunidad SDS en el Día de las Enfermedades Raras y todos los días. Estamos agradecidos de tenerla como miembro de nuestra comunidad y estamos ansiosos por ver cómo transforma las vidas de tantas personas que viven con una enfermedad rara. __________________________________________________________________________________ ¡Mira nuestras nuevas infografías sobre SDS (disponibles en inglés y español)! __________________________________________________________________________________ Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

"My journey as a mother of a child with a rare disease began when I had my 20-week ultrasound while pregnant with my son Alex", shares mom Paula. Paula shared their story beautifully in a detailed blog on the "Extra Lucky Moms" blog. Check it out! Below, with Paula's permission, we are sharing some short excerpts. "When Alex was five months old, he caught a cold. I watched as his little chest keep rising and falling. Then I could see his ribs and collar bone as he tried to suck in air. Something was wrong. His breathing was extremely labored. I rushed him to the emergency room. They immediately took him to a triage room. While they were examining him, I watched as my baby stopped breathing completely. It felt like time stopped, and it may have only lasted about 20 seconds in reality, but it was enough time for his entire body to turn this awful dark purple color. From head to toe, he was the color of an eggplant. I remember looking at the nurse and finally saying “Do something, he’s not breathing!” "After Alex’s ankle surgery [for a serious infection], one of the doctors recommended we see a genetic specialist. She was the first doctor to look at his entire medical history and suggest that there might be something that ties all of his seemingly random medical events together. So, we made an appointment with another specialist and more tests were done. Alex kept getting sick, coming down with colds, having labored breathing, and having to go to the emergency room. We were at the emergency room or at a doctor’s office almost every two to four weeks. We were hoping for some answers. While we waited for his genetic test results to come back in, our pediatrician noticed that Alex was flapping his hands a lot at one of his appointments. He would also occasionally walk on his toes. She started to ask me questions about his speech and his vocabulary. I shared this his vocabulary was limited but I attributed that to all the time he has been spending in the hospital. Then she hit me with something I was not expecting. She recommended we see a behavioral pediatrician to have him evaluated for Autism Spectrum Disorder. He did so many things well that once again, I naively believed that this would simply be an evaluation to check this off the list and rule it out. So, another appointment with another specialist was made. Then came the two weeks in October of 2020 that I will never forget. First, I received the call from the genetics office. They had Alex’s test results in and confirmed that he had a very rare genetic disorder called Shwachman Diamond Syndrome. All the person from the genetics office could tell me about it was that it is a bone marrow disorder and that I needed to make a follow up appointment with the hematology and oncology team at the children’s hospital. I had so many questions but she could not answer any of them because it was not her specialty. Her job on that call was just to deliver the diagnosis, not provide any answers. So like anyone would do, I went to the internet. And this is when my heart broke again. Shwachman Diamond Syndrome is a bone marrow disease that impacts every single system of the body." Read the full story on the "Extra Lucky Moms" blog, here.

In this issue: What is a pseudogene and why does it matter? Important genetic testing considerations for SDS. Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you! SBDS pseudogene complicates receiving an accurate genetic diagnosis for SDS Long diagnostic journeys, otherwise known as the diagnostic odyssey, are not uncommon across rare diseases, specifically SDS. The barriers to diagnosis often vary but can include limited access to providers knowledgeable about SDS, nonspecific initial SDS symptoms that can overlap with other conditions (e.g., pancreatic insufficiency can also be seen in patients with cystic fibrosis), and difficulties accessing genetic testing (see our Science Snapshot from 2023-02-05). However, even once genetic testing has been completed, some individuals with SDS face additional barriers to receiving a genetic diagnosis due to false-negative or false-positive results, again prolonging the diagnostic odyssey. In the article we are highlighting this week, inaccuracies in data analysis and special considerations for genetic testing for SDS, and the SBDS gene more specifically, are discussed. The authors describe a 3-month-old female in Korea with suspected SDS due to typical SDS symptoms (neutropenia, anemia, failure to thrive, decreased pancreatic enzymes, and elevated liver enzymes) who participated in genetic testing for SDS. Genetic testing revealed increased levels of one variant (i.e., mutation) commonly seen in individuals with SDS, but the proportion of this variant in comparison to other genetic changes was still lower than expected. This prompted the authors to complete a different type of genetic testing, called Sanger sequencing, which analyzes the SBDS gene one genetic position at a time. Sanger sequencing not only identified the previously detected variant, but it also detected a second genetic variant which is another variant commonly seen in individuals with SDS. Identification of this second variant in SBDS confirmed this individual’s diagnosis of SDS. But why was this second genetic variant not identified using the first method of genetic testing? Our genetic information, or DNA, collectively known as the genome, is a collection of over three billion letters (i.e., bases, A, T, G, or C) in a very specific sequence to form genes. However, less than 1% of these genes are used as instructions for building proteins (i.e., protein-coding genes). The bases in the remaining 99% of our genome contain important regulatory regions, protective DNA regions, and pseudogenes which can be compared to a “genomic fossil.” As a result of evolution, these pseudogenes were once considered to be functional protein-coding genes but are now inactive and obsolete genes in our genomic information today. These pseudogenes are highly similar in their sequence to that of their functional, protein-coding genes’ counterparts, and depending on the level of similarity (i.e., homology), can be difficult to differentiate between when performing genetic sequencing and data analysis. Some of the defects in pseudogenes that result in their inactivation are outlined in the image below. The SBDS gene, the gene mutated in most individuals with SDS, has a pseudogene, or genomic fossil, in another part of the genome. Depending on the sequencing method, protein-coding gene sequences can be switched with pseudogenes, such as SBDS, resulting in a false-positive or false-negative result. This YouTube video, published by PBS, explores pseudogenes through a historical lens and shares other real-life examples of pseudogenes and the important role they used to play. Compared to NGS methods, Sanger sequencing reads/identifies one genetic base at a time without fragmenting the original sequence. As a result, there is no re-alignment necessary, dramatically reducing the risk of inaccurate genetic testing results. Sanger sequencing is considered the gold standard of genetic testing for this reason, but is more time-consuming, labor intensive in its preparation, and expensive in comparison to NGS methods. In this week’s article, Sanger sequencing was performed as a second method of genetic testing and successfully identified two variants in the SBDS gene, confirming an SDS diagnosis for the 3-month-old female. The authors from this week’s article encourage readers to acknowledge “the risk of erroneous diagnosis of disease-causing genes with pseudogenes when performing short-read NGS.” Another report from April 2020, written by Yamada et al. (PMID: 32412173), discusses a similar experience with short-read NGS in multiple individuals with SDS and advocates for the use of other genetic testing methods (e.g., Sanger sequencing or long-read sequencing) to identify and/or confirm SBDS variants. Accurate genetic diagnoses of SDS are important for implementing appropriate screening protocols and treatment regimens. For those with negative genetic testing or one SBDS variant detected using short-read NGS and a clinical presentation suspicious for SDS, follow-up genetic testing could be considered using Sanger sequencing, long-read NGS sequencing, deletion analyses, and/or RNA sequencing to confirm the presence (or absence) of another variant in SBDS. __________________________________________________________________________________ For more information regarding pseudogenes, you can refer to the Talking Glossary of Genomic and Genetic Terms on the National Human Genome Research Institute’s website or to this article published by Blueprint Genetics, a genetic testing company. Variant Allele Frequency of Pseudogene-Related Variants in Short-read Next-Generation Sequencing Data May Mislead Genetic Diagnosis: A Case of Shwachman-Diamond Syndrome. Lee H, Lee JA, Lee H, Lee JS, Ko JM, Kim MJ, Seong MW. Ann Lab Med. 2023 Nov 1;43(6):638-641. doi: 10.3343/alm.2023.43.6.638. PMID: 37387500 Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

In Loving Memory Steve, Niamh's beloved husband, shares Niamh's story. On Thursday 11th August 2022, our world changed forever. This is the day our beloved Niamh passed away from a short illness caused by a bacterial infection which proved tragically fatal. On the Tuesday of that week she was in great form, we'd been out on a sunny day enjoying a few drinks in a beer garden and nice Chinese meal. On the Wednesday she fell ill and we took her to hospital, by the Thursday she had left us. The infection was called necrotising fasciitis, its a rare but dangerous bacterial infection. Niamh had chronic neutropenia which meant she was more likely to catch this, and sadly less able to fight it due to having a very weak immune system. Niamh had only found out within a year before she passed away of her diagnosis of SDS, which led to her neutropenia condition. Niamh actually took comfort and encouragement from her SDS diagnosis, it helped explain some of why she had suffered since a baby, she felt a new additional support from the online SDS community, and it gave her hope to find a way to live a more healthy life through leaning more about the condition. Cruelly ironic, we had an appointment with her consultant to learn more about SDS on the day she died. Niamh was in and out of hospital as a baby, regularly sick throughout her childhood, and barely a month went by as an adult without seeing one of her numerous medical consultants for the several conditions she was living with. Sadly this is the reality of living with SDS. She also suffered significant loss emotionally, in particular her beloved mother Mary passed away whilst Niamh was still in her teens. But despite all of this, Niamh was the loveliest, bubbliest, most cheerful, caring, generous and silliest person you could ever have the fortune to meet. Anyone that knew her said she would light up a room when she entered. Born and bred in Dublin, Ireland, she came from a large & loving Irish family, and she was extremely close to all from the close & extended family. She also made huge efforts to always spend time with her many friends, she was loyal and great company to all. A special mention to her best friend Karen, they knew each other since school and were like sisters, supporting each other through good times and bad. Niamh was well known in her community, since we moved into the neighbourhood 10 years ago she set upon herself to organise the first ever street party here (and also the 2nd and 3rd!) before covid put a halt on those. As a stop gap she dragged her karaoke machine onto the road and we played socially distanced bingo to keep everyone entertained through difficult isolating times. And she never stopped trying to get involved with local people and getting people together, no better shown than when within the year before she died she founded the Dublin 7 Women's Shed, which is now going from strength to strength with well over 100 members. Some of Niamh's very best friends though did not have 2 legs but 4. She was a lover of all animals, and in particular dogs. Whilst not working during covid Niamh minded several local dogs on a part time basis and took great joy out of this, as did all the doggies! And whilst we never had children, we did have our own little dog Basil, a Cavalier King Charles. Sadly Basil passed away 2 weeks after Niamh, he was 14 years old, and just as heart broken as everybody else, he loved his mammy very much. I met Niamh backpacking around New Zealand in 2006. Niamh loved a holiday whether it was exploring a new place, travelling round beautiful Ireland with Basil, or soaking up some rays in the sun. She said her favourite trip was when we went to Cuba, we did this on a group tour and typical of Niamh, she was the life and soul of the group and quickly nicknamed the Daiquiri Queen. Niamh loved to be busy when she was able, and also loved the outdoors, so her recent taking up of gardening suited her well. Her specialities were growing of spuds, tomatoes, sweetpea and sunflowers. Niamh loved to laugh, whether it be cheesy puns or sticking googly eyes everywhere. We'd regularly attend comedy gigs together. She had a daft and silly sense of humour, her giggle, often starting as a cackle and sometimes becoming so unstoppable that it almost caused her to choke and quickly grab her inhaler, was unique, unmissable and infectious, and full of joy. Niamh loved music and going to gigs, especially outdoor festivals. She always had a fun loving 60s/70s vibe and would have fit in well when the Beatles and Donovan were banging out the tunes. She could dance around to cheesy pop, and head-bang to something more rocky and punky. Her favourite band were Ash, and their song Shining Light we've since adopted as its such a beautiful description of Niamh, our shining light. Another band we got into recently are called Dream Wife. And that for me is the perfect description of Niamh. She was loving and caring. She was supportive and understanding. She was smart and funny. She was brave and courageous. She was great fun, the best craic you can imagine. She was beautiful from head to toe. She was my best friend and my soul mate. Life is unbelievable tough now without Niamh by our side. She was loved by so many, and we were all lucky to be loved by Niamh. Niamh was always one who saw the best of people and the positives in situations wherever they existed. So in that vain, along with some close family and friends, we'll be participating in a remembrance run this November, doing this both in Niamh's memory and also to raise funds for the SDS Alliance. https://www.dublinlive.ie/news/dublin-news/my-wife-died-rare-disease-27714675 https://www.gofundme.com/f/in-memory-of-niamh-curesds Niamh Lynch-Livsey, aged 44 years, forever young, always loved, always in our hearts.

In this issue: Recap of publication on Ataluren to pave the path for clinical trials. Learn more about how it works in this post. Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you! An update on the development of Ataluren, a therapeutic approach targeting the c.183_184TA>CT mutation in the SBDS gene Over the past few years, important research has been ongoing in Dr. Valentino Bezzerri and Dr. Marco Cipolli’s laboratory in Italy to investigate the use of Ataluren to treat individuals with SDS. We previously wrote about this work, including a detailed summary by Dr. Bezzerri in a SDS & Science Snapshot edition from May 2022 and October 2023. This week, the publication has finally hit the shelves and is now available for free online. It expands the pre-clinical laboratory based research to solidify the rationale to enable clinical trials for Ataluren for a subset of SDS patient. The authors show, that Ataluren improved ribosome assembly and total protein synthesis in SDS-patient-derived cells in the lab Restored myelopoiesis in myeloid progenitors in the lab Improved neutrophil chemotaxis in an experimental model Reduced neutrophil dysplastic markers in the lab. Restored full-length SBDS protein production in osteoblasts (bone producing cells) donated by patients, suggesting that its beneficial role may go beyond the blood producing stem cells. The authors summarize: "Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation". Dr. Bezzerri also shared his work at the 2023 SDS POPS summit in May and joined us for a lively discussion at our first ever Ask-an-Expert Community Chat. It was fantastic. Check out the recording, below. As previous highlighted, the group tested the effect of Ataluren in the laboratory on cells of individuals with SDS who harbor the c.183_184TA>CT mutation in their SBDS gene. These preclinical studies showed: Improved SBDS protein levels and improved ribosome assembly and total protein synthesis; Reduced the elevated levels of p53 protein, which is found in excess in SDS tissues; and Improved migration of neutrophils, important cells in the immune system frequently reduced in individuals with SDS. These results are promising for Ataluren and its use as a "personalized medicine" approach for treating SDS patients carrying nonsense variants, such as c.183_184TA>CT. These preclinical results support the idea of developing of a Phase I/II clinical trial in the future for Ataluren in SDS patients who have a nonsense mutation. The SDS Alliance team will remain in communication with the SDS community about these trials when/if they become available. Be sure to sign up for updates! The figure below summarizes the findings published in the current article. The top of the figure shows what normally happens in SDS cells that harbor a nonsense variant. The bottom panel shows the mechanism of Ataluren and the improvements it makes on the cellular environment. What is the significance of the c.183_184TA>CT mutation in SBDS gene? A large percentage of SDS patients carry the variant (i.e., mutation), c.183_184TA>CT, in addition to the most common “splice site” variant. For instance, the c.183_184TA>CT variant is present in more than half of SDS patients. This genetic change leads to the generation of a premature stop in building the SBDS protein, similar to inserting a period in the middle of a sentence. These types of variants, known as nonsense variants, generally result in unstable protein intermediates and are rapidly degraded in the cell or produce a protein that has lost its function. What is Ataluren? Ataluren (PTC124) was launched in 2007 by PTC Therapeutics (NJ, USA), which promotes careful attention to “incorrect punctuation” in cells (e.g., an extra period in the middle of a sentence). This attention allows for more selective synthesis of proteins with normal structure (i.e., proteins without the extra period in the middle of the sentence). Furthermore, Ataluren has shown less toxicity and better safety than other drugs used for similar purposes. The use of Ataluren as a potential therapeutic agent for genetic disorders has been proposed for the treatment of Duchenne Muscular Dystrophy (DMD) and Cystic Fibrosis (CF). Most importantly, Ataluren has been approved for the treatment of DMD in Europe (but not in the US). Data from clinical trials showed that chronic Ataluren treatment is beneficial to DMD patients undergoing standard care, because it delays the progression of ambulation impairment and the worsening of pulmonary and cardiac functions. Interestingly, clinical studies revealed that the best results are observed in younger individuals, suggesting major benefits of early ataluren administration. Why is Ataluren not widely used? Despite promising pre-clinical results, Ataluren unfortunately failed in clinical studies for CF and was therefore discontinued. This early work suggested there may be highly variable clinical benefits in using Ataluren to treat individuals with CF. Because of such variable levels of effectiveness of Ataluren, it is important to perform extensive preclinical testing using cells in the laboratory, such as the recent work published by Cipolli et al., before trying Ataluren in people with SDS in clinical trials. Find additional information about Ataluren and its treatment of individuals with DMD by watching this YouTube video. Ataluren improves myelopoiesis and neutrophil chemotaxis by restoring ribosome biogenesis and reducing p53 levels in Shwachman-Diamond syndrome cells. Cipolli M, Boni C, Penzo M, Villa I, Bolamperti S, Baldisseri E, Frattini A, Porta G, Api M, Selicato N, Roccia P, Pollutri D, Marinelli Busilacchi E, Poloni A, Caporelli N, D'Amico G, Pegoraro A, Cesaro S, Oyarbide U, Vella A, Lippi G, Corey SJ, Valli R, Polini A, Bezzerri V.Br J Haematol. 2024 Jan;204(1):292-305. doi: 10.1111/bjh.19134. Epub 2023 Oct 24. PMID: 37876306 Do you enjoy the SDS & Science Snapshots? 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In this issue: Rare Disease Day is around the corner! How can I get involved? Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you! Share Your Colors on Rare Disease Day! WHAT IS RARE DISEASE DAY? Rare Disease Day is the official international awareness-raising campaign for rare diseases, observed annually on the last day of February. The primary goal of this campaign is to increase awareness among the general public and decision-makers about rare diseases and their influence on the lives of families living with these conditions. Rare Disease Day was launched by EURORDIS Rare Diseases Europe and its Council of National Alliances in 2008. EURORDIS continues to lead the international campaign with a global patient community. Patient organizations from North America joined in 2009, followed by all continents by 2010. National Alliances, such as the Nation Organization for Rare Disorders (NORD) in the United States, ensure Rare Disease Day coordination at a national level, collaborating with local patient organizations and often organizing national events targeting policymakers. The number of participating countries has grown annually, with thousands of events now occurring on all continents in or around February. Since 2008, events have been held in over 100 countries. Fun Fact: You can virtually attend the NIH Rare Disease Day Event with SDS Alliance! Our Genetics Project Manager, Ashley Thompson, MS, CGC will be attending this event in-person to represent SDS Alliance and the SDS community this coming week. Stay tuned for our Snapshot next week for updates on these events and others! CELEBRATE THE UNIQUENESS OF BEING RARE With over 300 million people globally living with a rare disease (and an estimated 5000 individuals with SDS in the US and Europe), we join hands with you across borders and amidst the 6000+ rare diseases to advocate for equitable access to diagnosis, treatment, care, and social opportunities. The key message for Rare Disease Day 2024 is SHARE YOUR COLORS! Here are some ways to get involved in this year's campaign: 1.GET INVOLVED ON SOCIAL MEDIA Share your Rare Disease Day event videos - such as the timeless video we created for SDS, below - and photos on social media using #RareDiseaseDay and tag @rarediseaseday. You can also express your support for those living with rare diseases in your community by sharing a photo with painted hands on social media. Explore the Rare Disease Day website for downloads including images, profile picture frames, Instagram filters, and Zoom backgrounds, and more that you can use on social media! Use crucial rare disease statistics to convey that while each disease may be rare, collectively, they impact a vast number of people. 300 million people worldwide live with a rare disease. There are over 6000 different rare diseases. 72% of rare diseases are genetic. 70% of these genetic rare diseases begin in childhood. There are an estimated 5000 individuals living with SDS in the US and Europe, and many more are undiagnosed! 2. ORGANIZE AN EVENT! Every year, thousands of events across over 100 countries commemorate Rare Disease Day. Most events will be online, allowing people worldwide to participate. Plan an online event in or around February for Rare Disease Day to heighten awareness of rare diseases in your community. Here are some successful ideas from global organizers: Illuminate your home for Rare Disease Day: see the Light Up for Rare Toolkit for more information. Raise awareness on Facebook and Instagram Live, and invite your friends. Hold an art, photography, or essay-writing competition. Organize a walk. Plan a sporting event. Present your story to your local authorities. 3. BECOME A FRIEND Become a Rare Disease Day friend to showcase your organization or company’s support for the campaign! Simply fill in your details to create a profile page on the Rare Disease Day website. This will display your commitment to supporting people living with a rare disease. 4. TELL YOUR STORY! Raise awareness about rare diseases and their impact on people’s lives by sharing your personal experience of living with SDS or caring for someone who does. Submit your written or video testimony on the Rare Disease Day website and explore stories already shared by others! 5. TAKE ACTION LOCALLY In addition to organizing events, you can act locally in your country, region, or area to raise awareness of rare diseases! On Rare Disease Day, we advocate for equity for people living with a rare disease worldwide. CONTACT THE PRESS Reach out to local or regional newspapers and radio stations to cover your Rare Disease Day event. Send out a press release to your area’s media, highlighting the issues most crucial to rare disease patients in your country. Watch the webinar ‘How to Use Rare Disease Day to Advance Your Advocacy Objectives’ to learn the basics! GET POLITICAL Write to key decision-makers about the pressing issues facing rare disease patients in your country, urging them to prioritize rare diseases! Advocate to policymakers for equitable access to diagnosis, treatment, care, and social opportunities for those living with a rare disease. For guidance on advocating for rare diseases within Universal Health Coverage, refer to the Rare Disease Day Equity Toolkit. Invite politicians to your organization, to an event you’re hosting, or to a rare disease research lab. If you live in Europe, encourage your MEP to join the Parliamentary Advocates for Rare Diseases Network. If you live in the United States, register for Rare Disease Week on Capitol Hill hosted by the Rare Disease Legislative Advocates. 7. DOWNLOAD COMMUNICATION MATERIALS The official Rare Disease Day communication materials and logo are freely available for your Rare Disease Day events' promotion. Materials available in Mandarin, English, Arabic, Spanish, Portuguese, French, Hindi, and Russian. Also available for download: The official Rare Disease Day logo Website countdown Rare Disease Day style guide Fonts Webinar toolkits. If you, your friends, family, and colleagues take part in Rare Disease Day, don’t forget to share your photos from activities worldwide by uploading them to the Rare Disease Day website! We cannot wait to see how the SDS community lights up for rare this week! __________________________________________________________________________________ Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

In this issue: Why does diversity matter in rare disease research and how can I get involved? Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you! Embracing Diversity in Clinical Research: A Global Perspective As we honor Black History Month in the United States, it's essential to recognize the importance of diversity in clinical research and trials. Diversity in this context refers to including people from all walks of life – different races, ethnicities, backgrounds, and countries – in research studies. Why does this matter for those of us in the rare disease community? Embracing individuals from diverse backgrounds in clinical research is fundamental for advancing medical knowledge and improving healthcare outcomes worldwide. When clinical trials include people from diverse backgrounds, it helps scientists understand how treatments work for everyone. Every person is unique, and factors like where they live, their genes, and their culture can affect how they respond to treatments. By including a wide range of people in research, scientists, physicians, and other researchers can make sure that treatments are safe and effective for everyone, including those with rare diseases. Below is a video from a session at the 2023 Global Genes RARE Health Equity Forum: Understanding the Patient Perspective – How to Ensure Diverse Patient Participation in Clinical Trials and Research. In this session, the panelists discuss how patients can/should be on the front lines with their community ecosystem, and what that relationship should look like between community leaders and researchers. While we often hear about the need for diversity in terms of race and ethnicity, it's equally important to consider a broader global perspective. Rare diseases affect people all over the world, and what works for one person might not work for another. By involving researchers from different countries, we can learn from each other and find better treatments that work for everyone, no matter where they live. At Shwachman-Diamond Syndrome Alliance, we recognize that our community is diverse, encompassing individuals of various racial, ethnic, and cultural backgrounds from around the world, and we believe that everyone's voice deserves to be heard. By actively working together and engaging with our diverse global community, we aim to accelerate progress toward improved treatments and outcomes for individuals with SDS across the world. Together, let's continue to champion diversity and inclusivity in clinical research, ensuring that everyone has access to equitable and effective healthcare. __________________________________________________________________________________ The Rare Disease Diversity Coalition (RDDC) serves as a fantastic resource to the rare disease community – bringing together rare disease experts, patient organizations, health and diversity advocates, and industry leaders with a deep knowledge of the medical, industry, regulatory, and cultural challenges facing people of color with rare disease. __________________________________________________________________________________ Check out the EveryLife Foundation for Rare Diseases Rare Diversity Hub for information about current efforts to increase diversity in clinical research and learn how you can get involved! __________________________________________________________________________________ For more information about the importance of engaging a diverse global community in clinical research and trials, you can listen to these podcasts from Global Genes in addition to watching other sessions from the 2023 Global Genes RARE Health Equity Forum: Turning Words into Action: Equity, Diversity, and Inclusion in Rare Disease Addressing the Barriers to Patient Participation in Clinical Trials __________________________________________________________________________________ Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

Our SDS Story and what lead to Hero Kids in the Making Wg Williams, Elijah's dad, shares their story. "At only 15 months old, my son started undergoing lots of medical testing and treatments associated with his Shwachman-Diamond syndrome (SDS). He was only about 28 months old when his medical treatment-related anxiety started to become concerning. This became a separate new issue of his negative well-being. His anxiety would start to trigger in the parking lot of the doctor's office and only heightened from there. When he heard his named called in the waiting room he would start to cry in fear. At the time I was looking in the marketplace for the ideal childhood product that would inform, distract and reward my son in his participation in these procedures. I was looking for something in which the sugar-coat wasn’t so thick, and the distraction did not suggest that pain wouldn’t exist. I found no such children's product. I knew from having 11 nieces and nephews that regardless of what adults told children, they created fictitious monsters for their fears and imagery heroes overcome them. I wanted my son to see himself as a brave hero overcoming his reasonable fears associated with the pain and uncharted aspects of his medical tests and treatments. I then started to think that I could create such a tool myself. Being a big sci-fi fan and amateur writer, I remembered a quote I had learned; “Any sufficiently advanced technology is indistinguishable from magic”. This was from Arthur C. Clarke's “Profiles of the Future: An Inquiry into the Limits of the Possible”, a non-fiction book. I wanted my son to see himself as a brave hero overcoming his reasonable fears associated with the pain and uncharted aspects of his medical tests and treatments. I then started to think that I could create such a tool myself. I was thinking of a story that would be on a kid’s level of understanding and within their childhood interests. This would be a fun fantasy tale to grasp a child's imagination but also inspire bravery. I wanted an origin type story with cute magical animals that kids would adore. I wanted to include how these kids, who are actual heroes, could become their own hero kid in the making. I wanted a story easily understood by very young kids but still interesting and exciting to kids 10 years old. Children like him will always be heroes and modern medicine is truly magical. This story although fantasy, would also have to be an accurate kid’s self-help instruction manual for these medical procedures. The end result was this children’s picture book, Hero Kids in the Making!" About Wg Williams' children's picture book: Finally, a tool that prepares children for medical procedures in a fun way! This colorful storybook was especially created to help reduce childhood fears in their inevitable encounter with medical devices. "Hero Kids in the Making" is a children's picture book that redirects the imagination of a pediatric patient from a fearful perspective and towards a hero making tale that inspires bravery. This fun rhyming story turns medical procedures into cute, magical creatures. Instruments such as stethoscopes, syringes and imaging equipment are transformed into these magical animals, now in disguise. It's a fantasy hero making version of what the child will really experience during a doctor's or hospital visit. When a child familiar with this fantasy tale experiences medical procedures, they instantly become a hero character of the story themselves. The Coloring Book collaboration: When the SDS Alliance heard bout the book, the team fell in love with the story immediately. We started to think about how we could make it more accessible (easy to download and print) and more interactive for the kids. This is how the coloring book idea came to be. And luckily for the community, a 9-your-old child with SDS volunteered to create illustrations. The Hero Kids in the Making COLORING BOOK is now available on our kids' corner page. Check it out, today. To request printed copies and/or stickers, email us at connect@SDSAlliance.org