How collaboration changes the world for people with rare diseases
25 February 2021
By Peter Linsley, Kerry Holland
In recognition of #RareDiseaseDay, Elsevier is making select research articles and book chapters freely available for two months
About 10 years ago, when Dr Gabriela Repettoopens in new tab/window was a resident in pediatrics at the University of Wisconsin–Madison, she received an email from the mother of two boys with intellectual disability, congenital anomalies and seizures. Gabriela and her team had recently diagnosed the two boys with a rare recessive condition. No causative gene was known at the time; Gabriela’s team had made the diagnosis through clinical findings only.
The email from the boys’ mother explained that, armed with the information about their diagnosis, she had found a few families with a similar diagnosis in other countries. She had also found a young researcher working to uncover the cause of the condition.
Within months, the causative gene was identified through collaborations between these families and researchers in nine countries across three continents.
Continued collaborations helped gather information to guide drug choice to treat the condition – a form of epilepsy – and there is ongoing research on animal models aimed at identifying therapeutic targets.
Gabriela, who is now Professor of Genetics at Facultad de Medicina Clinica Alemana, Universidad del Desarrollo in Santiago, Chile, recalls the impact these developments had on her:
Although I had participated in international collaborative projects before, I still remember this as a powerful experience of the momentum generated by that email, and the results of the strong connections between families, clinicians and researchers globally.
Gabriela is one of dozens of authors whose work Elsevier is making freely available for 60 days, beginning on Rare Disease Dayopens in new tab/window (#RareDiseaseDayopens in new tab/window) February 28, 2021. Content includes Clinicsopens in new tab/window review articles, bookopens in new tab/window chapters, and articles in the Cell Press Trendsopens in new tab/window portfolio, all intended to support researchers and clinicians in identifying the molecular basis of these diseases, advancing drug discovery and drug repurposing efforts, translating findings to the clinic, and counseling patients and families. Leading articles from Elsevier’s Clinics and books detail a range of specific diseases, from rare congenital malformations to neurological disorders.
Rare diseases, by definition, affect a small number of individuals compared to the general population. In the United States, a disease is called rare if it affects fewer than 200,000 people at any given timeopens in new tab/window. In Europe, the ratio is 1 affected person in 2,000opens in new tab/window. The total number of known, named rare diseases worldwide falls somewhere between 6,000 and 8,000 conditions. Although each individual disease is uncommon, their collective prevalence is estimated at 6 percent to 8 percent of the world population, implying that 450 million people have a rare diseaseopens in new tab/window. So in a sense, rare diseases are not as rare as they seem.
For people who suffer from them, and for their families, being diagnosed with a rare disease can be unsettling, so when doctors know how to proceed, it provides reassurance.
Dr Michael Frumovitzopens in new tab/window, Professor of Gynecologic Oncology and Associate Chief Patient Experience Officer at the MD Anderson Centeropens in new tab/window in Texas also has work featured in the collection. He highlighted the difference sharing knowledge can make, not just in a practical sense but in terms of the impact it can have on sufferers. He explained:
I have had multiple patients tell me their doctor had said to them, ‘I have never seen a patient with this type of cancer before. I’m not sure what to do.’ This can be incredibly discouraging, disappointing and scary for patients. When we tell them we have substantial experience in treating women with their rare cancer, the relief in their face is immediately clear. We hope we can share our expertise with providers so that they can say to their patients, 'I may not have seen this before, but I know what to do.’
Most rare diseases are genetic in origin and are often tied to single affected gene. Given the genetic basis and varying symptoms, genetic testing is generally the most accurate way to go about diagnosis. But even with a diagnosis, treatments still have not been developed for the vast majority of these diseases.
Most rare diseases are genetic in origin and are often tied to single affected gene. Given the genetic basis and varying symptoms, genetic testing is generally the most accurate way to go about diagnosis. But even with a diagnosis, treatments still have not been developed for the vast majority of these diseases.
Understanding and tackling rare disease requires a multi-pronged approach, pooling together knowledge acquired from various scientific disciplines, such as immunology, genetics, molecular medicine and pharmacology. When these disciplines come together, the results for patients can be life changing.
Dr Robert M Kliegmanopens in new tab/window, Professor and Chair Emeritus in the Department of Pediatrics at Nelson Service for Undiagnosed and Rare Diseases, Children’s Wisconsinopens in new tab/window, has worked in pediatrics for about 50 years. He understands the tragedy of rare diseases – and the hope that comes through collaboration and progress:
I, along with my colleagues, have always been saddened when a child dies of some mysterious illness, sometimes acute but sometimes chronic, and there is no good answer for the family or medical team. With advances in diagnostic imaging and genetic sequencing, many of these mysteries are now able to be diagnosed and even treated. We have seen many families with children who were undiagnosed for many years finally have an answer and thus a better understanding of their child’s now diagnosed disease
Included among these articles is a paper co-authored by Dr Weida Tongopens in new tab/window, Director of the Division of Bioinformatics and Biostatistics at the National Center for Toxicological Research, US Food and Drug Administrationopens in new tab/window, summarizing current standing and future possibilities offered by the clinical implementation of NGS-based genetic testing in rare disease.
Dr Tong explained why this was so critical and how it can make a different to sufferers and their families:
The average length of accurate diagnosis of a rare disease is 4.8 years and involves more than seven physicians or specialists who may be geographically distributed. The genetic diagnosis may not be directly associated with any treatment options, and physicians will continue to treat symptoms, albeit in a more informed way based on likely prognosis of the case. Therefore, genetic diagnosis could be of benefit beyond treatment management as it can offer information to families, many who just want to know what is wrong with their family member and can also inform fertility decisions.
Please see the links below to freely access this content through April 30, 2021.
About Rare Disease Day
The last day of February each year promotes awareness of rare diseases and the patients that suffer from them, as well as access to medical treatment and representation. Advocacy is critical for rare disease patients and their familiesopens in new tab/window. Whether it is improving disease understanding, connecting families with one another and with researchers, fundraising for research, or sharing resources, rare disease initiatives provide much needed support to patient communities. The National Organization of Rare Disordersopens in new tab/window, Perlaraopens in new tab/window, the Rare Genomics Instituteopens in new tab/window, the Iberoamerican Alliance for Rare Diseasesopens in new tab/window, and Global Genesopens in new tab/window are just a few organizations that have provided meaningful outcomes for patients and families. Meanwhile, Orphanetopens in new tab/window and NIH – GARDopens in new tab/window (Genetic and Rare Diseases Information Center) gather and share information on thousands of rare diseases, along with other resources, to improve diagnosis, care, and treatment.
Access to worldwide promotion of this event can be found via #RareDiseaseDay.
Free access to research on rare diseases
This content is freely available through April 30, 2021:
Book chapters
Chapter 3 - Rare Diseases: Genomics and Public Healthopens in new tab/window, Gabriela M. Repetto, Boris Rebolledo-Jaramillo, Applied Genomics and Public Healthopens in new tab/window (First Edition)
Chapter 85 - Tetralogy of Fallotopens in new tab/window, Mar Bennasaropens in new tab/window, Josep M. Martinezopens in new tab/window, Obstetric Imaging: Fetal Diagnosis and Care (Second Edition)
Chapter 15 - Multicystic Dysplastic Kidneyopens in new tab/window, April T. Bleichopens in new tab/window,Jodi S. Dasheopens in new tab/window, Obstetric Imaging: Fetal Diagnosis and Care (Second Edition)
Chapter 3 - Charcot-Marie-Tooth diseaseopens in new tab/window, Phu Duong,opens in new tab/window John Svaren,opens in new tab/window Chromatin Signaling and Neurological Disorders
Chapter 150 - Trisomy 18opens in new tab/window, Stephanie L. Gawopens in new tab/window, Lawrence D. Plattopens in new tab/window, Obstetric Imaging: Fetal Diagnosis and Care (Second Edition)
Chapter 4a - Marfan Syndromeopens in new tab/window, J.de Backer,opens in new tab/window Aneurysms-Osteoarthritis Syndrome
Chapter 11 - Cerebral Cavernous Malformations, Molecular Biology, and Geneticsopens in new tab/window, Gwenola Boulday,opens in new tab/window Elisabeth Tournier-Lasserve,opens in new tab/window Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics (Seventh Edition)
Chapter 29 - The myotonic dystrophiesopens in new tab/window, Richard T.Moxley III,opens in new tab/window James E. Hilbert,opens in new tab/windowGiovanni Meola,opens in new tab/window
Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Sixth Edition)
Chapter 6 - von Willebrand Diseaseopens in new tab/window, Bethany T. Samuelson Bannow,opens in new tab/window Barbara A. Konkleopens in new tab/window, Consultative Hemostasis and Thrombosis (Fourth Edition)
Chapter 28 - Myasthenia gravisopens in new tab/window, Derek G. Waller, Anthony P. Sampson, Medical Pharmacology and Therapeutics (Fifth Edition)
Chapter 24 - Angelman syndromeopens in new tab/window, Jennifer M. Mathews,opens in new tab/window Emily K. Cook,opens in new tab/window Seth S. Margolis,opens in new tab/window
Charles A.Williams,opens in new tab/window Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Sixth Edition)
Chapter 10 - Sotos syndromeopens in new tab/window, Chloe Laneopens in new tab/window, Megan Freethopens in new tab/window, Chromatin Signaling and Neurological Disorders
Chapter 3A - Congenital Adrenal Hyperplasia Owing to 21-Hydroxylase Deficiencyopens in new tab/window,Maria I. Newopens in new tab/window,
Oksana Lekarevopens in new tab/window, Denesy Mancenidoopens in new tab/window, Alan Parsaopens in new tab/window, Tony Yuenopens in new tab/window, Genetic Steroid Disorders
Chapter 11 - Primary Sjögren’s Syndrome and Epigeneticsopens in new tab/window, Amandine Charras,opens in new tab/window Christelle Le Dantec,opens in new tab/window Orsia D. Konsta,opens in new tab/window Wesley H. Brooks,opens in new tab/window Anne Bordron,opens in new tab/window Yves Renaudineauopens in new tab/window, The Epigenetics of Autoimmunity
Chapter 30 - Disorder: Medium-chain acyl-CoA dehydrogenase deficiencyopens in new tab/window, Patricia Jonesopens in new tab/window, Khushbu Patelopens in new tab/window, Dinesh Rakhejaopens in new tab/window,A Quick Guide to Metabolic Disease Testing Interpretation (Second Edition)
Chapter 13 - Cushing’s Syndromeopens in new tab/window, Agata Juszczakopens in new tab/window, Damian G. Morrisopens in new tab/window, Ashley B. Grossmanopens in new tab/window, Lynnette K. Niemanopens in new tab/window, Endocrinology: Adult and Pediatric (Seventh Edition)
Chapter 44 - Wilson diseaseopens in new tab/window, Golder N. Wilson, Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Sixth Edition)
Chapter 4 - Dravet Syndrome: A Sodium Channel Interneuronopathyopens in new tab/window, W.A. Catterall, Ion Channels in Health and Disease
Chapter Two - Mucopolysaccharidosis type II (Hunter syndrome): Clinical and biochemical aspects of the disease and approaches to its diagnosis and treatmentopens in new tab/window, Shifaza Mohamedopens in new tab/window,
Qi Qi Heopens in new tab/window, Arti A. Singhopens in new tab/window, Vito Ferroopens in new tab/window, Advances in Carbohydrate Chemistry and Biochemistry
Clinics articles
Basel D: Dysmorphology in a Genomic Eraopens in new tab/window, Clinics in Perinatology, 2020.
Larson-Nath C, Vitola BE: Neonatal Acute Liver Failureopens in new tab/window, Clinics in Perinatology, 2020.
Lalor LE, Chiu YE: Rare Vesiculopustular Eruptions of the Neonatal Periodopens in new tab/window. Clinics in Perinatology, 2020.
Tallar M, Routes J: Omenn Syndrome Identified by Newborn Screeningopens in new tab/window, Clinics in Perinatology, 2020.
Geddes GC, Samudrala SS, Earing MG: Neonatal Assessment of Infants with Heterotaxyopens in new tab/window, Clinics in Perinatology, 2020.
Bence CM, Densmore JC: Neonatal and Infant Appendicitisopens in new tab/window. Clinics in Perinatology, 2020.
Andolina JM, Metzger LC, Bisho J: The Oley Foundation and Consumer Support Groupsopens in new tab/window, Gastroenterology Clinics, 2019.
Mezoff EA, Cole CR, Cohran VC: Etiology and Medical Management of Pediatric Intestinal Failureopens in new tab/window
, Gastroenterology Clinics, 2019.
Harris C, Scolapio JS: Initial Evaluation and Care of the Patient with New-Onset Intestinal Failureopens in new tab/window
, Gastroenterology Clinics, 2019.
Van Gossum A, Demetter P: Hepatobiliary Complications of Chronic Intestinal Failureopens in new tab/window, Gastroenterology Clinics, 2019.
Kurzer JH, Weinberg OK: Acute Leukemias of Ambiguous Lineage: Clarification on Lineage Specificityopens in new tab/window, 2019.
Derkay CS, Bluher AE: Update on Recurrent Respiratory Papillomatosisopens in new tab/window, Otolaryngologic Clinics of North America, 2019.
Summar ML, Mew NA: Inborn Errors of Metabolism with Hyperammonemia: Urea Cycle Defects and Related Disordersopens in new tab/window, Pediatric Clinics of North America, 2018.
Tarvin SE, O’Neil KM: Systemic Lupus Erythematosus, Sjӧgren Syndrome, and Mixed Connective Tissue Disease in Children and Adolescentsopens in new tab/window, Pediatric Clinics of North America, 2018.
Basel D, McCarrier J: Ending a Diagnostic Odyssey: Family Education, Counseling, and Response to Eventual Diagnosisopens in new tab/window, Pediatric Clinics of North America, 2017
van Rhee F, Greenway A, Stone K: Treatment of Idiopathic Castleman Diseaseopens in new tab/window, Hematology/Oncology Clinics of North America, 2018.
Magierowicz M, Tomowiak C, Leleu X, Poulain S: Working Toward a Genomic Prognostic Classification of Waldenstrӧm Macroglobulinemia: C-X-C Chemokine Receptor Type 4 Mutation and Beyondopens in new tab/window, Hematology/Oncology Clinics of North America, 2018
Hannah-Shmouni F, Chen W, Merke DP: Genetics of Congenital Adrenal Hyperplasiaopens in new tab/window, Endocrinology and Metabolism Clinics of North America, 46:2, 2017.