Stephen C. Groft

Inherited Arrhythmias A National Heart, Lung, and Blood Institute and Office of Rare Diseases Workshop Consensus Report About the Diagnosis, Phenotyping, Molecular Mechanisms, and Therapeutic Approaches for Primary Cardiomyopathies of Gene Mutations Affecting Ion Channel Function

The National Heart, Lung, and Blood Institute and Office of Rare Diseases at the National Institutes of Health organized a workshop (September 14 to 15, 2006, in Bethesda, Md) to advise on new research directions needed for improved identification and treatment of rare inherited arrhythmias. These included the following: (1) Na+ channelopathies; (2) arrhythmias due to K+ channel mutations; and (3) arrhythmias due to other inherited arrhythmogenic mechanisms. Another major goal was to provide recommendations to support, enable, or facilitate research to improve future diagnosis and management of inherited arrhythmias. Classifications of electric heart diseases have proved to be exceedingly complex and in many respects contradictory. A new contemporary and rigorous classification of arrhythmogenic cardiomyopathies is proposed. This consensus report provides an important framework and overview to this increasingly heterogeneous group of primary cardiac membrane channel diseases. Of particular note, the present classification scheme recognizes the rapid evolution of molecular biology and novel therapeutic approaches in cardiology, as well as the introduction of many recently described diseases, and is unique in that it incorporates ion channelopathies as a primary cardiomyopathy in consensus with a recent American Heart Association Scientific Statement.

Empowerment of patients: lessons from the rare diseases community

2Empowerment is an action-oriented notion with the focus on removal of formal or informal barriers, and on transformation of relations between communities and institutions. Defi ned as such, empowerment is a necessity for patients with rare diseases, which are chronic, diffi cult to manage, so rare that coordinated eff orts are imperative to make progress, and largely disregarded by the research or medical community and policy makers. It has been eff ectively applied in the rare diseases community, as exemplifi ed by the role of patients’ organisations in fostering appropriate policy, research, and health-care provision. A WHO theoretical model of empowerment strategies and outcomes serves as a framework on exemplary progress made in patient empowerment with rare diseases. 3

Phenylketonuria Scientific Review Conference: State of the science and future research needs

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

The case for a global rare-diseases registry

Rare diseases are a clinically heterogeneous group of about 6500 disorders, and in fewer than 200 000 individuals in the USA. They are commonly diagnosed during childhood, often inherited, and can have deleterious long-term eff ects. Although any one condition is rare, their cumulative public health burden is substantial, with 6–8% of people having a rare disease at some point during life. Because of the rarity, no single institution, and in many cases no single country, has suffi cient numbers of patients to do generalisable clinical and translational research. Geographic spread of patients has been a major impediment to recruitment into clinical trials. Most rare diseases do not have a specifi c International Classifi cation of Diseases code, which hampers research that uses existing databases. Before the USA, the its emphasis on public health research. Although a full analysis of all present funding for health research in India and what it is spent on is not available, the funding from both domestic and international sources has increased substantially in India over the past decade. What then are the key goals that policy should address to boost research towards health care for all in India? First, a national research tracking mech anism should be developed to guide funding and commissioning of highquality research into the major under-represented causes of disease burden and into neglected health-system issues. Second, a systematic plan is needed to make research initiatives more interactive with policies and implementation of health programmes, so that research is more relevant for the health system and policy, and the knowledge generated is used more often by policy makers. Third, rigorous evaluation research should become an essential component of all major population health programmes and policies, to understand how these could be refi ned to improve health outcomes and how the underserved segments of the Indian population could be better reached to improve health equity. For these goals to be achieved, the major national organisations attempting to strengthen health research in India should come together to provide eff ective stewardship. These organisations should collaboratively develop mechanisms that enable agreement on tangible medium-term and long-term targets for health research in the country, a plan of action, and methods to track progress in research utilisation to achieve health care for all in India. Although solutions for India will have to be tailored to its circumstances, there are useful lessons to be learnt from the systematic eff orts of other countries aimed at matching research with public health priorities to more eff ectively improve population health. *Lalit Dandona, V M Katoch, Rakhi Dandona Public Health Foundation of India, New Delhi 110070, India (LD, RD); Institute for Health Metrics and Evaluation, University of Washington, Seattle, Washington, USA (LD); and Department of Health Research and Indian Council of Medical Research, Ministry of Health and Family Welfare, Government of India, New Delhi, India (VMK) lalit.dandona@phfi .org

International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases

Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their “diagnostic odyssey,” improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

The need for worldwide policy and action plans for rare diseases

There are more than 6000 rare diseases (defined as affecting <5/10 000 individuals in Europe, <200 000 people in the United States). The rarity can create problems including: difficulties in obtaining timely, accurate diagnoses; lack of experienced healthcare providers; useful, reliable and timely information may be hard to find; research activities are less common; developing new medicines may not be economically feasible; treatments are sometimes very expensive; and in developing countries, the problems are compounded by other resource limitations. Emphasis is required to support appropriate research and development leading to better prevention, diagnosis and treatments of rare diseases. Notably, clinical trials using already existing drugs may result in new, affordable, treatment strategies. Moreover, rare diseases may teach us about common disorders.

Rare Diseases – Avoiding Misperceptions and Establishing Realities: The Need for Reliable Epidemiological Data

The rare disease community suffers from the absence of reliable epidemiological data on the prevalence and incidence of rare diseases in the national and global populations. The rare diseases community includes all of the stakeholders involved in the research and development and dissemination of products and information for the diagnosis, prevention or treatment of rare diseases or conditions. To replace many of the perceived myths with realities, several global efforts are required if we are going to sustain and increase the reported progress with the thousands of rare diseases. One is the identification and expansion of worldwide partnerships and collaborations of Patient Advocacy Groups for individual rare diseases. Another requirement is to develop a global research infrastructure of qualified investigators to stimulate and coordinate research efforts by seeking ways to provide access to clinical trials at multi-national research sites with common protocols and multi-disciplinary research teams. Providing ready access to the information about rare diseases, patient advocacy groups, research studies and products in research protocols will continue to improve the lives of patients and their families. Many scientists, public and private sector organizations, patient advocacy groups, foundations, and the pharmaceutical, biotechnology, and medical devices industries are committed to translating research discoveries that will be useful in the care of patients with rare diseases over their lifespan. Evidence from well constructed epidemiological studies will provide the evidence that point to the value of additional clinical studies to increase the understanding of rare diseases.

Rare diseases epidemiology

Rare Diseases.- Rare Diseases - Avoiding Misperceptions and Establishing Realities: The Need for Reliable Epidemiological Data.- Methods and Approaches.- Rare Diseases Epidemiology Research.- Evidence-Based Medicine and Rare Diseases.- Prevention, Diagnosis and Services.- The Importance of Case Reports in Advancing Scientific Knowledge of Rare Diseases.- Patient Registries: Utility, Validity and Inference.- Biobanking in Rare Disorders.- Evaluation of the Validity and Utility of Genetic Testing for Rare Diseases.- Population-Based Surveillance for Rare Congenital and Inherited Disorders: Models and Challenges.- Statistical Methods for the Geographical Analysis of Rare Diseases.- Clinical Trials and Rare Diseases.- Pharmacoepidemiology.- A Regulatory Overview About Rare Diseases.- Economics and Social Epidemiology.- Economic Considerations in the Provision of Treatments for Rare Diseases.- Rare Diseases Social Epidemiology: Analysis of Inequalities.- Quality of Life and Rare Diseases.- Cost of Illness and Economic Evaluation in Rare Diseases.- Epidemiology of Group of Rare Diseases.- The Burden of Rare Cancers in Europe.- Hereditary Channelopathies in Neurology.- Osteochondral Diseases and Fibrodysplasia Ossificans Progressiva.- The Prevalence of Congenital Anomalies in Europe.- Rare Autoimmune Diseases.- Epidemiology of Rare Anaemias in Europe.- Inherited Metabolic Rare Disease.- The Contribution of Rare Diseases to Understanding the Epidemiology of Neurodevelopmental Disabilities.- Policy and Ethics Issues in Rare Diseases.- Creating a European Union Framework for Actions in the Field of Rare Diseases.- National Plans and Strategies on Rare Diseases in Europe.- Ethical Aspects on Rare Diseases.- Patient Organizations Role.- Advocacy Groups and Their Role in Rare Diseases Research.

Undiagnosed Diseases Network International (UDNI): White paper for global actions to meet patient needs

In 2008, the National Institutes of Healths (NIH) Undiagnosed Disease Program (UDP) was initiated to provide diagnoses for individuals who had long sought one without success. As a result of two international conferences (Rome 2014 and Budapest 2015), the Undiagnosed Diseases Network International (UDNI) was established, modeled in part after the NIH UDP. Undiagnosed diseases are a global health issue, calling for an international scientific and healthcare effort. To meet this demand, the UDNI has built a consensus framework of principles, best practices and governance; the Board of Directors reflects its international character, as it includes experts from Australia, Canada, Hungary, Italy, Japan and the USA. The UDNI involves centers with internationally recognized expertise, and its scientific resources and know-how aim to fill the knowledge gaps that impede diagnosis. Consequently, the UDNI fosters the translation of research into medical practice. Active patient involvement is critical; the Patient Advisory Group is expected to play an increasing role in UDNI activities. All information for physicians and patients will be available at the UDNI website.

Rare Diseases Research: Expanding Collaborative Translational Research Opportunities

Extensive public-private partnerships, including the National Institutes of Health (NIH) and the rare diseases community, which is seeing a renewed industry interest in smaller niche markets, have resulted in an increase of interventions for rare diseases. Significant collaborative efforts are required among the pharmaceutical industry, foundations, patient-advocacy groups, academic and government investigators and funding programs, regulatory scientists, and reimbursement agencies to meet the unmet diagnostic and treatment needs for approximately 25 million people in the United States with 7,000 rare diseases. The expanding role and outreach activities of patient-advocacy groups have increased public awareness. In the United States, a rare disease is defined as a disorder or condition with a prevalence of <200,000 people. In 2011, the NIH provided >