Newborn screening (NBS) for inherited disorders is recognized as an essential public health intervention to improve health outcomes in the newborn population. The implementation of an NBS programme requires an evaluation of effectiveness, safety, cost-effectiveness, feasibility, and budget impact. Determining which of the known disorders should be included in NBS programmes is a public health policy challenge. In this context, economic evaluation aims to contribute to the sustainability of public health systems, but the appropriate economic evaluation framework for these interventions is still unclear. Existing NBS programmes vary widely in the number and type of disorders screened, even among the most developed European countries, despite the fact that the core criteria for guiding policy decision-making are standard. In Spain, where delivery of NBS programmes is marked by heterogeneity between regions, guidelines based on the best available scientific evidence are being established in order to achieve standardization of NBS policies and programmes at a national level. This paper provides a general overview of existing evidence-based health-policy initiatives aimed at enhancing the equity and efficiency of the NBS programme in Spain and their impact on health decisions. We also describe existing challenges to reduce uncertainty, and the variations observed in decisions relating to the content and procedures used in NBS programmes.

Fragile X syndrome (FXS) is caused by a full mutation (> 200 cytosine-guanine-guanine (CGG) repeats) in the 5′-untranslated region of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, which leads to methylation and silencing of expression, generating the total or partial absence of its product, FMR1 protein (FMRP). When the repetitions are between 55 and 200 CGG repeats, it is called a premutation and is related to a wide spectrum of conditions such as fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X-associated neuropsychiatric disorders. High levels of FMR1 messenger RNAs are implicated in premutation pathophysiology, which differs from the deficiency or absence of FMRP in FXS. In recent years, numerous attempts have been made to find treatments that can counteract the effects of the absence of FMRP and improve symptoms associated with the condition, such as intellectual disability, anxiety, autism, stereotypies, language delay, and aggressive behavior. Here, we review current treatments in addition to targeted treatments that can reverse some of the neurobiological abnormalities in those with FXS. We also review molecular interventions that will hopefully lead to a promising future for those affected by FXS and their families.

Aim: This article describes results from a survey targeting healthcare professionals (HCPs) leading newborn screening (NBS) initiatives in Europe. The survey was developed within the framework of a dedicated working group set up by the International Rare Diseases Research Consortium (IRDiRC) to gather collective efforts relating to NBS. The objectives of the survey were to gain a better understanding of approaches being tested for the expansion of NBS and to raise awareness of the significant momentum across Europe to evaluate novel technologies for use in future NBS programs.

Methods: A web-based survey including 57 questions was developed to gather information about genomic newborn screening initiatives in Europe that are using next-generation sequencing (NGS) as a first-tier test. Responses were analyzed qualitatively, and aggregated results are presented herein. The identity of some initiatives is not presented to preserve confidentiality.

Results: The findings of the survey indicated that most initiatives are in the planning stage and have not yet started. Although all 14 studies are heterogeneous in design, there is broad consensus that NGS approaches to NBS will, in the short term, be implemented in parallel with current screening programs. The results of this survey can be used to inform the design of studies still in the early planning stages.

Conclusion: Here, we provide an overview of NGS-based initiatives in Europe. Importantly, the initiatives described herein will generate evidence to evaluate the utility and feasibility of NGS approaches to NBS, thereby shortening the pathway to responsible implementation of NGS in NBS and informing future research efforts.

The detection of rare diseases utilizing advanced artificial intelligence (AI) techniques has garnered considerable attention in recent years. Numerous approaches have been proposed to detect diverse rare diseases by leveraging a range of medical data, including medical images, electronic health records, and sensory data. In order to safeguard the privacy of health data, considerable investigation has been undertaken on a novel learning paradigm known as federated learning, which has been applied to the domain of rare disease detection. Nonetheless, this nascent research direction remains in its infancy, necessitating greater scrutiny and attention. Within this survey, our primary focus lies in providing fresh perspectives, deliberating the challenges, and enumerating potential research directions concerning the application of federated learning techniques in rare disease detection. Furthermore, we provide a succinct summary of existing advancements using AI techniques for rare disease detection, as well as the utilization of federated learning within healthcare informatics. Moreover, we furnish a compilation of publicly available datasets that can be employed to validate novel federated learning algorithms for the purpose of detecting rare diseases.

Aim: Gene therapies have been tested over the past three decades, and after a first market authorization in 2017, the field is starting to deliver. The study aims to analyze the current development dynamics of gene therapies for rare diseases using the GENOTRIAL database®, which gathers information on gene therapy clinical trials and studies conducted between 2017 and 2023 in Europe.

Methods: The study involved extracting and filtering clinical trial data from the EudraCT database. Trials with the keyword "Gene Therapy" were selected and filtered using the "Rare disease" filter. Manual verification was conducted to ensure that the selected trial only concerned gene therapy treatments authorized in Europe for rare diseases in phases I to III. A total of 300 European country-related clinical investigations representing a total of 93 European-specific clinical studies were included in the GENOTRIAL database. The trials were classified by development phases, temporal status, sponsors and investigating countries, rare diseases with their related therapeutic area, and approval regulatory information of the identified gene therapies.

Results: Analysis reveals that rare diseases present a promising area for gene therapy development. On average, eight rare disease gene therapy trials are launched each year in Europe. The main sponsors of European clinical trials of gene therapies for rare diseases are from US, followed by the United Kingdom and France. The United Kingdom conducts the highest number of investigations in Europe, followed by France, Italy, Spain, and Germany. Nutritional and metabolic diseases are the most represented therapeutic area, followed by rare oncology, blood and lymphatic diseases, and ocular diseases. The analysis identifies 73 gene therapy medical products covering 35 diseases at various stages of development, with 12 new therapies approved in recent years for 8 rare diseases, while 15 other gene therapies are at an advanced stage of phase III in their development plan for 11 other rare diseases.

Conclusion: Gene therapy has shown significant progress and potential in treating rare genetic diseases. Europe has emerged as a promising region for gene therapy clinical trials in rare diseases. Efforts are now required to catch up with the USA and UK regarding the number of clinical trials sponsored by European groups.

Background: Rare diseases (RDs) are serious often chronic progressive diseases that affect a smaller number of individuals. RDs can manifest in any region of the body and have systemic effects that are detrimental to individual health. Although RDs are individually rare, there are various debilitating disorders arising from RDs. One of the disorders that have been shown to have a negative impact on the health of RD patients is temporomandibular disorders (TMD). There is a dearth of data on the rare diseases and potential manifestations of TMD. The objective of this systematic review is to provide an overview of rare diseases and temporomandibular joint (TMJ) manifestations.

Method: The criterion for analysis of a rare disease and temporomandibular manifestations was inclusion in the Orphanet Classification of Rare Diseases and/or the National Organization for Rare Disorders (NORD)/The Genetic and Rare Diseases (GARD) databases. Only rare diseases with TMJ manifestations were recorded.

Results: A total of 54 RDs with TMJ manifestations and different TMD diagnoses were recorded. There were thirty-five studies derived from the Pubmed search, and the Orphanet input had 19 results. Overall, 13 different types of TMJ manifestations and TMD diagnoses were recorded in rare diseases.

Conclusion: TMJ manifestations associated with rare diseases are not uncommon. Healthcare professionals can play an important role in diagnosing and managing the complexity of RDs with TMJ manifestations. A multidisciplinary approach to TMD patients with rare diseases is advisable.

Gene therapy medicinal products (GTMPs) may generate unexpected risks to public health and individual patients. Pharmacovigilance serves the purpose of detecting, assessing, understanding, and preventing adverse effects or any other medicine-related problems. This article aims to provide an overview of the significance of pharmacovigilance and particularities in the domain of gene therapy with a brief description of the European regulatory framework. Viral vectors, insertional mutagenesis, viral latency or reactivation, as well as duration and accuracy of the patient’s clinical follow-up, are some of the main concerns. Two recent examples of signals illustrate some of these safety issues. The first concerns onasemnogene abeparvovec, an adeno-associated virus-based gene replacement therapy for treating spinal muscular atrophy. This GTMP initially raised safety concerns about hepatotoxicity, cardiotoxicity, and neurotoxicity, necessitating recommendations for close monitoring. During the post-marketing period, two fatal cases of acute liver failure led the European Medicine Agency (EMA) to strengthen the recommendations for liver function monitoring. The second example pertains to betibeglogene autotemcel, a genetically modified autologous CD34+ cell-enriched population that contains hematopoietic stem cells transduced with lentiviral vectors encoding the β A-T87Q-globin gene. After the report of a case of acute myeloid leukemia in a patient treated with an investigational product using the same lentiviral vector, the European Commission triggered a regulatory safety procedure. After careful assessment, the EMA’s ad hoc safety committees stated that the viral vector was unlikely to be the cause. However, due to commercial reasons, betibeglogene autotemcel was finally withdrawn from the market by the marketing authorization holder. Pharmacovigilance activities and systems continuously evolve to keep pace with advancements in new therapies and technologies. They must also address varied situations and adhere to evolving regulations. GTMPs likely stand out as one of the most demanding areas within pharmacovigilance. Therefore, their effective oversight requires the full commitment of pharmacological and clinical experts, as well as active involvement from patients, to ensure optimal outcomes.

In Australia, over 300,000 newborns undergo newborn bloodspot screening (NBS) annually, with approximately 1 in 1,000 identified with a rare but actionable condition through this pathway. Prior to 2018, the inclusion criteria for adding conditions in NBS panels was inconsistent nationally, leading to the development of the Australian National Newborn Bloodspot Screening Policy Framework. This framework promotes systematic and evidence-based inclusion of conditions using criteria closely informed by traditional Wilson and Junger screening principles. Current policy initiatives are focused on achieving national consistency in the conditions screened. NBS programs, initiated in the 1960s, have used a variety of techniques, including but not limited to tandem mass spectrometry and immunological assays. The acceleration of genomic technologies has the potential to greatly increase the number of conditions screened and match affected newborns with innovative treatment options, including advanced (gene, immune modulation, and RNA) therapies. This review describes the evolution, current status quo, and outlook for Australian NBS programs with a focus on the implications of wider adoption of genomic newborn screening (gNBS) in our culturally, geographically, and genetically diverse population. We discuss the potential for transformative benefits for families with children identified by gNBS and how this must be balanced against the potential for a range of unintended negative consequences. We emphasise the importance of a nationally agreed, coordinated, and streamlined approach to the addition and removal of conditions from Australian NBS programs, which considers the utility, cost, ethical, and equity aspects of gNBS.

Newborn screening (NBS) was introduced in the Philippines in 1996, and the Newborn Screening Act of 2004 mandated its provision to all Filipino newborns. The program initially covered five conditions and has expanded to the current panel of 29 conditions. This report focuses on the steps taken for successful NBS implementation and the challenges that must be overcome to make NBS sustainable. While often considered a public health program, NBS is really a system of interacting parts that must be carefully considered and planned prior to embarking on their implementation. The basic challenges are the same in both high-income and low-middle-income countries (LMICs), but they are more difficult to overcome in LMICs. In addition to the technical aspects of screening, including supplies and maintenance, considerations must include human resources, professional and public education, and government support. Challenges may occur at any point in implementation and continuation, and it is important to learn from the experiences of others in order to make the process more efficient. Here, we report on the experiences in one LMIC, the Philippines, in creating and sustaining a NBS system so that others may gain from these experiences.

The International Rare Disease Research Consortium, or IRDiRC, is a global consortium of key stakeholders from different facets of rare disease research that together seek to drive advances in diagnostics, therapeutics, and patient outcomes. The consortium facilitates a global and cross-disciplinary exchange of ideas to tackle key issues in rare diseases through the development of recommendations, data standards, tools, and guidelines that harmonize research efforts and improve efficiency. While IRDiRC has made significant contributions to the development of new therapies and diagnostics since its establishment in 2011, much work remains to alleviate the burden of rare diseases. The consortium has demonstrated its success in providing a global platform to advance rare disease research through collaborative efforts worldwide and continues to identify and address barriers to health equity for all rare disease patients.