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Discusses the issues on screening of maternal phenylketonuria. Risk of children born to mothers with high blood phenylalanine levels; Prenatal care for women with persistent phenylalanine elevations; Recommendations in dealing with phenylketonuria.

Rare genetic disorders affect as many as 3%-5% of all babies born. Approximately 10,000 such disorders have been identified or hypothesized to exist. Treatment is supportive except in a limited number of instances where specific therapies exist. Development of new therapies has been hampered by at least two major factors: difficulty in diagnosing diseases early enough to enable treatment before irreversible damage occurs, and the high cost of developing new drugs and getting them approved by regulatory agencies. Whole-genome sequencing (WGS) techniques have become exponentially less expensive and more rapid since the beginning of the human genome project, such that return of clinical data can now be achieved in days rather than years and at a cost that is comparable to other less expansive genetic testing. Thus, it is likely that WGS will ultimately become a mainstream, first-tier NBS technique at least for those disorders without appropriate high-throughput functional tests. However, there are likely to be several steps in the evolution to this end. The clinical implications of these advances are profound but highlight the bottlenecks in drug development that still limit transition to treatments. This article summarizes discussions arising from a recent National Institute of Health conference on nucleic acid therapy, with a focus on the impact of WGS in the identification of diagnosis and treatment of rare genetic disorders., (© 2022 Wiley Periodicals LLC.)

Progress in newborn screening (NBS) has been driven for 60 years by developments in science and technology, growing consumer advocacy, the actions of providers involved in the care of rare disease patients, and by federal and State government funding and policies. With the current explosion of clinical trials of treatments for rare diseases, the pressure for expansion has grown, and concerns about the capacity for improvement and growth are being expressed. Genome and exome sequencing (GS/ES) have now opened more opportunities for early identification and disease prevention at all points in the lifespan. The greatest challenge facing NBS stems from the conditions most amenable to screening, and new treatment development is that we are screening for rare genetic diseases. In addition, understanding the spectrum of severity requires vast amounts of population and genomic data. We propose recommendations on improving the NBS system and addressing specific demands to grow its capacity by: better defining the criteria by which screening targets are established; financing the NBS system's responsiveness to opportunities for expansion, including engagement and funding from stakeholders; creating a national quality assurance, data, IT, and communications infrastructure; and improving intra-governmental communications. While our recommendations may be specific to the United States, the underlying issues should be considered when working to improve NBS programs globally.

It would be difficult to overestimate the importance of persistent, thoughtful parents and their importance in the development of treatments for their children's rare disorders. Almost a century ago in Norway, observant parents led a brilliant young physician-scientist to his discovery of the underlying cause of their children's profound developmental delay-i.e., phenylketonuria, or PKU. Decades later, in a recovering war-ravaged Britain, an equally persistent mother pressed the scientists at Birmingham Children's Hospital to find a way to treat her seriously damaged daughter, Sheila, who suffered from PKU. Living on the financial edge, this mother insisted that Bickel and colleagues develop such a diet, and she volunteered Sheila to be the patient in the trial. The scientists concluded that the low phenylalanine diet helped but needed to be started very early-so, newborn screening was born to permit the implementation of this. Many steps brought us to where we are today, but these courageous parents made it all begin.

Importance: Newborn screening (NBS) identifies infants with specific congenital disorders for which earlier intervention cannot only prevent a lifetime of chronic disability but also, most importantly, save lives. In this article, we discuss complexities associated with NBS processes in the United States, with a focus on challenges in neuromuscular disorders., Observations: As new interventions for neuromuscular disorders become available, the clinical community must prepare to overcome the challenges of adding new diseases to screening panels and understand the rigorous evidence review at the federal level and the complex process of state-level implementation. In this regard, NBS programs for Pompe disease and spinal muscular atrophy can guide the path of Duchenne muscular dystrophy and other neuromuscular disorders as future candidates for NBS., Conclusions and Relevance: The availability of advanced screening methods, the emergence of effective treatment, and the support of professional organizations may facilitate the expansion of NBS, such that an increasing number of infants can be identified in the newborn period who will benefit from life-saving interventions.

Background: The evidence review processes for adding new conditions to state newborn screening (NBS) panels rely on data from pilot studies aimed at assessing the potential benefits and harms of screening. However, the consideration of ethical, legal, and social implications (ELSI) of screening within this research has been limited. This paper outlines important ELSI issues related to newborn screening policy and practices as a resource to help researchers integrate ELSI into NBS pilot studies., Approach: Members of the Bioethics and Legal Workgroup for the Newborn Screening Translational Research Network facilitated a series of professional and public discussions aimed at engaging NBS stakeholders to identify important existing and emerging ELSI challenges accompanying NBS., Results: Through these engagement activities, we identified a set of key ELSI questions related to (1) the types of results parents may receive through newborn screening and (2) the initiation and implementation of NBS for a condition within the NBS system., Conclusion: Integrating ELSI questions into pilot studies will help NBS programs to better understand the potential impact of screening for a new condition on newborns and families, and make crucial policy decisions aimed at maximized benefits and mitigating the potential negative medical or social implications of screening.

Mike, a memorable young patient with untreated phenylketonuria, as well as others affected by genetic disorders that could be treated if diagnosed in infancy, launched my six-decade career. This autobiographical article reflects on my childhood, early research, and professional experiences in pediatric genetics. My laboratory research focused on inborn errors of metabolism, including the glycogen storage diseases. My effort to organize newborn screening through the recommended uniform screening panel shaped and standardized newborn screening nationwide. Looking ahead, the expansion of whole-genome and whole-exome sequencing into newborn screening raises ethical and policy issues regarding informed consent procedures and the storage and use of residual blood spots.

Duchenne muscular dystrophy (DMD/Duchenne) is one of the ten most severe and common pediatric genetic diseases and affects an estimated 1 in every 5000 male births. While Duchenne is a 100% fatal disease, the clinical community has demonstrated that immediate identification and early clinical interventions can add years, even decades to an individual's life span. In anticipation of the changing therapeutic landscape for the Duchenne community, Parent Project Muscular Dystrophy established a newborn screening (NBS) initiative. This initiative included a Bioethics and Legal Issues Workgroup to consider the bioethics and legal issues of NBS for Duchenne. The workgroup's discussion focused only on Duchenne NBS and met through conference calls over a one-year period of time seeking consensus on various identified issues. This article reports on the findings and recommendations from that workgroup., Competing Interests: Conflicts of InterestThe authors declare no conflicts of interest., (© 2018 by the authors.)

Background: Newborn screening for Duchenne muscular dystrophy (DMD) is currently being initiated in Zhejiang Province, China and is under consideration in other countries, including the United States. As China begins to implement DMD newborn screening (DMD-NBS), there is ongoing discussion regarding the steps forward for follow up care of positively identified patients as well as false positive and false negative results., Data Sources: Relevant papers related to DMD-NBS, and NBS in China were reviewed in PubMed., Results: The current state of DMD-NBS is discussed, along with the steps needed to effectively screen infants for this disease in China, recommendations for establishment of follow up care in patients with positive and negative screens, and measurement of patient outcomes., Conclusions: Zhejiang Province, China is ready to implement DMD-NBS. Future challenges that exist for this program, and other countries, include the ability to track patients, assist with access to care, and ensure adequate follow-up care according to evidence-based guidelines. In addition, China's large rural population, lack of specialty providers, and difficulty in educating patients regarding the benefits of treatment create challenges that will need to be addressed.

Federal advisory committees (or commissions, councils, or task forces) are created either by congressional action or a federal department to bring together a variety of viewpoints on specific policy issues. The committees or advisory bodies are generally directed to advise various bodies within the government, either by congressional mandate, government decree, or executive order. The committees are often created to aid the government in subject matters with difficult issues. In the Department of Health and Human Services (HHS), current advisory committees range from advising the Secretary, Department of Health and Human Services, on immunization practices, to organ donation, blood safety, to issues related to newborn and child screening. This article describes the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children. Its history offers insight into connection of the development of policy guidelines and the creation of legislation to implement that policy. Its current activities have affected and will continue to affect not only state newborn screening programs but also the policy and practice of screening children for heritable disorders., (Published by Elsevier Inc.)

Clinical follow-up of children identified by newborn screening is critical in ensuring that the short-term and long-term needs of the newborn infant are managed. Within the United States, one of the biggest challenges in the newborn screening programme is clinical follow-up, and there still remains wide variation in practice patterns among states on how infants are followed up. In addition, there is lack of consistency in the treatment and diagnostic protocols used by health care providers. There is growing interest in the establishment of a systematic process for follow-up and for the development of a nationwide infrastructure that will ensure that all children will be provided consistent and effective treatment in a timely manner. Within this framework of optimal diagnosis and therapy, there must also be opportunities to study the natural history of these conditions, to monitor short- and long-term health outcomes, to assist with policy decision-making, to validate the effectiveness of screening, to define the clinical spectrum of the diseases, and to provide opportunities for the advancement of novel therapeutic interventions and screening/diagnostic technologies. It will only be through the development of a structured clinical follow-up system that we will be able to make certain these newborn infants are provided the most appropriate treatment for their disease variants and allow researchers to make more rapid advances in improving the clinical management of these conditions.