Newborn screening for Duchenne muscular dystrophy-early detection and diagnostic algorithm for female carriers of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is the most common pediatric-onset form of muscular dystrophy, occurring in 1 in 5,000 live male births. DMD is a multi-system disease resulting in muscle weakness with progressive deterioration of skeletal, heart, and smooth muscle, and learning disabilities. Pathogenic/likely pathogenic (P/LP) variants in the DMD gene, which encodes dystrophin protein, cause dystrophinopathy. All males with a P/LP variant in the X-linked DMD gene are expected to be affected. Two to 20% of female heterozygotes with a P/LP variant develop symptoms of dystrophinopathy ranging from mild muscle weakness to significant disability similar to Becker muscular dystrophy. Recently, with improvements in therapies and testing methodology, there is stronger evidence supporting newborn screening (NBS) for DMD for males and females because females may also develop symptoms. A consented pilot study to screen newborns for DMD was initiated in New York State (NYS) and conducted from 2019 to 2021. The identification of female carriers and the realization of the subsequent uncertainty of providers concerning follow-up during the pilot led to the development of algorithms for screening and diagnosis of carrier females, including both NBS and cascade molecular testing of family members.

Newborn screening for neurodevelopmental diseases: Are we there yet?

In the US, newborn screening (NBS) is a unique health program that supports health equity and screens virtually every baby after birth, and has brought timely treatments to babies since the 1960's. With the decreasing cost of sequencing and the improving methods to interpret genetic data, there is an opportunity to add DNA sequencing as a screening method to facilitate the identification of babies with treatable conditions that cannot be identified in any other scalable way, including highly penetrant genetic neurodevelopmental disorders (NDD). However, the lack of effective dietary or drug-based treatments has made it nearly impossible to consider NDDs in the current NBS framework, yet it is anticipated that any treatment will be maximally effective if started early. Hence there is a critical need for large scale pilot studies to assess if and how NDDs can be effectively screened at birth, if parents desire that information, and what impact early diagnosis may have. Here we attempt to provide an overview of the recent advances in NDD treatments, explore the possible framework of setting up a pilot study to genetically screen for NDDs, highlight key technical, practical, and ethical considerations and challenges, and examine the policy and health system implications.

Regional models of genetic services in the United States.

PURPOSE: To outline structures for regional genetic services support centers that improve access to clinical genetic services. METHODS: A workgroup (WG) and advisory committee (AC) (1) conducted a comprehensive review of existing models for delivering health care through a regional infrastructure, especially for genetic conditions; (2) analyzed data from a needs assessment conducted by the National Coordinating Center (NCC) to determine important components of a regional genetic services support center; and (3) prioritized components of a regional genetic services support system. RESULTS: Analysis of identified priorities and existing regional systems led to development of eight models for regional genetic services support centers. A hybrid model was recommended that included an active role for patients and families, national data development and collection, promotion of efficient and quality genetic clinical practices, healthcare professional support for nongeneticists, and technical assistance to healthcare professionals. CONCLUSION: Given the challenges in improving access to genetic services, especially for underserved populations, regional models for genetic services support centers offer an opportunity to improve access to genetic services to local populations. Although a regional model can facilitate access, some systemic issues exist-e.g., distribution of a workforce trained in genetics-that regional genetic services support centers cannot resolve.

Correction: Regional models of genetic services in the United States.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Foundation of the Newborn Screening Translational Research Network and its tools for research.

In the past 20 years, several policy activities were undertaken that shaped today's newborn screening (NBS) programs and their associated NBS research activities: the Newborn Screening Task Force Report; the Child Health Act of 2000, Screening for Heritable Disorders; the American College of Medical Genetics and Genomics' (ACMG's) Newborn Screening Uniform Panel; and the ACMG expert panel to examine the development of a national collaborative study system for rare genetic diseases. These activities helped conceptualize the Newborn Screening Translational Research Network (NBSTRN) infrastructure and lay the foundation for its current activities. After 10 years, NBSTRN has grown into an organization that provides tools and resources for researchers to conduct research relevant to NBS programs for rare diseases for which data has been siloed locally. Infrastructure includes tools for the analytical and clinical validation of screening tests; the collection, analysis, sharing, and reporting of longitudinal laboratory and clinical data on newborn-screened individuals; and a web-based tool that allows researchers to acquire dried blood spots available for use in research from state NBS programs. NBSTRN also provides tools for researchers such as informed consent templates, disease registries, state NBS profiles, and consultation on planning pilot studies. In time, the growing data will become a resource itself.

Including ELSI research questions in newborn screening pilot studies.

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.

Clinical Outcomes Associated With Sickle Cell Trait: A Systematic Review.

Background: Although sickle cell trait (SCT) is largely a benign carrier state, it may increase risk for certain clinical outcomes. Purpose: To evaluate associations between SCT and clinical outcomes in children and adults. Data Sources: English-language searches of PubMed, CINAHL, the Cochrane Library, Current Contents Connect, Scopus, and Embase (1 January 1970 to 30 June 2018) and bibliographies of review articles. Study Selection: Observational controlled studies (published in English) in children or adults that examined an association between SCT and any of 24 clinical outcomes specified a priori in the following 6 categories: exertion-related injury; renal, vascular, pediatric, and surgery- or trauma-related outcomes; and overall mortality. Data Extraction: A single reviewer extracted study data, which was checked by another; 2 reviewers independently assessed study quality; and strength of evidence was assessed by consensus. Data Synthesis: Of 7083 screened studies, 41 met inclusion criteria. High-strength evidence supported a positive association between SCT and risk for pulmonary embolism, proteinuria, and chronic kidney disease. Moderate-strength evidence supported a positive association between SCT and exertional rhabdomyolysis and a null association between SCT and deep venous thrombosis, heart failure or cardiomyopathy, stroke, and pediatric height or weight. Absolute risks for thromboembolism and rhabdomyolysis were small. For the remaining 15 clinical outcomes, data were insufficient or strength of evidence was low. Limitation: Publication bias was possible, and high-quality evidence was scant. Conclusion: Sickle cell trait is a risk factor for a few adverse health outcomes, such as pulmonary embolism, kidney disease, and exertional rhabdomyolysis, but does not seem to be associated with such complications as heart failure and stroke. Insufficient data or low-strength evidence exists for most speculated complications of SCT. Primary Funding Source: National Human Genome Research Institute.

Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.

Inborn errors of metabolism (IEM) are genetic disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. In the U.S., many IEM are detected through state newborn screening (NBS) programs. To inform research on IEM and provide necessary resources for researchers, we are providing: tabulation of ten-year state NBS data for selected IEM detected through NBS; costs of medical foods used in the management of IEM; and an assessment of corporate policies regarding provision of nutritional interventions at no or reduced cost to individuals with IEM. The calculated IEM incidences are based on analyses of ten-year data (2001-2011) from the National Newborn Screening Information System (NNSIS). Costs to feed an average person with an IEM were approximated by determining costs to feed an individual with an IEM, minus the annual expenditure for food for an individual without an IEM. Both the incidence and costs of nutritional intervention data will be useful in future research concerning the impact of IEM disorders on families, individuals and society.

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.

Insurance coverage of medical foods for treatment of inherited metabolic disorders.

PURPOSE: Treatment of inherited metabolic disorders is accomplished by use of specialized diets employing medical foods and medically necessary supplements. Families seeking insurance coverage for these products express concern that coverage is often limited; the extent of this challenge is not well defined. METHODS: To learn about limitations in insurance coverage, parents of 305 children with inherited metabolic disorders completed a paper survey providing information about their use of medical foods, modified low-protein foods, prescribed dietary supplements, and medical feeding equipment and supplies for treatment of their child's disorder as well as details about payment sources for these products. RESULTS: Although nearly all children with inherited metabolic disorders had medical coverage of some type, families paid "out of pocket" for all types of products. Uncovered spending was reported for 11% of families purchasing medical foods, 26% purchasing supplements, 33% of those needing medical feeding supplies, and 59% of families requiring modified low-protein foods. Forty-two percent of families using modified low-protein foods and 21% of families using medical foods reported additional treatment-related expenses of $100 or more per month for these products. CONCLUSION: Costs of medical foods used to treat inherited metabolic disorders are not completely covered by insurance or other resources.

Expanding research to provide an evidence base for nutritional interventions for the management of inborn errors of metabolism.

A trans-National Institutes of Health initiative, Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism (NDSI-IEM), was launched in 2010 to identify gaps in knowledge regarding the safety and utility of nutritional interventions for the management of inborn errors of metabolism (IEM) that need to be filled with evidence-based research. IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. For some of these IEM, effective management depends primarily on nutritional interventions. Further research is needed to demonstrate the impact of nutritional interventions on individual health outcomes and on the psychosocial issues identified by patients and their families. A series of meetings and discussions were convened to explore the current United States' funding and regulatory infrastructure and the challenges to the conduct of research for nutritional interventions for the management of IEM. Although the research and regulatory infrastructure are well-established, a collaborative pathway that includes the professional and advocacy rare disease community and federal regulatory and research agencies will be needed to overcome current barriers.

Report of MDA muscle disease symposium on newborn screening for Duchenne muscular dystrophy.

This report summarizes the progress made in newborn screening for Duchenne muscular dystrophy (DMD). This subject was discussed fully at a symposium held on September 11-12, 2012, in Bethesda, Maryland, by a group of experts from multiple disciplines. The meeting was triggered by the simultaneous combination of improvements in methods for newborn screening for DMD and greater potential for treatment. On the screening side, a two-tier system of newborn screening was introduced that enabled creatine kinase levels and DMD gene analysis to be done on the same dried blood spots obtained at birth. Treatment improvements included promising results from exon skipping as well as multiple studies showing long-term benefits of glucocorticoids and data indicating that early intervention of both forms of therapy was the most beneficial. Conclusions from this symposium with supportive data could have a significant impact on propelling efforts for approval of newborn screening for DMD.

Factors influencing creatine kinase-MM concentrations in newborns and implications for newborn screening for Duchenne muscular dystrophy.

INTRODUCTION: Newborn screening for Duchenne muscular dystrophy can be performed via a first-tier creatine kinase-MM measurement followed by reflex testing to second-tier molecular analysis of the DMD gene. In order to establish appropriate cut-offs for the creatine kinase-MM screen, factors that influence creatine kinase-MM in newborns were investigated. MATERIALS AND METHODS: Creatine kinase-MM data from a consented pilot study in New York State were collected over a two-year period and combined with de-identified validation data and analyzed. Univariate analysis and multiple linear regression analysis were performed. RESULTS: The analysis indicated that age of newborn at specimen collection, gestational age and birth weight were significant influencers of CK-MM levels in newborns. In addition, to a lesser extent, sex, race/ethnicity and seasonal temperature also affect CK-MM levels in newborns. CONCLUSIONS: To reduce false positive and false negative cases, newborn screening programs should be cognizant of factors that influence CK-MM when determining cut-offs for the assay. Variability based on age at specimen collection and birth weight are primarily observed within the first week of life. Therefore, particularly during this time period, multi-tiered cut-offs based on age of collection and lower cut-offs for premature and low birth weight babies are recommended. Other cut-off determinants may include sex, race/ethnicity and seasonal temperature.

Newborn screening for Duchenne muscular dystrophy: A two-year pilot study.

OBJECTIVE: Duchenne muscular dystrophy (DMD) is an X-linked disorder resulting in progressive muscle weakness and atrophy, cardiomyopathy, and in late stages, cardiorespiratory impairment, and death. As treatments for DMD have expanded, a DMD newborn screening (NBS) pilot study was conducted in New York State to evaluate the feasibility and benefit of NBS for DMD and to provide an early pre-symptomatic diagnosis. METHODS: At participating hospitals, newborns were recruited to the pilot study, and consent was obtained to screen the newborn for DMD. The first-tier screen measured creatine kinase-MM (CK-MM) in dried blood spot specimens submitted for routine NBS. Newborns with elevated CK-MM were referred for genetic counseling and genetic testing. The latter included deletion/duplication analysis and next-generation sequencing (NGS) of the DMD gene followed by NGS for a panel of neuromuscular conditions if no pathogenic variants were detected in the DMD gene. RESULTS: In the two-year pilot study, 36,781 newborns were screened with CK-MM. Forty-two newborns (25 male and 17 female) were screen positive and referred for genetic testing. Deletions or duplications in the DMD gene were detected in four male infants consistent with DMD or Becker muscular dystrophy. One female DMD carrier was identified. INTERPRETATION: This study demonstrated that the state NBS program infrastructure and screening technologies we used are feasible to perform NBS for DMD. With an increasing number of treatment options, the clinical utility of early identification for affected newborns and their families lends support for NBS for this severe disease.

Nutritional treatment for inborn errors of metabolism: indications, regulations, and availability of medical foods and dietary supplements using phenylketonuria as an example.

Medical foods and dietary supplements are used to treat rare inborn errors of metabolism (IEM) identified through state-based universal newborn screening. These products are regulated under Food and Drug Administration (FDA) food and dietary supplement statutes. The lack of harmony in terminology used to refer to medical foods and dietary supplements and the misuse of words that imply that FDA regulates these products as drugs have led to confusion. These products are expensive and, although they are used for medical treatment of IEM, third-party payer coverage of these products is inconsistent across the United States. Clinicians and families report termination of coverage in late adolescence, failure to cover treatment during pregnancy, coverage for select conditions only, or no coverage. We describe the indications for specific nutritional treatment products for IEM and their regulation, availability, and categorization. We conclude with a discussion of the problems that have contributed to the paradox of identifying individuals with IEM through newborn screening but not guaranteeing that they receive optimal treatment. Throughout the paper, we use the nutritional treatment of phenylketonuria as an example of IEM treatment.

The Progress and Future of US Newborn Screening.

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.

Metagenomics Approaches to Investigate the Neonatal Gut Microbiome.

Early infancy is critical for the development of an infant's gut flora. Many factors can influence microbiota development during the pre- and postnatal periods, including maternal factors, antibiotic exposure, mode of delivery, dietary patterns, and feeding type. Therefore, investigating the connection between these variables and host and microbiome interactions in neonatal development would be of great interest. As the "unculturable" era of microbiome research gives way to an intrinsically multidisciplinary field, microbiome research has reaped the advantages of technological advancements in next-generation sequencing, particularly 16S rRNA gene amplicon and shotgun sequencing, which have considerably expanded our knowledge about gut microbiota development during early life. Using omics approaches to explore the neonatal microbiome may help to better understand the link between the microbiome and newborn diseases. Herein, we summarized the metagenomics methods and tools used to advance knowledge on the neonatal microbiome origin and evolution and how the microbiome shapes early and late individuals' lives for health and disease. The way to overcome limitations in neonatal microbiome studies will be discussed.

Newborn Screening for Duchenne Muscular Dystrophy: First Year Results of a Population-Based Pilot.

Advancements in therapies for Duchenne muscular dystrophy (DMD) have made diagnosis within the newborn period a high priority. We undertook a consortia approach to advance DMD newborn screening in the United States. This manuscript describes the formation of the Duchenne Newborn Screening Consortium, the development of the pilot protocols, data collection tools including parent surveys, and findings from the first year of a two-year pilot. The DMD pilot design is population-based recruitment of infants born in New York State. Data tools were developed to document the analytical and clinical validity of DMD NBS, capture parental attitudes, and collect longitudinal health information for diagnosed newborns. Data visualizations were updated monthly to inform the consortium on enrollment. After 12 months, 15,754 newborns were screened for DMD by the New York State Newborn Screening (NYS NBS) Program. One hundred and forty screened infants had borderline screening results, and sixteen infants were referred for molecular testing. Three male infants were diagnosed with dystrophinopathy. Data from the first year of a two-year NBS pilot for DMD demonstrate the feasibility of NBS for DMD. The consortia approach was found to be a useful model, and the Newborn Screening Translational Research Network's data tools played a key role in describing the NBS pilot findings and engaging stakeholders.

Long-term follow-up in newborn screening: A systems approach for improving health outcomes.

BACKGROUND: Newborn screening is a complex system of interrelated multidimensional components singly focused on safeguarding the health of our nation's newborns. The long-term health outcome and well-being of individuals identified by newborn screening represents a meaningful measurement of the performance of the newborn screening system. This assessment of long-term follow-up requires a systems approach that connects stakeholders, processes, and outcomes through the collection, integration, evaluation, and sharing of key data and metrics. METHODS: A review of the principles of a systems approach and its application to newborn screening long-term follow-up was performed. Past and current efforts by HRSA/MCHB that address individual components of newborn screening were assessed and utilized to outline lessons learned and suggest next steps. RESULTS: The principle features of a systems approach applied to the creation and utilization of a health information exchange system for the long-term follow up of screen positive patients is defined. The application of this approach is in progress through the HRSA/MCHB's Effective Follow-up in Newborn Screening project. CONCLUSIONS: While several elements are in place to realize a systems approach, the authors think that the key is an integrated, multidirectional health information exchange system that functions locally, regionally and nationally, and enables information exchange between private and public health sectors.