Linking Angelman and dup15q data for expanded research (LADDER) database: a model for advancing research, clinical guidance, and therapeutic development for rare conditions.

Angelman syndrome (AS) and duplication 15q (dup15q) syndrome are rare neurogenetic conditions arising from a common locus on the long arm of chromosome 15. Individuals with both conditions share some clinical features (e.g. intellectual disability, epilepsy) and often require lifelong care. Disease-modifying therapies for both conditions are emerging, resulting in a significant need for a better understanding of the natural history of both AS and dup15q. Patient advocacy groups for both conditions recognized a need for a data repository that would link data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments, resulting in the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database. This paper describes the development and functionality of the LADDER Database - including challenges, lessons learned, and preliminary feasibility - and how it can be used as a model for other rare conditions.

The LADDER database: a model for advancing research, clinical guidance, and therapeutic development for rare conditions This paper describes the development and functionality of the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database, which is a data repository for two rare neurogenetic conditions: Angelman syndrome (AS) and duplication 15q (dup15q) syndrome. AS and dup15q syndrome arise from genetic abnormalities on chromosome 15 and share some clinical features (e.g. intellectual disability, epilepsy). LADDER was developed by patient advocacy organizations representing each condition in partnership with RTI International. LADDER links data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments for both AS and dup15q syndrome. The LADDER Database can be used as a model for expanding research and enhancing clinical trial readiness in other rare conditions.

Psychological distress among postpartum women who took opioids during pregnancy: the role of perceived stigma in healthcare settings.

This study examined the relationship between perceived stigma in healthcare settings during pregnancy and psychological distress and well-being in the postpartum period among individuals who took opioids while pregnant. Analyses included 134 birth mothers of opioid-exposed infants. At 0-1 months postpartum, perceived stigma and psychological distress were measured using the Prenatal Opioid use Perceived Stigma scale and measures from the Patient-Reported Outcome Measurement Information System (PROMIS). Food insecurity, housing instability, and Adverse Childhood Experiences (ACEs) were also assessed. Linear and generalized linear mixed-effect models were conducted to compare PROMIS scale scores and unmet needs by stigma, adjusting for site/location, age, race/ethnicity, marital status, education, public insurance, and parity. More than half of participants (54%) perceived stigma in healthcare settings. Individuals reporting stigma had higher depression, anxiety, and anger scores (p < 0.001) indicating greater psychological distress in the postpartum period compared to those reporting no stigma, after controlling for demographic characteristics. In addition, they scored significantly lower on the PROMIS meaning and purpose scale, an indicator of well-being (p = 0.002). Those reporting stigma were more likely to have food insecurity (p = 0.003), three or more ACEs (p = 0.040), verbal or physical abuse during pregnancy (p < 0.001), and less emotional support (p = 0.006) than those who did not. An association was observed between perceived stigma in the prenatal period and psychological distress in the postpartum period, providing support for stigma reduction interventions and education for healthcare providers on trauma-informed care.

Two years of newborn screening for Duchenne muscular dystrophy as a part of the statewide Early Check research program in North Carolina.

PURPOSE: Current and emerging treatments for Duchenne muscular dystrophy (DMD) position DMD as a candidate condition for newborn screening (NBS). In anticipation of the nomination of DMD for universal NBS, we conducted a prospective study under the Early Check voluntary NBS research program in North Carolina, United States. METHODS: We performed screening for creatine kinase-MM (CK-MM), a biomarker of muscle damage, on residual routine newborn dried blood spots (DBS) from participating newborns. Total creatine kinase testing and next generation sequencing of an 86-neuromuscular gene panel that included DMD were offered to parents of newborns who screened positive. Bivariate and multivariable analyses were performed to assess effects of biological and demographic predictors on CK-MM levels in DBS. RESULTS: We screened 13,354 newborns and identified 2 males with DMD. The provisional 1626 ng/mL cutoff was raised to 2032 ng/mL to improve specificity, and additional cutoffs (900 and 360 ng/mL) were implemented to improve sensitivity for older and low-birthweight newborns. CONCLUSION: Population-scale screening for elevated CK-MM in DBS is a feasible approach to identify newborns with DMD. Inclusion of birthweight- and age-specific cutoffs, repeat creatine kinase testing after 72 hours of age, and DMD sequencing improve sensitivity and specificity of screening.

Pilot protocol for the Parent and Infant Inter(X)action Intervention (PIXI) feasibility study.

This paper provides the detailed protocol for a pilot study testing the feasibility, acceptability, and initial efficacy of a targeted two-phase, remotely delivered early intervention program for infants with neurogenetic conditions (NGC) and their caregivers. The Parent and Infant Inter(X)action Intervention (PIXI) is designed to support parents and infants with a NGC diagnosed in the first year of life. PIXI is implemented in two phases, with the first phase focusing on psychoeducation, parent support, and how to establish routines for supporting infant development. Phase II helps parents learn targeted skills to support their infant's development as symptoms may begin to emerge. The proposed non-randomized feasibility pilot study will establish the feasibility of a year-long virtually implemented intervention program to support new parents of an infant diagnosed with an NGC.

Psychometric Properties of the Prenatal Opioid Use Perceived Stigma Scale and Its Use in Prenatal Care.

OBJECTIVE: To examine the psychometric properties of the Prenatal Opioid Use Perceived Stigma (POPS) scale and to assess the relationship of POPS scores to adequate prenatal care. DESIGN: Prospective cohort study. SETTING: Medical centers in Alabama, Ohio, and Pennsylvania (N = 4). PARTICIPANTS: Women (N = 127) who took opioids during pregnancy and whose infants participated in the Outcomes of Babies With Opioid Exposure Study. METHODS: Participants reported their perceptions of stigma during pregnancy by responding to the eight items on the POPS scale. We evaluated the instrument's internal consistency reliability (Cronbach's alpha), structural validity (factor analysis), and convergent validity (relationship with measures of similar constructs). In addition, to assess construct validity, we used logistic regression to examine the relationship of POPS scores to the receipt of adequate prenatal care. RESULTS: The internal consistency of the POPS scale was high (Cronbach's α = .88), and all item-total correlations were greater than 0.50. The factor analysis confirmed that the items cluster into one factor. Participants who reported greater perceived stigma toward substance users and everyday discrimination in medical settings had higher POPS scores, which supported the convergent validity of the scale. POPS scores were significantly associated with not receiving adequate prenatal care, adjusted OR = 1.47, 95% confidence interval [1.19, 1.83], p < .001. CONCLUSION: The psychometric testing of the POPS scale provided initial support for the reliability and validity of the instrument. It may be a useful tool with which to assess perceived stigma among women who take opioids, a potential barrier to seeking health care during pregnancy.

Research Gaps in Fragile X Syndrome: An Updated Literature Review to Inform Clinical and Public Health Practice.

OBJECTIVE: The phenotypic impact of fragile X syndrome (FXS) has been well-documented since the discovery of the fragile X messenger ribonucleoprotein 1 gene 30 years ago. However, gaps remain in clinical and public health research. The purpose of this literature review was to determine the extent to which these gaps have been addressed and identify targeted areas of future research. METHODS: We conducted an electronic search of several scientific databases using a variety of key words. The search focused on 5 areas identified as research gaps by an earlier review: (1) diagnosis, (2) phenotypic presentation, (3) familial impact, (4) interventions and treatments, and (5) life span perspectives. Inclusion criteria included publication between 2014 and 2020, focus on human subjects, and publication in English. A total of 480 articles were identified, 365 were reviewed, and 112 are summarized in this review. RESULTS: Results are organized into the following categories: (1) FXS phenotype and subtypes (FXS subtypes, medical profile, cognitive/developmental profile, social and behavioral profile); (2) needs of adults; (3) public health needs (clinical diagnosis and newborn screening, health care needs, and access); (4) treatment (treatment priorities, pharmacological treatments, and behavioral and educational interventions); and (5) families (economic burden and mother-child relationship). CONCLUSION: Despite the progress in many areas of FXS research, work remains to address gaps in clinical and public health knowledge. We pose 3 main areas of focused research, including early detection and diagnosis, determinants of health, and development and implementation of targeted interventions.

Outcomes of Babies with Opioid Exposure (OBOE): protocol of a prospective longitudinal cohort study.

BACKGROUND: While the health, social, and economic impacts of opioid addiction on adults and their communities are well known, the impact of maternal opioid use on the fetus exposed in utero is less well understood. METHODS: This paper presents the protocol of the ACT NOW Outcomes of Babies with Opioid Exposure (OBOE) Study, a multi-site prospective longitudinal cohort study of infants with antenatal opioid exposure and unexposed controls. Study objectives are to determine the impact of antenatal opioid exposure on brain development and neurodevelopmental outcomes over the first 2 years of life and explore whether family, home, and community factors modify developmental trajectories during this critical time period. RESULTS: Primary outcomes related to brain development include cortical volumes, deep cerebral gray matter volumes, resting-state functional connectivity measures, and structural connectivity measures using diffusion tensor imaging. Primary neurodevelopmental outcomes include visual abnormalities, cognitive, language, and motor skills measured using the Bayley Scales of Infant Development and social-emotional and behavioral problems and competence measured by the Brief Infant-Toddler Social and Emotional Assessment. CONCLUSIONS: The OBOE study has been designed to overcome challenges of previous studies and will help further understanding of the effects of antenatal opioid exposure on early infant development. IMPACT: This study will integrate MRI findings and comprehensive neurodevelopmental assessments to provide early insights into the functional topography of the brain in this high-risk population and assess MRI as a potential biomarker. Rather than conducting neuroimaging at a single time point, the study will include serial MRI assessments from birth to 2 years, allowing for the examination of trajectories throughout this period of rapid brain development. While previous studies often have had limited information on exposures, this study will use umbilical cord assays to accurately measure amounts of opioids and other substances from 20 weeks of gestation to birth.

A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence-based literature. We present a consensus statement and comprehensive literature review that proposes a standard of care practices for the management of AS at a critical time when therapeutics to alter the natural history of the disease are on the horizon. METHODS: We compiled the key recognized clinical features of AS based on consensus from a team of specialists managing patients with AS. Working groups were established to address each focus area with committees comprised of providers who manage >5 individuals. Committees developed management guidelines for their area of expertise. These were compiled into a final document to provide a framework for standardizing management. Evidence from the medical literature was also comprehensively reviewed. RESULTS: Areas covered by working groups in the consensus document include genetics, developmental medicine, psychology, general health concerns, neurology (including movement disorders), sleep, psychiatry, orthopedics, ophthalmology, communication, early intervention and therapies, and caregiver health. Working groups created frameworks, including flowcharts and tables, to help with quick access for providers. Data from the literature were incorporated to ensure providers had review of experiential versus evidence-based care guidelines. CONCLUSION: Standards of care in the management of AS are keys to ensure optimal care at a critical time when new disease-modifying therapies are emerging. This document is a framework for providers of all familiarity levels.

A Voluntary Statewide Newborn Screening Pilot for Spinal Muscular Atrophy: Results from Early Check.

Prior to statewide newborn screening (NBS) for spinal muscular atrophy (SMA) in North Carolina, U.S.A., we offered voluntary screening through the Early Check (EC) research study. Here, we describe the EC experience from October 2018 through December 2020. We enrolled a total of 12,065 newborns and identified one newborn with 0 copies of SMN1 and two copies of SMN2, consistent with severe early onset of SMA. We also detected one false positive result, likely stemming from an unrelated blood disorder associated with a low white blood cell count. We evaluated the timing of NBS for babies enrolled prenatally (n = 932) and postnatally (n = 11,133) and reasons for delays in screening and reporting. Although prenatal enrollment led to faster return of results (median = 13 days after birth), results for babies enrolled postnatally were still available within a timeframe (median = 21 days after birth) that allowed the opportunity to receive essential treatment early in life. We evaluated an SMA q-PCR screening method at two separate time points, confirming the robustness of the assay. The pilot project provided important information about SMA screening in anticipation of forthcoming statewide expansion as part of regular NBS.

Emergence of Developmental Delay in Infants and Toddlers With an FMR1 Mutation.

BACKGROUND: Children with FMR1 gene expansions are known to experience a range of developmental challenges, including fragile X syndrome. However, little is known about early development and symptom onset, information that is critical to guide earlier identification, more accurate prognoses, and improved treatment options. METHODS: Data from 8 unique studies that used the Mullen Scales of Early Learning to assess children with an FMR1 gene expansion were combined to create a data set of 1178 observations of >500 young children. Linear mixed modeling was used to explore developmental trajectories, symptom onset, and unique developmental profiles of children <5 years of age. RESULTS: Boys with an FMR1 gene full mutation showed delays in early learning, motor skills, and language development as young as 6 months of age, and both sexes with a full mutation were delayed on all developmental domains by their second birthday. Boys with a full mutation continued to gain skills over early childhood at around half the rate of their typically developing peers; girls with a full mutation showed growth at around three-quarters of the rate of their typically developing peers. Although children with a premutation were mostly typical in their developmental profiles and trajectories, mild but significant delays in fine motor skills by 18 months were detected. CONCLUSIONS: Children with the FMR1 gene full mutation demonstrate significant developmental challenges within the first 2 years of life, suggesting that earlier identification is needed to facilitate earlier implementation of interventions and therapeutics to maximize effectiveness.

Developmental Outcomes Among Young Children With Congenital Zika Syndrome in Brazil.

Importance: Although birth defects in children with congenital Zika syndrome (CZS) are expected to result in significant intellectual disabilities, the extent of delay and profiles of development have yet to be fully described. Objectives: To describe the neurodevelopmental profiles of children with CZS and to test whether prenatal and postpartum characteristics were associated with the severity of developmental delays. Design, Setting, and Participants: This is a case series of the trajectories of developmental, behavioral, and medical needs of 121 young children with CZS who were assessed at a specialized rehabilitation center in Recife, Brazil, beginning in January 2018 as part of 5-year longitudinal study. Children were included if they had serologic confirmation of Zika virus and met clinical criteria accompanied by parental report of suspected exposure to Zika virus during pregnancy. Exposures: Prenatal Zika virus exposure. Main Outcomes and Measures: The Brazilian version of the Bayley Scales of Infant and Toddler Development, Third Edition, was administered by trained assessors as part of an initial comprehensive assessment battery. Caregiver interviews and medical record reviews were conducted to gather basic demographic information and medical comorbidities. Linear regression was used to identify potential factors for development. Results: The sample included 121 young children (mean [SD] age, 31.2 [1.9] months; 61 [50.4%] girls). At age approximately 2.5 years, nearly all children in this sample demonstrated profound developmental delays across all domains of functioning, with a mean (SD) developmental age equivalent to approximately 2 to 4 months (eg, cognitive domain, 2.24 [3.09] months; fine motor subscale, 2.15 [2.93] months; expressive language subscale, 2.30 [2.52] months). A relative strength was found in receptive language, with scores on this scale significantly higher than most other domains (eg, cognition: t = 3.73; P < .001; fine motor: t = 6.99; P < .001). Head circumference at birth was the single strongest factor associated with outcomes across all developmental domains (eg, cognitive: ß = 1.41; SE, 0.67; P = .04; fine motor: ß = 1.36; SE, 0.49; P = .007). Conclusions and Relevance: The findings of this study provide important information regarding the severity of disability that these children and their families will experience. The findings also establish an initial point from which to monitor developmental trajectories, medical comorbidities (eg, seizures), effectiveness of interventions, and cumulative consequences on families.

Early Development of Infants with Turner Syndrome.

OBJECTIVE: To examine the early cognitive, temperament, and adaptive functioning of infants and toddlers with Turner syndrome (TS). METHODS: Cognitive abilities were measured using the Mullen Scales of Early Learning at 1 year of age for 31 girls with TS and compared with neurotypical female (N = 53) and male (N = 54) control groups. Temperament (Carey Toddler Temperament Scales) and adaptive functioning (Vineland Adaptive Behavior Scales-Second Edition) were measured at 1 year of age and compared with normative data. An exploratory analysis of cognitive/developmental trajectories was also conducted comparing age 12-month to 24-month time points for 22 TS subjects. RESULTS: Infants with TS performed largely within the average range for adaptive behavior, temperament, and early cognitive development with some increased risk for delays in language and significant increased risk for delays in motor skills (p < 0.001). Although exploratory, there was some suggestion of slower rates of progression in fine-motor and visual reception skills from 12 to 24 months of age. CONCLUSIONS: Infants and toddlers with TS exhibit a relatively positive neurodevelopmental profile overall, with some indication of an increasing gap in function in fine-motor and visual perceptual abilities as compared to neurotypical peers. It is unclear whether these apparent differences represent normal variability in this very young population or, perhaps, are early precursors of later phenotypic characteristics of TS in the school-age and young adult years.

Early Check: translational science at the intersection of public health and newborn screening.

BACKGROUND: Newborn screening (NBS) occupies a unique space at the intersection of translational science and public health. As the only truly population-based public health program in the United States, NBS offers the promise of making the successes of translational medicine available to every infant with a rare disorder that is difficult to diagnose clinically, but for which strong evidence indicates that presymptomatic treatment will substantially improve outcomes. Realistic NBS policy requires data, but rare disorders face a special challenge: Screening cannot be done without supportive data, but adequate data cannot be collected in the absence of large-scale screening. The magnitude and scale of research to provide this expanse of data require working with public health programs, but most do not have the resources or mandate to conduct research. METHODS: To address this gap, we have established Early Check, a research program in partnership with a state NBS program. Early Check provides the infrastructure needed to identify conditions for which there have been significant advances in treatment potential, but require a large-scale, population-based study to test benefits and risks, demonstrate feasibility, and inform NBS policy. DISCUSSION: Our goal is to prove the benefits of a program that can, when compared with current models, accelerate understanding of diseases and treatments, reduce the time needed to consider inclusion of appropriate conditions in the standard NBS panel, and accelerate future research on new NBS conditions, including clinical trials for investigational interventions. TRIAL REGISTRATION: Clinicaltrials.gov registration # NCT03655223 . Registered on August 31, 2018.

Early Identification of Fragile X Syndrome through Expanded Newborn Screening.

Over the past 20 years, research on fragile X syndrome (FXS) has provided foundational understanding of the complex experiences of affected individuals and their families. Despite this intensive focus, there has been little progress on earlier identification, with the average age of diagnosis being 3 years. For intervention and treatment approaches to have the greatest impact, they need to begin shortly after birth. To access this critical timespan, differential methods of earlier identification need to be considered, with an emerging focus on newborn screening practices. Currently, barriers exist that prevent the inclusion of FXS on standard newborn screening panels. To address these barriers, an innovative program is being implemented in North Carolina to offer voluntary screening for FXS under a research protocol, called Early Check. This program addresses the difficulties observed in prior pilot studies, such as recruitment, enrollment, lab testing, and follow-up. Early Check provides an opportunity for stakeholders and the research community to continue to gain valuable information about the feasibility and greater impact of newborn screening on the FXS population.