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.

Newborn Screening Conditions: Early Intervention and Probability of Developmental Delay.

OBJECTIVES: The purpose of this study is to explore which newborn screening (NBS) conditions are automatically eligible for early intervention (EI) across states and to determine the extent to which each disorder should automatically qualify for EI because of a high probability of developmental delay. METHODS: We examined each state's EI eligibility policy and reviewed the literature documenting developmental outcomes for each NBS condition. Using a novel matrix, we assessed the risk of developmental delay, medical complexity, and risk of episodic decompensation, revising the matrix iteratively until reaching consensus. Three NBS conditions (biotinidase deficiency, severe combined immunodeficiency, and propionic acidemia) are presented in detail as examples. RESULTS: Most states (88%) had Established Conditions lists to autoqualify children to EI. The average number of NBS conditions listed was 7.8 (range 0-34). Each condition appeared on average in 11.7 Established Conditions lists (range 2-29). After the literature review and consensus process, 29 conditions were likely to meet national criteria for an Established Condition. CONCLUSION: Despite benefiting from NBS and timely treatment, many children diagnosed with NBS conditions are at risk for developmental delays and significant medical complexity. The results demonstrate a need for more clarity and guidance regarding which children should qualify for EI. We suggest that most NBS conditions should automatically qualify based on the probability of resulting in a developmental delay. These findings suggest a future opportunity for collaboration between NBS and EI programs to create a consistent set of Established Conditions, potentially expediate referrals of eligible children, and streamline children's access to EI services.

Airway Findings in Patients with Hunter Syndrome Treated with Intravenous Idursulfase.

People with Hunter syndrome are known to be affected by a variety of airway pathologies. Treatment of Hunter syndrome with the enzyme replacement therapy (ERT) idursulfase is now the standard of care. However, it is not known how ERT changes the progression of airway involvement. To evaluate this, we performed a retrospective analysis of bronchoscopies performed on children with Hunter syndrome who were part of intrathecal ERT trials. Findings for airway pathology were extracted from bronchoscopy reports and analyses were performed for cross-sectional and longitudinal changes in airway disease. One-hundred and thirty bronchoscopies from 23 subjects were analyzed. Upper airway disease (adenoid hypertrophy and/or pharyngomalacia) was reported in 93% and 87% of bronchoscopies, respectively. Laryngeal abnormalities were recognized in 46% of cases. There were lower airway (tracheal and or bronchial) findings in 64% of all bronchoscopies and prevalence increased with age. Evaluations over time adjusted for repeat evaluations showed that increasing airway involvement was associated with older age (p = 0.0007) despite ongoing ERT. No association was discovered between age of intravenous ERT initiation and progression of airway disease. Individuals with Hunter syndrome who are receiving intravenous enzyme replacement therapy showed the progression of airways disease supporting the need for regular airway monitoring and intervention.

Quality of care metrics for patients with inborn errors of metabolism.

Despite recent calls to action and a heavy emphasis on timeliness of care in guidelines for common inborn errors of metabolism, there is a dearth of specific measurable quality metrics for these conditions and little to no electronic decision support for their management. We have developed a novel set of process-oriented metrics based on the aforementioned guidelines that can be calculated from data already contained in most major EHRs, which we believe are responsive to the needs of the metabolism community.

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.

Toileting Abilities Survey as a surrogate outcome measure for cognitive function: Findings from neuronopathic mucopolysaccharidosis II patients treated with idursulfase and intrathecal idursulfase.

An outcome measure of toileting skills, the Toileting Abilities Survey or TAS, with sensitivity to detect change in a neurodegenerative disorder such as MPS II, was developed. The TAS was used in a research study of patients (n = 86) with the neuronopathic form of MPS II to measure treatment benefit of intrathecal idursulfase. Treatment with idursulfase and intrathecal idursulfase is associated with significantly higher individual and overall toileting skills versus treatment with idursulfase alone.

Optimizing Preconception Health among Young Women: What Are We Missing?

STUDY OBJECTIVE: To evaluate whether receipt of specific preconception counseling topics differs between teen, young adult, and older mothers. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: A survey of 291 primarily low-income, minority mothers with young children at pediatric practices in Baltimore, Maryland was conducted. Multivariable logistic regression models generated relative odds of preconception counseling receipt comparing teens (ages 14-19 years) and young adults (ages 20-24 years) to adult women (age ≥25 years) controlling for demographic characteristics, parity, and pregnancy intention. RESULTS: Teen mothers were less than half as likely to be counseled about taking folic acid, 4 times more likely to be counseled about vaccines, and twice as likely to be counseled about mental health before pregnancy compared with adult mothers. CONCLUSION: Adolescent preventive care might promote some aspects of preconception health, but topics related specifically to pregnancy outcomes might be missed. Because of the high rate of unplanned teen pregnancy in the United States, additional strategies to promote preconception health in this population are warranted.