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www.rti.orgRTI International is a registered trademark and a trade name of Research Triangle Institute.
Newborn Screening for Fragile X Syndrome and Other Developmental Disabilities
Don Bailey, Ph.D.AUCD Webinar
October 22, 2019
Primary funders
RTI Center for Newborn Screening, Ethics, and Disability Studies
I am presenting on behalf of our interdisciplinary team
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LisaGehtland
MelissaRaspa
AnneWheeler
HollyPeay
AnneEdwards
Psychology Medicine Chemistry Bioethics Genetic
counseling Public health Early childhood
special education
Family studies Nutrition Social Work Biology Sara
Andrews
VeronicaRobles
DonBailey
BlakeHarper
KathiPorter
CaseyOkoniewski
BarbaraBiesecker
MartinDuparc
DanielleToth
BethBoyea
AngelaGwaltney
BrookeMigliore
Our primary partners
NancyKing
MichaelCotten
CynthiaPowell
MeganLewis
RTI Center for Newborn
Screening, Ethics, and Disability
Studies
RTI Center for Communication
Science
Duke University
NC State Laboratory of Public HealthFunding
Partners and Advocates
Wake Forest Baptist
Medical Center
UNCChapel Hill
ScottShone
Goals for today
Describe a parallel universe to the world of early intervention (EI), one that is disease-specific and cure-oriented
Raise some broad questions about pre-symptomatic screening and treatment
Describe fragile X syndrome as an example of many challenges we will be facing in early intervention
Describe Early Check, a newborn screening research project Raise questions about the role of EI in a new world of medicalization
of treatment Ask whether and how can use EI (as we know it) to justify newborn
screening for developmental disabilities
What is newborn screening? Testing children at birth for serious health
problems that are not obvious and cannot be detected through clinical presentation
Usually done on dried blood spots Data demonstrate that treating the
condition BEFORE symptoms occur results in significantly better outcomes than treating the condition AFTER symptoms become obvious.
Essentially considered a medical emergency
Follow-up and treatment programs are available and can be implemented
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Newborn screening policy in the U.S.
Rigorous review and recommendation by a national committee of experts DHHS Secretary determines whether a condition should be on the
RUSP(Recommended Uniform Screening Panel) States decide 35 conditions on RUSP States are gradually implementing newly recommended conditions
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Many conditions will not make the RUSP in the near future
10 conditions have been nominated but not initially recommended or sent to evidence review– SMA, Niemann-Pick, neonatal hyperbilirubinemia, Krabbe disease,
hemoglobin H disease, Fabry disease, 22q11.2 deletion, GAMT, CTX, CMV
– SMA most recently approved, CMV most recently nominated
Major reasons for not recommending– No accurate and cost-effective screening test– Implementation too complicated or expensive– No pilot study data– No data on pre-symptomatic treatment efficacy
Frustrations are evident– Advocates think the pace of expansion is too slow– States think the pace of expansion is too fast
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BUT, this “rational” world is rapidly changing There are more than 3000 known genetic causes of intellectual
disability! Methods now exist to detect these disorders before symptoms appear New and sometimes expensive treatments promise hope for a cure or
at least stop disease progression Disease-specific advocacy groups are becoming powerful change
agents These factors are pushing for a rapid expansion of newborn screening What is the role of EI in this new world of diagnosis and treatment?
Patient advocacy groups are becoming powerful influencers
New methods to identify high-risk infants before symptoms appear
Pre-symptomatic hematopoietic stem cell transplantation, targeted therapeutics, and gene therapy are changing the meaning of EI Spinal muscular atrophy
– Autosomal recessive disorder caused by mutation in SMN1 gene
– Insufficient SMN protein to maintain survival of motor neurons
– Symptoms usually appear by 6 months of age, death by two years if untreated (Type 1)
– Later onset and more milder versions (Types 2-4) determined by SMN2copy number
• Treatment history• Supportive, palliative care,
breathing machines• ACOG recommendation for
SMA carrier testing• Spinraza (antisense
oligonucleotide)• Zolgensma (gene therapy)
Spinraza
Zolgensma
But determining certainty of risk can be a challenge X-Linked Adrenaleukodystrophy
– X-linked disorder caused by mutation in ABCD1 gene
– Progressive loss of myelin that surrounds brain and spinal cord nerves
– Symptoms usually appear in boys between 4-8 years of age
– VLCFA and ABCD1 genetic testing can confirm diagnosis but not disease state
– MRI can detect disease before symptoms
• Treatment history• Lorenzo’s oil (unproven)• Corticosteriods (when
there is adrenal insufficiency)
• Bone marrow transplant (when MRI shows lesions)
• Gene therapy (still experimental)
Assessing parents’ tolerance for uncertainty
Some important questions
Just because we CAN identify causes of health problems, does that mean we SHOULD identify them, and when?
How much evidence is required and will it need to be provided for each specific disorder?
How certain must we be in disease prediction to justify screening? How do cost and social justice factor into decisions about screening?
What is fragile X syndrome?
Most common known inherited cause of intellectual disability X-linked, single gene disorder A trinucleotide repeat expansion disorder A family disorder
Fragile X was initially discovered as a chromosome problem
1991 - FMR1 gene discovered
FMR1 GeneXq27.3
CGG repeat expansions
NOW: Complicated pathways, lots of potential medication “targets”
Fragile X syndrome is difficult to diagnose in the early years
(2009)
What’s the problem with late identification? Long and expensive “diagnostic odyssey” Most do not get early intervention during the first two years of life Almost 1/3 of families have a second child with FXS before the first is
diagnosed
Some early thoughts about newborn screening and disability
(1994)
(1995)
Should FXS be identified through newborn screening?
FXS is a good example of a disorder with no medical treatment that needs to be provided early, but for which early detection benefit children and families
FXS is also a good case example of complex clinical and ethical issues – Should reproductive risk and cascade testing factor into NBS policy decisions?– Is access to early intervention considered “treatment” and what benefit would need to
be demonstrated from EI?– Protein-based testing vs. CGG repeat testing– Cut-offs for screen-positive cases– Deciding whether to report carrier status– Whether and how are carrier infants affected
Series of articles in Pediatrics about FX screening
(2008)(2009)
(2011) (2012)
(2015) (2016)
(2017)
Early Check was built to help solve these problems An Innovation Award from NCATS, with additional support from NICHD, The
John Merck Fund, Asuragen, Cure SMA A research study designed to
– Develop and evaluate methods to offer free, voluntary screening to 120,000 parents/year for conditions not currently part of newborn screening (NBS)
– SMA and FXS as initial prototypes– Acquire data to inform policy (which conditions should be included in NBS) gauge parents’ interests in screening for new conditions develop and test feasibility of the full complement of systems needed to implement screening understand early natural history of “screen positive” infants identify infants who could participate in pre-symptomatic treatment trials
The foundation for– A long-term research resource to which new conditions can be added when ready– An envisioned future in which states offer a voluntary panel of “non-RUSP” conditions
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Early Check Flow
What is unique about Early Check? Collaboration among multiple research partners Statewide recruitment Systematic evaluation of “virtual” recruitment methods E-consent, second consent for FX carrier results Central Institutional Review Board (UNC-Chapel Hill) Short and long-term follow-up, individually tailored to
each disorder – detailed SOPs for each EC task Telegenetic counseling
A major goal is to test recruitment strategies
We want to offer Early Check to every birthing parent in the state
We want to study “virtual” recruitment strategies
Ultimately we want to determine the best combination of approaches and what the “ceiling” might be that we can expect through virtual recruitment
Soon we will begin in-person recruitment in selected locations
GOAL: 25,000 enrollees per year by end of 2020
Phased studies of targeted outreach strategies
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Phase 1: Postnatal(letter, flyer,
postcard reminder)
Phase 2: Pre- & Postnatal
(Social media: FB, Instagram)
Phase 3: Multiple hospital,
community, and state strategies
Telegenetic Counseling for Return of Screening ResultsTechnology HIPAA-compliant Low cost Free app download--uses data if no wifi available Multiple users can join on multiple devices (e.g.,
partner, interpreter) Screen sharing, multi-party document signing, A/V
recording, provider note storage Convenient, user-friendly, easy self-service
scheduling with automated reminders for all parties Parents appear to be at ease using online meeting
platform from home while newborn sleeps nearby. No complaints
Educational Web Content
Early intervention model being tested for FXS
Phase I – Modified Parents as Teachers curriculum, establishing rapport, understanding family needs (4-8 sessions over 8-12 weeks)
Phase II – iBasis VIPP -- Promote caregiver responsiveness and synchrony; target social communication, physiological arousal and emerging sensory differences; identify and address atypical behaviors as they arise (6-11 sessions between 6-12 months)
Planning a “virtual” early intervention center
• There is a significant need to provide support, surveillance, and intervention via remote methods for families of children with rare disorders such as FXS
• We have recently received funding to plan a virtual EI center to support both families and EI professionals
• The Center will have four core components• Tele-genetic counseling• Remote developmental assessments via PANDA box (Parent Assisted
Neurodevelopmental Assessment)• EI support for families and professionals, building on PiXi activities and experience• Web-based family support, including a knowledge center and possible application
of mindfulness training for parents using tele-support
One of our long-term goals
Determine whether identifying disorders such as FXS at birth makes a difference in the lives of children
If so, is this difference greater than that obtained if we wait until symptoms appear and children become eligible for EI?
This question will be difficult to answer– True control group not feasible– We don’t know the natural history of many aspects of FX– We need to determine what outcomes should be used as the litmus test for
newborn screening An important question for us is how family benefits factor into
screening policy
How much can we change developmental trajectories in FXS?Female growth rate = .62Male growth rate = .4794 females
345 males
What outcomes should we expect and when?
Functional skillsDevelopmental trajectoriesMemoryExecutive functionAttentionResponse inhibitionADHD
Mood and anxietySensory-motorAcademic skillsClassroom behavior
Adaptive behaviorSelf-injuryProblem behaviorAggressionAutism
ObesitySeizuresSleep problemsTemperamentBehavioral styleEmployment
BIG QUESTIONS
• Will we ever be able to say with confidence that early intervention is so powerful that it is sufficient to justify newborn screening?
• Will we have to answer this question for each disorder?
Some concluding thoughts There will always be a need for Early Intervention But the rapidly changing landscape of gene discovery and treatment will
certainly influence what we do– Be aware of the power of a diagnosis for families– Learn how to support families dealing with uncertainty– Provide pre-symptomatic treatment for infants with diagnosed conditions Information Support Surveillance Preventive and responsive treatments
Develop partnerships with disease specialists and the medical community
Know that most medical treatments will not be perfect
