1. Newborn Screening: National and International Hurdles and Progress
R. Rodney Howell, M. D.
Professor of Pediatrics, Chairman Emeritus
Member, Hussman Institute for Human Genomics
Miller School of Medicine, University of Miami
Miami, Florida
President
International Society of Neonatal Screening
Neonatal Health Innovation Forum
University of Minnesota
Minneapolis, Minnesota
October 14, 2016

2. International Issues Facing Newborn Screening
The issues facing the newborn screening community world-wide are very similar with the exception of much greater resource restrictions in many countries of the world than exists in the developed countries
One of the priorities of the ISNS in the coming years will be to focus on the development of newborn screening programs in resource limited countries
Providing assistance in these countries will focus on the initiation of programs that will identify those conditions of greatest importance to the country, and assist in the establishment of cost effective programs where both the diagnoses and treatments can be carried out in these locations
The condition(s) of focus will vary greatly depending on the location. For example, Haiti, a country with profoundly limited resources and a very high incidence of sickle cell disease lacks a country-wide program for screening for this important disorder; considerable interest is present to support the local people in initiating such a program

3. Issues of Resource Availability is Not Limited to the Developing Countries
At the current time, there are remarkable developments of important new therapies for previously untreatable, fatal diseases of childhood
There have been several additions to the Recommended Uniform Panel of important conditions whose diagnostic follow-up and confirmation require considerable more time, expertise and funding in order to implement. Examples of this are Pompe Disease, MPS 1 and X-Linked Adrenoleukodystrophy
Recent FDA approval of an important new drug for Duchenne Muscular Dystrophy, the first specific drug approved for this condition in the United States will certainly result in nomination of this condition to the Advisory Committee for Heritable Diseases in Newborns and Children
Similarly, the very positive trials for an effective treatment of the most common fatal genetic disease in childhood, Spinal Muscular Atrophy (SMA) will no doubt lead to a similar nomination for SMA
I will discuss these important findings and the very likely impact on the newborn screening community, that will almost certainly lead to resource limitations in virtually all state laboratories, and most importantly in the newborn screening follow-up centers in the United States.

4. Rigorous Process Now in Place to Review Nominations for Inclusion in the Core Panel- September 2016
16 nominations submitted to HRSA/MCHB and reviewed by staff since the original panel was established
16 completed nominations forwarded to ACHDNC Chair (Pompe Disease and adrenoleukodystrophy have been nominated twice). Only those conditions that appear to be well founded are sent for evidence review, which is an expensive and time- consuming task.
MPS I and X-ALD (second nomination) were both very recently added to the recommended panel
Fabry, Niemann-Pick , adrenoleukodystrophy (first nomination), Pompe Disease (first nomination) 22q11,2 deletion syndrome, Hemoglobin H , Krabbe, spinal muscular atrophy (SMA) and neonatal hyperbilirubinemia were not recommended for addition to the core panel.
The Committee has recommended that Pompe Disease, Severe Combined Immunodeficiency, Severe Cyanotic congenital heart disease, X-linked adrenoleukodystrophy, and MPS I be added to the recommended uniform screening panel (RUSP).

5. Duchenne Muscular Dystrophy

13. Some Challenging Issues with Newborn Screening Follow-up, Confirmation and Treatment Institution in Duchenne Muscular Dystrophy
All babies with positive newborn screening tests will require specific genetic testing since approved drugs currently are mutation-specific and knowing the exact mutation is required before specific treatment, if available can begin
Since the condition is x-linked, it will be important to provide sophisticated genetic counselling, which will likely include arrangements for carrier testing on the mother and possibly other members of the family
All currently approved treatments are effective only for preserving muscle, and not in producing new muscle. In view of this treatment will be required early, and plans for this must be developed during large pilot studies.
Depending on the pattern of x-inactivation, an occasional female will be identified with a dystrophin mutation. Females are usually asymptomatic, but on rare occasions, can develop muscular and cardiac symptoms. Plans must be made for this eventuality.

15. Fortunately, Major Collaborative Efforts have Begun to Carry out Large Pilot Study in Duchenne Muscular Dystrophy
Under the leadership of the Parent Project for Muscular Dystrophy and the Muscular Dystrophy Association, and a Steering Committee led by Dr. Michele Lloyd-Puryear
Plans to involve large state laboratory (CA), working with Perkin-Elmer Corporation
Discussions are underway to involve the Newborn Screening Translational Network

16. Key Questions and Issues
Usual Care and Course
Screening and Short-Term Follow-Up
Diagnosis
Benefits & Harms - Screening & Diagnosis (unrelated to treatment)
Treatment and Long-Term Follow-up
Intermediate Outcome Measures
Primary Health Outcomes (Patient)
Secondary Outcomes (Patient, Caregivers)
Benefits & Harms - Treatment & Long-Term Follow-up
Health Care System Needs

17. Duchenne Newborn Screening Efforts Underway
Duchenne NBS Steering Committee
6 Working Groups
Expanded Duchenne Newborn Screening Pilot Planning: what infrastructure is needed?
Development of Educational Materials:
for Clinical Professionals
for Patient Community
CK Validation Effort with PerkinElmer & California State Health Dept.
National DBMD Carrier study underway – led by PPMD
Health economic data collection
Evidence review and Generation of evidence to support nomination of Duchenne to RUSP

18. Duchenne Newborn Screening Steering Committee
Outreach & Education to Patients & HCPs WG
Care Considerations for Infants with DMD WG
Laboratory Performance WG
NBSTRN Integration and LPDR WG
Ethical & Legal Considerations WG
Evidence Review WG

19. Proposed Distribution of Results: Screening Algorithm for DMD
Normal CK
NBS State Lab Abnormal CK
* Emory DNA Lab
* Follow up Plan for Test Results:
CK performed at NBS State Health Lab
Normal results sent to Family via Pediatric care provider.
Abnormal CK to Emory DNA Laboratory
If DMD/BMD mutation found results to Family via MH and referred to DMD Clinic.
If female, parents see genetic counselor at DMD Clinic.
If other muscular dystrophy mutation found, family informed and sent to DMD Clinic.
If CK Elevated and no mutation found, the family is informed and patient advised to follow up in DMD Clinic for re-testing of CK.
CK Testing
Results to Family via MH
DMD
Clinic

20. Items Needed for Pilot Short Term Follow-up Long term Follow-up
Need engagement of Muscular Dystrophy [MD] clinical infrastructure
LPDR with CDEs for newborns and infants underdevelopment
Long term Follow-up
Need to establish guidelines for newborns-2 years of age
Determine clinical outcome measures
Monitoring females
Monitoring other muscular dystrophies?
Clinical trial arm testing therapies in newborns

21. Items Needed for Pilot Refinement of CK screen: CA/PKI study
Education/Training
Informed consent process development
Development of education and training materials for parents; for providers; for laboratory; for NBS program
Quality Assurance
Have analytic specificity parameters from Emory
Working with CDC to set up QA/QC
Refinement of CK screen: CA/PKI study
Begin working with R4S: Need analytic parameters from CA study