Genetics Visiting Professor (GVP) Grand Rounds Presented by: AAP Chapter 3 and the Lower Hudson Valley Perinatal Network (LHVPN) Advances in Newborn Screening David Kronn, MD, FACMG, FAAP Director, Inherited Metabolic Disease Center Maria Fareri Children’s Hospital at Westchester Medical Center Associate Professor of Pediatrics New York Medical College
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Dr. David GVP Advances in Newborn Screening 2008.ppt
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Genetics Visiting Professor (GVP) Grand Rounds
Presented by: AAP Chapter 3 and the Lower Hudson Valley Perinatal Network
(LHVPN)
Advances in Newborn Screening
David Kronn, MD, FACMG, FAAP Director, Inherited Metabolic Disease Center
Maria Fareri Children’s Hospital at Westchester Medical CenterAssociate Professor of Pediatrics
New York Medical College
• The Genetics Visiting Professorship is a competitive award of the American Academy of Pediatrics (AAP) Newborn Screening Program, and funded through a joint public/private partnership between the Maternal and Child Health Bureau/Health Resources and Services Administration, the National Coordinating Center for the Regional Genetics and Newborn Screening Service Collaboratives, housed at the American College of Medical Genetics, and the AAP.
Genetics Visiting Professorship
GVP: Partnership Between AAP and LHVPN
Lower Hudson Valley Perinatal Network (LHVPN) has the the goal of making sure all babies are born healthy. Together we work to advocate for and educate consumers and professionals about maternal, child and family health issues impacting the region.
The goals of the GVP program are:– Updates on what new genetic diseases have been added to the
newborn screen– Managing abnormal results (disease and carrier states) from the
newborn screen– Review of the primary care provider's role in caring for
newborns with genetic diseases diagnosed by newborn screen– Discussing newer genetic diagnostic techniques such as
microarray analysis
Summary Questions• What is Newborn Screening?• What role has New York played in the
development of Newborn Screening?• How do we choose which diseases to screen?• What are the demographics of Newborn
Screening in New York State?• What have been the consequences of
expanding Newborn Screening?• What can we expect form Newborn Screening in
the future?• What is tandem mass spectroscopy?
What is Newborn Screening?
“The goal of newborn screening is early detection of children at increased risk for selected metabolic or genetic diseases so that medical treatment can be promptly initiated to avert metabolic crises and prevent irreversible neurological and developmental sequelae.”
Newborn Screening in New York -A Guide for Health Professionals 1991
Rationale for Treatment of Genetic Disease
Newborn Screening
Early Diagnosis
Intervention Prior to Onset of Symptoms
Prevention of Disease Progression
Phenylketonuria (PKU)
• Frequency about 1 in 10,000 births in Caucasian population
• Phenylalanine is neurotoxic at high levels• Defect in enzyme phenylalanine hydroxylase• 1 to 2 % of cases due to defect in
dihydropteridine reductase (DHPR) or in the synthesis of biopterin
• Treatment is for life• Maternal PKU effects
Time Line for Specimen Collection
Day of Life 1 2 3 4 5
SpecimenQuality
A B C C C
Age (hours) Birth 24 48 72 96
Newborn Screening: Early Discharge
Missing the diagnosis
Threshold Level
AbnormalMetaboliteLevel
Time
Algorithim for Newborn Screening
Newborn Screening Results
Screen Negative BorderlineScreen Positive
Referral to Specialty Center
Case Complete Repeat Specimen
Negative Positive
Negative Positive
Specific evaluation for confirmation of diagnosis
What role has New York played in the development of Newborn
Screening?
Dr. Robert Guthrie
(1916-1995)
History of Newborn Screening in New York State• 1930’s George Jervis at Letchworth Village State School in Thiells, NY
identified 50 clients with metal retardation attributed to PKU
• 1963 Robert Guthrie, microbiologist-pediatrician at State University of New York, Buffalo, devised simple inexpensive which allowed screening for PKU
• 1964 Robert Guthrie coordinated a 29 state pilot study of screening in 400,000 newborns for PKU, proved so successful that many states instituted newborn screening immeadiately
• 1965 New York State law for newborn screening, Public Health Law 2500a went into effect, mandating that every newborn be screened for PKU
• 2002 Introduction of MS/MS technology for the testing of PKU, MSUD, Homocystinuria, and MCAD Deficiency
• 2006 Addition of Krabbe Disease to the panel
How do we choose which diseases to screen?
The Cardinal Principles of Screening
• The disorder has a relatively high incidencehigh incidence so that the cost per diagnosed individual is reasonable
• An effective and not overly expensive treatment is available
•A relatively inexpensive screening test is available that is suitable for high volume testing (preferably automatable)
•The screening test has a very high sensitivity ( i.e. a very low rate of false negatives) and high specificity ( i.e. low rate of false positives which require expensive follow-up)
Some of the basic criteria for determining which inherited disorders for newborn screening include:
Criteria for Newborn Screening
• Disorder produces irreversible damage before onset of symptoms
• Treatment by Umbilical-Cord Blood Transplantation
• Long-term follow-up required
Krabbe Disease Screening - Concerns
• Screening– What is the false positive rate? It appears high– Does the burden of disease warrant screening?
• Diagnosis– Can we differentiate between infantile and adult onset
forms of the disease?– Will false positives who turn out to be carriers require
genetic counseling and family studies?• Treatment
– Can a HLA match be found for every patient screened positive?
– What is the longterm outcome of treatment?– Who will pay?
Krabbe Disease
Update as of December 2008– Over 80 referrals for low enzyme activity– Majority of patients have low levels on repeat but
above that expected for affected patients majority due to polymorphisms in the gene.
– Two patients so far have been identified with infantile Krabbe Disease and have been transplanted, one patient died of transplant complication
– Four other patients have enzyme assays suggesting juvenile or adult onset disease, they are all stable at this point
Future Newborn Screening Disorders – the latest new kids on the block• Lysosomal Storage Disorders
– Enzyme Replacement Therapy and Bone Marrow/ Umbilical Cord Cell Transplants more readily available.
• Peroxisomal Disorders– Adrenoleukodystrophy. Studies have shown the
benefit of Lorenzo’s Oil in presymptomatic individuals
• SCID– Clear benefit from transplantation
What is Tandem Mass Spectrometry?
What does MS/MS offer?
•Increased specificity, decreased false positives
•One test many diseases
•Many diseases do not meet the criteria for Newborn screening,but public opinion and availability of technology warrant offering testing for the larger group of diseases.
Mass Spectrometry 101Mass Spectrometry 101
TMS
Source Analyzer
First Mass Analyzer
Separation by molecular weight and charge - m/z
Collision cell
Fragmentation in inert gas chamber
Selective massmeasurement
Second Mass Analyzer
Note: Acylcarnitine analysis by loss of butyl ester, common 85mw fragment Amino acid analysis by loss of neutral molecule 102mw Different scan function can be produced in series
New Emerging Technologies• Microarray is now replacing individual
FISH and subtelomere analysis “molecular chromosomes”
• Molecular Screening is moving towards full sequencing of genes
• Gene identification in silico as a result of the human genome project
• Advances in therapeutics is driving the progress in newborn screening– If you can treat it, we should screen for it!
GVP GranteesThe LHVPN provides:
– Perinatal Health Education Materials Health education brochures available free of charge to distribute to clients and the community.
– Perinatal Health Education Sessions Community based education and information updates on issues that affect the health of mothers, fathers, babies and families. These sessions can be tailored to meet unique needs and are conducted upon request.
– Tri-annual Education & Networking Conferences Perinatal health related education for professionals who work with or on the behalf of women, children, men and families.
– Perinatal Health Speakers’ Bureau - Local experts available to deliver broad based provider and consumer education focusing on maternal, child and family health issues, racial and ethnic disparities, intersection of chronic disease and perinatal health, cultural competence, and life course as it impacts perinatal health. (We are recruiting local experts)
Visit us at: www.LHVPN.netContact us at: [email protected] or 914-493-6435
Through the national AAP, Chapter 3 provides:
– Fact sheets, Policy statements, Parent resources, State resources and tools for practitioners regarding genetics conditions and newborn screening.
– On our website (ny3aap.org) is a link to the National Center of Medical Home Initiatives for Children with Special Needs (www.medicalhomeinfo.org) which is an AAP initiative sponsored by the Maternal and Child Health Bureau of the Department of Health and Human Services.
– National Center of Medical Home Initiatives for Children with Special Needs (contact at: [email protected]) has a wealth of information regarding genetics conditions, screening policies, state specific initiatives, etc.
– Chapter 3 coordinated the Visitor Professorship with the LHVPN.
Visit us at: www.NY3AAP.orgContact us at: [email protected] or 516-326-0310