Transcript Newborn Screening

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
Genetics Visiting Professorship
• 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.
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:
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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
24
Age (hours) Birth
Specimen
Quality
2
A
3
48
B
4
72
C
5
96
C
C
Newborn Screening: Early Discharge
Missing the diagnosis
Abnormal
Metabolite
Level
Threshold Level
Time
Algorithim for Newborn Screening
Newborn Screening Results
Borderline
Screen Negative
Case Complete
Screen Positive
Referral to Specialty Center
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
Some of the basic criteria for determining which inherited
disorders for newborn screening include:
• The disorder has a relatively high 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)
Criteria for Newborn Screening
• Disorder produces irreversible damage
before onset of symptoms
• Treatment is effective if begun early
• Natural history of disorder is known
MS/MS
Acylcarnitines
9 OA
ACMG Recommended Panel
Amino acids
5 FAO
6 AA
3 Hgbpathies
6 Others
Hb SS
Hb S/ßTh
Hb S/C
CH
BIOT
CAH
GALT
HEAR
CF
CORE PANEL
IVA
GA I
HMG
MCD
MUT
3MCC
Cbl A,B
PROP
BKT
MCAD
VLCAD
LCHAD
TFP
CUD
PKU
MSUD
HCY
CIT
ASA
TYR I
SECONDARY TARGETS
6 OA
8 FAO
8 AA
1 Hb Pathies
2 Others
Cbl C,D
MAL
IBG
2M3HBA
2MBG
3MGA
SCAD
GA2
M/SCHAD
MCKAT
CPT II
CACT
CPT IA
DE RED
HYPER-PHE
TYR II
BIOPT (BS)
ARG
TYR III
BIOPT (REG)
MET
CIT II
Var Hb
GALK
GALE
What are the Demographics of
Newborn Screening?
New York State Newborn Screening
Program 1965-2007
Disorder
Infants Tested
PKU
Testing
Initiated
1965
11.54 Million
Confirmed
Cases
538
Disease
Incidence
1:21,000
Galactosemia
1968
10.59 Million
185
1:57,000
MSUD
1968
10.59 Million
40
1:265,000
Homocystinurua 1975
8.62 Million
26
1:334,0000
Homozygous
Sickle Cell
Primary
Hypothroidism
Biotinidase
Deficiency
1975
8.62 Million
4683
1978
7.89 Million
3944
1:2,000
1987
5.07 Million
58
1:87,000
1:1,840
U.S. Newborn Screening – 2008
Using or Close to Using MS-MS
Screening
Not Screening
Optional or Moving Quickly
What have been the
consequences of expanding
Newborn Screening?
Positive Consequences
• Early detection of potentially life
threatening conditions
• Early treatment and prevention of
sequelae
Negative Consequences
• High False Positive Rates
– Impact on families
– Impact on health system
• Uncovering variant conditions with unclear
pathogenesis
• Detection of carriers
Potential Impact of False Positives
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USA 4,100,000 births per year
1:2,400 confirmed diagnoses
10 - 20 False Positives per diagnosis
25,000 – 50,000 False Positives
• Lets look at New York State 2007 Data
– Review 2007 report
Why Parents May Be Vulnerable
• Peak health worries occur in the 25-34
age group
• In general young people worry more than
older people
• Younger people more active and problem
focused
• Older people more passive and emotion
focused
Lindsay et al., Worry over the lifespan. Psychological Medicine 2006; 1-9
A Few Examples of Negative
Consequences
We increasingly need to be aware of the complexities of
testing and to communicate this sensitively to our patients
• “It was scary and when I found out my daughter
was fine I felt like we’d gone through a lot for
nothing.”
• “I was upset as they (the physicians) were
elusive about why my child had to return for a
repeat test.”
• “The pediatrician said that a blood test was
needed, but she didn’t know what it was for”
• “We were told ‘no news is good news’. They
never called back with the results”
Medium Chain Acyl-CoA
Dehydrogenase Deficiency
Medium Chain Acyl CoA Dehydrogenase Deficiency
• Most common FAOD, incidence up 1 in 10,000
• Exclusively hepatic presentation - most frequently seen as
hypoketotic hypoglycemia provoked by fasting
• May be a history of sibling death
• Affected individuals usually normal until an episode occurs
•Newborn screening by ms/ms with elevated octanoylcarntine
• Specific abnormalities seen on urine organic acid analysis,
acylcarnitine, plasma free fatty acid and acylglycine analysis
• MCAD gene has been cloned to chromosome 1p31. A single
mutation at nucleotide 985, A to G accounts for 90% of disease
carrying alleles.
• Treatment revolves around prevention of fasting, the use
of carnitine remains controversial
MCADD Screening
Method: Octanoylcarnitine level by Tandem Mass Spectrometry
MCAD Deficiency: Octanoylcarntine Peak
Newborn Screening Consequences
• Detection of Unaffected Carriers
– ACMG recommendation on carrier screening
advises waiting to test until individuals can
consent themselves for testing, provided the
result has no bearing on health to that point.
– No clear policy on how to deal with these
patients
– A major concern for Cystic Fibrosis
• Look at 2007 report again!
Cautionary Tales!
Expanded Screening Problems
• Overall we seem to be dealing with lots of
false positives
• Are SCAD and 3-MCC Diseases?
• Low C0 levels from the NICU
Newborn Screening Consequences
– Additional Concerns
• Patients born in adjoining states may not have
had access to the same expanded screening
• Siblings born in different states and different
countries
• Siblings born before and after the expansion of
newborn screening
• The demographic on the newborn screening
card can sometimes be incorrect and lead to
delays in locating patients for follow up testing
What can we expect form
Newborn Screening in the future?
Krabbe Disease
Infantile Krabbe Disease
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Globoid cell leukodystrophy
Autosomal recessive disorder
Incidence ~1/100,000
Enzyme defect lysosomal galactocerebrosidase
Inability to degrade glycolipids found almost exclusively
in myelin
Clinically presents with dystonia (lead-pipe) rigidity of the
limbs and abnormal posturing) from about 6 months
Patients have irritability, poor feeding, motor regression
and seizures.
MRI: White matter changes and calcification particularly
affecting the basal ganglia
Death usually by two years of age.
Newborn Screening for Krabbe
Disease
• Measurement of artificial product by ESIMS/MS
• Diagnosis by enzyme analysis and DNA
analysis
• Additional studies to confirm diagnosis
– Brain MRI, CSF Protein, EEG, Neuro Eval.
• 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 101
TMS
Selective mass
measurement
Collision cell
Source
Analyzer
Fragmentation in
inert gas chamber
First Mass Analyzer
Second Mass Analyzer
Separation by molecular
weight and charge - m/z
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
Mass spectrometry
+CH
CH3COCH3
CH3+COCH3
+COH
3
CH3C+OCH3
+COCH
Sample
Inlet
Ionization
& Adsorption
of Excess Energy
3
Fragmentation
(Dissociation)
Mass Analysis
Detection
Fragmentation of butylated
PhenylalanineH
H
H
H
H
CH2
H3N+
COOC 4H9
120
100
103
%
77
0
CH
60
70
80
91
93
90
100
110
120
130
140
150
160
170
180
190
200
m/z
210
Normal amino acid profile
Deuterated internal standards for Quantification
Pro
100
d3-Leu
d4-Ala
%
d5-Phe
d6-Tyr
Ser
d8-Val
d3-Met
Glu
Gly
0
140
160
180
200
220
240
260
m/z
280
Normal vs PKU
d3-Leu
100
Ala
d4-Ala
Normal
d5-Phe
Leu
Phe
Tyr
%
Met
d6-Tyr
d3-Met
0
Elevated Phenylalanine
100
Phe
PKU
%
0
140
160
180
200
220
240
260
m/z
280
Conclusions and More Concerns
•New technology developments have allowed for the
expansion of newborn screening - MS/MS
•Public opinion has made newborn screening a legislative
initiative
•Some of these diseases do not meet the classical model of
a screened disease
•Further pilot programs are needed to validate the
technology
•Who will pay for all the follow-up?
•Does the horizon bring screening for even more diseases?
Final Thoughts
• The expansion of newborn screening has
become a political mandate and has in large
part been patient directed
• The pathology and long term outcome for
some of these diseases is still unclear
• Ruling out a disease can be very expensive
• There is no MS/MS available in New York
State for follow-up
• TMS is here to stay!
Abnormal Newborn Screening Results
• Contact:
– To obtain NY State Newborn Screening Results for your
patients call (800) 535-3079
– To register call (518) 473-7552
• Maria Fareri Children’s Hospital at Westchester
Medical Center is the NY State designated Newborn
Screening Referral Center
– Endocrine Disorders
• Endocrine Center (914) 366-3400
– Hemoglobin Disorders
• Hemoglobinopathy Center - (914) 347-6970
– Genetic Disorders/Cystic Fibrosis
• Cystic Fibrosis Center – (914) 493-7585
– Metabolic Disorders
• Inherited Metabolic Disease Center - (914) 304-5300
– HIV
• Infectious Diseases Center – (914) 493-8333
For reference see links on www.lhvpn.net/newbornscreening
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 Grantees
Through the national AAP, Chapter 3
provides:
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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.org
Contact us at: [email protected]
or 516-326-0310
The LHVPN provides:
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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.net
Contact us at: [email protected]
or 914-493-6435
Santa says:
“You’ve tested positive for the naughty gene”
Acknowledgements
AAP
Andrew D. Racine, MD, PhD, AAP, Chapter 3
Brenda Amos-Lewis
Ginny Chanda
Holly Griffin
LHVPN
Cheryl Hunter-Grant, LMSW, CLC
Lorraine Anglin, MPH
Jeet Lund
Michelle Gordon
Wadsworth Center/NYS Department of Health
Katharine B. Harris, MBA
MFCH
Heather Brumberg, MD, MPH
David Kronn, MD
Sarah Lawrence College
Caroline Lieber, MS, CGC
Please remember to hand in your
post-test/evaluations. Thank you.
MOD
Diane M. Ashton, MD, MPH
Dionne A. Durant, LMSW
Sue Rose
Funded in part by grants from the AAP and NYS Department of Health/Division of Family Health