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Newborn Screening Goal 4/26/2017 Newborn Screening Goal The early detection of conditions for which early and timely interventions can lead to the elimination or reduction of associated mortality, morbidity and disabilities American Academy of Pediatrics Report Pediatrics 106:389, 2000
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NEWBORN SCREENING
Greg Enns, MB, ChB, FAAPProfessor of Pediatrics
Director, Biochemical Genetics ProgramLucile Packard Children’s Hospital
October 22, 2015
Newborn Screening Goal
The early detection of conditions for which early and timely interventions can lead to the elimination or reduction of associated mortality, morbidity and disabilities
2American Academy of Pediatrics Report Pediatrics 106:389, 2000
When is screening a good idea Condition
◦ Of medical importance, significant morbidity and/or mortality◦ Natural history well understood
Screening Test◦ Safe, precise, validated test
Treatment◦ Effective treatment is available◦ It is beneficial to start treatment early, before the onset of symptoms
Cost-benefit Analysis◦ The overall expense of the screening program is acceptable given the expected
benefit to patients and families The social context
◦ The program, including testing, counseling and treatment is acceptable to the society in which it is being carried out
4
PHENYLKETONURIA (PKU)
Untreated PKUMental retardationDecreased deep tendon reflexes and spasticitySeizuresAcquired microcephalyPale pigmentation Dry skinMousy odor (phenylacetic acid in urine and sweat)
PKU Newborn Screening Outcome
PKU Clinical ManagementRegular appointments with the Metabolic
“team” physician, nutritionist, genetic counselor, nurse, social worker
Regular blood phenylalanine levels◦Once a week to once a month for the first 12
month (average once a week)◦Once a month to every 3 months throughout
childhood
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8
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History of Newborn Screening in California
• 1966 - PKU
• 1980 - Hypothyroidism, Galactosemia
• 1990 - Sickle Cell Disease, other Hemoglobinopathies
• 2002 - 2003 - MS/MS Pilot Project• 2005 - Expanded MS/MS screening
Current California Newborn Screening
550,000 Newborns per year
(~1/8 of neonates born annually in USA)
>99% screened
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12
THE “HEELSTICK TEST”
Courtesey Dr. Ed McCabe
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Filter Card Punch
Courtesey Dr. John Sherwin
Tandem Mass Spectrometry (MS/MS) Target Analytes for Newborn Screening
• Amino acids
• Acylcarnitines– Intermediates of:
• Organic acids• Fatty acids
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Acylcarnitine Profile
• Plasma/serum• >30 compounds
– fatty acids– organic acids
• Quick prep and run
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Acylcarnitines
Acyl group of varying chain length attached to carnitine
Acyl groups derived from organic acid metabolism and fatty acid oxidation
Examples include:◦Octanoylcarnitine (C8-acylcarnitine)◦Propionylcarnitine (C3-acylcarnitine)
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What is an acylcarnitine?
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(CH3)3N-CH2-CH-CH2-COO-+
=ORC- O
=
Hexanoylcarnitine R = CH3(CH2)3CH2-
O
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+Precursor (85.0): 28 MCA scans from Sample 6 (H38870 Asa-Nunies, W) of Data081004.wiff Max. 1.5e6 cps.
200 220 240 260 280 300 320 340 360 380 400 420 440 460 480 500m/z, amu
0.0
1.0e5
2.0e5
3.0e5
4.0e5
5.0e5
6.0e5
7.0e5
8.0e5
9.0e5
1.0e6
1.1e6
1.2e6
1.3e6
1.4e6
1.5e6
Inte
ns
ity, c
ps
218.5
260.5
227.5 459.7
263.5 311.6 437.6291.5221.3 375.6
347.6277.4
204.5 288.4 370.4 461.5327.4 342.5 482.4400.5 426.7237.4
C2-d3
C8-d3C10-d3
C16-d3
C2
C0-d9
C5-d9
C3-d3
C4-d3
C0
C14-d9
Normal Acylcarnitine
Profile
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MCAD Deficiency Acylcarnitine
ProfileOctanoylcarnitine
Medium-chain Acyl-CoA Dehydrogenase (MCAD) Deficiency
~1/10,000 in CaucasiansSudden infant death syndromeReye-like syndromeEpisodic illness 6-24 months as a consequence of
catabolismMay have myopathy, cardiomyopathyHypoketotic hypoglycemia
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FATTY ACID METABOLISM
• The primary energy source for:– Cardiac muscle– Skeletal muscle
• A necessary energy source during:– Fasting – Stress
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7.09e3 cps+Precursor (85): Expt. 3, 0.73 min (26 scans) from 070902-10
% % MultiView -- © 1996, SCIEX, a division of MDS Health Group.% % Original concept:% Dr. Ron Bonner% Dr. Lyle Burton% % Development:% Dr. Lyle Burton% Yves Legault% Shengping Ma% % With the help of:% Dr. Victoria Barclay% Scott Champ% Rob McDermid%
300 350 400 450 500m/z, amu
20
40
60
80
% In
tens
ity
4.14e3 cps+Precursor (85): Expt. 3, 0.73 min (26 scans) from 070902-12
% % MultiView -- © 1996, SCIEX, a division of MDS Health Group.% % Original concept:% Dr. Ron Bonner% Dr. Lyle Burton% % Development:% Dr. Lyle Burton% Yves Legault% Shengping Ma% % With the help of:% Dr. Victoria Barclay% Scott Champ% Rob McDermid%
300 350 400 450 500m/z, amu
20
40
60
80
% In
tens
ity
Retrospective analysisof original NBS sample
Control
LCHAD
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
Acylcarnitines (µM) in Original NBS Cards of LCHAD Deficient Patients
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m/z, amu
ControlC18:1
5000
m/z, amu
cps
5000
Sample 1
C18:1C16-OH C18-OH
m/z, amu
cps
Sample 2
C18:1
C16-OHC18-OH
5000
m/z, amu
cps
Sample 3C18:1
C16-OH
C18-OH
5000
m/z, amu
cps
Sample 4C18:1
C16-OH
C18-OH
5000
m/z, amu
cps
Sample 5
C18:1
C16-OHC18-OH
5000
m/z, amu
cps
Sample 6C18:1C16-OH
C18-OH
5000
m/z, amu
cps
Sample 7C18:1
C16-OH
C18-OH
5000
m/z, amu
cps
Sample 8C18:1
C16-OHC18-OH
5000
m/z, amu
cps
Sample 9C18:1
C16-OH
C18-OH
5000
m/z, amu
cps
Sample 10C18:1
C16-OH C18-OH
5000
cps
Control
C18:1
5000
m/z, amu
cps
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
24
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Newborns in California will soon get tested for more than 30 genetic illnesses that lead to serious health and developmental problems, a major increase in screening that will shore up the state's outdated protections for new babies.Gov. Arnold Schwarzenegger has already approved money for the new screening and is expected to sign the law finalizing it within the next two weeks. Most other states offer more newborn screening than California, which currently tests for only four.
August 4, 2004, Page 1A, San Jose Mercury News (CA)
STATE TO EXPAND TESTING OF NEWBORNS FOR GENETIC ILLS
Communication in Newborn Screening
26
Primary Care Provider
Private Sector Laboratories
Family
Central LaboratorySpecialists:
Biochemical GeneticistEndocrinologistHematologist
Area Service Center
10-19 Disorders
U.S. Newborn Screening
Conditions Required – Sept, 2007
30-39 Disorders 40-49 Disorders 50+ Disorders
34
43
44 45
50
48
35
46
50
50
14
4147
20-29 Disorders
46
37
30
14
3312
29
DC
51 1331
16
45
34
37
33
36
3030
‘Core’ 29 (21)
50
41
48
31
46
33 45
48
52
50
31
34
54 49
31
5049
25
31
31
46
Courtesey of Dr. Brad Therrell
genes-r-us
28http://genes-r-us.uthscsa.edu
29http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/
30
31
32www.cdph.ca.gov
33
34
35
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MS/MS Newborn Screening
A normal screening result does not exclude metabolic disease
37
Optimal Path to Diagnosis
38
• Metabolite or enzyme assay diagnostic testing
• DNA testing
PositiveNBS
UrgentReferral
Definitive Diagnosis
• To a geneticist or metabolic specialist
SUMMARY• Newborn screening does not detect everyone• Appropriate labs & investigations are needed to obtain final
diagnosis• A Uniform Screening Panel of 31 core disorders and 26
secondary disorders recommended by the DACHDNC has led to states testing for a similar number of disorders
39