Transcript gene202-10-22-2015-1..

NEWBORN SCREENING
Greg Enns, MB, ChB, FAAP
Professor of Pediatrics
Director, Biochemical Genetics Program
Lucile 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
American Academy of Pediatrics Report Pediatrics 106:389, 2000
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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
PHENYLKETONURIA (PKU)
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Untreated PKU
 Mental retardation
 Decreased deep tendon reflexes and spasticity
 Seizures
 Acquired microcephaly
 Pale pigmentation
 Dry skin
 Mousy odor (phenylacetic acid in urine and sweat)
PKU Newborn Screening Outcome
PKU Clinical Management
 Regular 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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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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THE “HEELSTICK TEST”
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Courtesey Dr. Ed McCabe
Filter Card Punch
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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?
=
O
+
O
=
RC- O
(CH3)3N-CH2-CH-CH2-COO-
Hexanoylcarnitine R = CH3(CH2)3CH217
+Precursor (85.0): 28 MCA scans from Sample 6 (H38870 Asa-Nunies, W) of Data081004.wiff
1.5e6
218.5
C0
Normal
Acylcarnitine
Profile
1.4e6
1.3e6
1.2e6
C2
1.1e6
In te n s ity , c p s
Max. 1.
260.5
1.0e6
9.0e5
8.0e5
7.0e5
C0-d9
C16-d3
227.5
459.7
6.0e5
5.0e5
C2-d3
4.0e5
3.0e5
263.5
0.0
200
C14-d9
C4-d3 311.6
C8-d3
291.5
221.3
C3-d3
2.0e5
1.0e5
C5-d9
347.6
277.4
204.5
288.4
237.4
220
240
260
280
C10-d3
300
327.4
320
375.6
342.5 370.4
340
360
m/z, amu
437.6
380
400.5
400
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426.7
420
440
461.5
482.
460
480
Octanoylcarnitine
MCAD Deficiency
Acylcarnitine
Profile
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Medium-chain Acyl-CoA Dehydrogenase (MCAD)
Deficiency
 ~1/10,000 in Caucasians
 Sudden infant death syndrome
 Reye-like syndrome
 Episodic illness 6-24 months as a consequence of
catabolism
 May have myopathy, cardiomyopathy
 Hypoketotic 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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Long-chain 3-hydroxyacyl-CoA
dehydrogenase (LCHAD) deficiency
Retrospective analysis
of original NBS sample
LCHAD
Control
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Acylcarnitines (µM) in Original NBS Cards
of LCHAD Deficient Patients
Control
Sample 4
C18:1
cps
cps
C18:1
5000
DEAD
5000
C18-OH
C16-OH
5000
Sample 5
cps
C18:1
C18:1
C18-OH
DEAD
C16-OH
C16-OH
C18:1
C18-OH
5000
5000
DEAD
C18:1
C18-OH
m/z, amu
Sample 7
C18:1
cps
C18-OH
C16-OH
m/z, amu
Sample 10
m/z, amu
Sample 3
C18-OH
C16-OH
m/z, amu
5000
cps
Sample 6
C18-OH
C16-OH
DEAD
m/z, amu
cps
5000
cps
cps
DEAD
C18:1
C18:1
Sample 9
C18:1
m/z, amu
Sample 2
C16-OH
C16-OH
C18-OH
m/z, amu
5000
5000
DEAD
C18-OH
m/z, amu
5000
cps
cps
Sample 1
m/z, amu
cps
5000
C16-OH
C18-OH
C16-OH
m/z, amu
m/z, amu
Sample 8
C18:1
cps
5000
Control
C18:1
m/z, amu
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STATE TO EXPAND TESTING OF
NEWBORNS FOR GENETIC ILLS
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)
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Communication in Newborn Screening
Private Sector
Laboratories
Central Laboratory
Specialists:
Biochemical Geneticist
Endocrinologist
Hematologist
Area Service Center
Family
Primary Care Provider
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‘Core’ 29 (21)
U.S. Newborn Screening
50+ Disorders
40-49 Disorders Conditions Required – Sept, 2007
30-39 Disorders
20-29 Disorders
genes-r-us
10-19 Disorders
Courtesey of Dr. Brad Therrell
DC
http://genes-r-us.uthscsa.edu
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http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/
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As of January 2014
Summary of Nominated Conditions to the Recommended Uniform Screening Panel (RUSP)
CONDITION
Adrenoleukodystrophy (ALD)
Adrenoleukodystrophy (ALD)
MPS I (alpha-Liduronidase
deficiency)
Pompe Disease
22q11 Deletion
Syndrome
Critical Congenital
Heart Disease
(CCHD)
Hyperbilirubinemia/
Kernicterus
Hemoglobin H
Disease
Spinal Muscular
Atrophy
Krabbe Disease
Fabry Disease
Niemann-Pick
Disease
Pompe Disease
Severe Combined
Immunodeficiency
(SCID)
Submission
to HRSA
N&P WG
Review
Committee Vote to
Send to ERG
ERG Preliminary
Report and/or
Update
Presentation
mm/yy
mm/yy
mm/yy
mm/yy
09/13
10/13
01/14
02/15; 05/15
02/12
08/12
NOT Approved 09/12
-
-
-
-
02/12
04/12
Approved 05/12
09/13; 01/14
02/15
Approved 02/15
TBD
02/12
04/12
Approved 05/12
09/12
05/13
Approved 05/13
03/15
01/11
12/11
NOT Approved 01/12
-
-
-
-
10/09
Approved 01/10
05/10
09/10
Approved 09/10
09/11
07/09
Approved 01/10
01/11
01/12
NOT Approved 01/12
-
04/09
Approved 09/09
01/10
05/10
NOT Approved 05/10
-
06/08
NOT Approved 11/08
-
-
-
-
01/08
12/07
Approved 08/08
NOT Approved 08/08
05/09
-
09/09
-
NOT Approved 09/09
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-
12/07
NOT Approved 10/08
-
-
-
-
10/07
Approved 01/08
08/08
10/08
NOT Approved 10/08
-
09/07
Approved 01/08
11/08
02/09
Approved 01/10
02/10
ERG Final
Report
Presentation
Committee Vote to
Add to the RUSP
Secretary
Approval to Add
to the RUSP
mm/yy
mm/yy
mm/yy
Acronyms:
N&P WG – Nomination and Prioritization Workgroup; ERG – (External) Evidence Review Group; TBD – To be determined
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www.cdph.ca.gov
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MS/MS Newborn Screening
A normal screening result does
not exclude metabolic disease
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Optimal Path to Diagnosis
Positive
NBS
Urgent
Referral
• To a geneticist or metabolic
specialist
Definitive
Diagnosis
• Metabolite or enzyme assay
diagnostic testing
• DNA testing
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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
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