1. NEWBORN SCREENING Greg Enns, MB, ChB, FAAP Professor of Pediatrics
Director, Biochemical Genetics Program
Lucile Packard Children’s Hospital
October 22, 2015

2. Newborn Screening Goal
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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

3. 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)
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PHENYLKETONURIA (PKU)

5. Untreated PKU Mental retardation
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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)

6. PKU Newborn Screening Outcome
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PKU Newborn Screening Outcome

7. PKU Clinical Management
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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

8. 4/26/2017

9. 4/26/2017

10. History of Newborn Screening in California
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History of Newborn Screening in California
PKU
Hypothyroidism, Galactosemia
Sickle Cell Disease, other Hemoglobinopathies
MS/MS Pilot Project
Expanded MS/MS screening

11. Current California Newborn Screening
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Current California Newborn Screening
550,000 Newborns per year
(~1/8 of neonates born annually in USA)
>99% screened

12. 4/26/2017
THE “HEELSTICK TEST”
Courtesey Dr. Ed McCabe

13. 4/26/2017
Filter Card Punch
Courtesey Dr. John Sherwin

14. Tandem Mass Spectrometry (MS/MS) Target Analytes for Newborn Screening
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Tandem Mass Spectrometry (MS/MS) Target Analytes for Newborn Screening
Amino acids
Acylcarnitines
Intermediates of:
Organic acids
Fatty acids

15. Acylcarnitine Profile
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Acylcarnitine Profile
Plasma/serum
>30 compounds
fatty acids
organic acids
Quick prep and run

16. 4/26/2017
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)

17. What is an acylcarnitine?
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What is an acylcarnitine? O =
RC- O O = +
(CH3)3N-CH2-CH-CH2-COO-
Hexanoylcarnitine R = CH3(CH2)3CH2-

18. Normal Acylcarnitine Profile
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Normal Acylcarnitine Profile

19. MCAD Deficiency Acylcarnitine Profile
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MCAD Deficiency Acylcarnitine Profile
Octanoylcarnitine

20. Medium-chain Acyl-CoA Dehydrogenase (MCAD) Deficiency
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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

21. The primary energy source for:
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FATTY ACID METABOLISM
The primary energy source for:
Cardiac muscle
Skeletal muscle
A necessary energy source during:
Fasting
Stress

22. Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
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Long-chain 3-hydroxyacyl-CoA
dehydrogenase (LCHAD) deficiency
Retrospective analysis
of original NBS sample
Control
LCHAD

23. Acylcarnitines (µM) in Original NBS Cards of LCHAD Deficient Patients
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Acylcarnitines (µM) in Original NBS Cards of LCHAD Deficient Patients
Control
C18:1
5000
m/z, amu
cps
Sample 4
C18:1
C16-OH
C18-OH
5000
m/z, amu
cps
Sample 8
C18:1
C16-OH
C18-OH
5000
m/z, amu
cps
DEAD
5000
Sample 1
C18:1
C16-OH
C18-OH
m/z, amu
cps
Sample 5
C18:1
C16-OH
C18-OH
5000
m/z, amu
cps
Sample 9
C18:1
C16-OH
C18-OH
5000
m/z, amu
cps
Sample 2
C18:1
C16-OH
C18-OH
5000
m/z, amu
cps
Sample 6
C18:1
C16-OH
C18-OH
5000
m/z, amu
cps
Sample 10
C18:1
C16-OH
C18-OH
5000
cps
m/z, amu
Sample 3
C18:1
C16-OH
C18-OH
5000
m/z, amu
cps
Sample 7
C18:1
C16-OH
C18-OH
5000
m/z, amu
cps
Control
C18:1
5000
m/z, amu
cps

24. 4/26/2017

25. STATE TO EXPAND TESTING OF NEWBORNS FOR GENETIC ILLS
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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)

26. Communication in Newborn Screening
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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

27. Conditions Required – Sept, 2007
4/26/2017 34 34 14 35 16 46 50 50 33 34 54 50 44 49 45 49 45 31 51 13 25 43 14 50 41 46 33 45 46 50 31 47 31 37 31 52 DC 41 50 48 12 31 48 37 30 33 48 29 31 46 30 36
‘Core’ 29 (21)
50+ Disorders
U.S. Newborn Screening
Conditions Required – Sept, 2007
40-49 Disorders
30-39 Disorders
20-29 Disorders
genes-r-us
10-19 Disorders
Courtesey of Dr. Brad Therrell

37. MS/MS Newborn Screening
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MS/MS Newborn Screening
A normal screening result does not exclude metabolic disease

38. Optimal Path to Diagnosis
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Optimal Path to Diagnosis
Urgent
Referral
Positive
NBS
Definitive Diagnosis
To a geneticist or metabolic specialist
Metabolite or enzyme assay diagnostic testing
DNA testing
Pediatricians should be aware of the unique signs and symptoms or clusters of common signs and symptoms that are suggestive of an LSD. If there is any clinical suspicion, the child should be urgently referred to a geneticist or metabolic specialist. Arriving at a definitive diagnosis is relatively simple. The gold standard is an enzyme assay performed on a blood sample. In some cases, DNA testing is performed as well.

39. SUMMARY Newborn screening does not detect everyone
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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