1. We will begin momentarily.

2. Pediatric Genetics
Newborn Screening Part I
Mark Korson, MD
VMP Genetics, LLC
Leah Burke, MD
University of Vermont

3. Weitzman Institute Learning Academy Pediatric Genetics
The NERGN project is supported by the Health
Resources and Services Administration (HRSA) of the
U.S. Department of Health and Human Services
(HHS) under grant number UH7MC30778; New
England Regional Genetics Network; total award
amount: 1.5 million; 100% from governmental
sources. This information or content and
conclusions are those of the author and should not
be construed as the official position or policy of, nor
should any endorsements be inferred by HRSA, HHS
or the U.S. Government.

4. 4
Disclosures
We do not have anything to disclose.

5. Newborn screening
Medicine Families
Politics

6. 6
Asbjørn Følling Asked by mother of two children
with ID to find the reason for their
unusual odor
Discovered phenylketones in their
urine
Disorder named Følling’s disease,
or phenylketonuria (PKU)
A BRIEF HISTORY OF NEWBORN SCREENING

7. Phenotype Intellectual disability
Seizures
Autistic/psychiatric
behaviors
Hypopigmentation
Musty odor
Patchy white matter
changes on MRI scan
UNTREATED PKU
Courtesy of Harvey L. Levy, MD

8. TIMELINE OF NEWBORN SCREENING
1934 - Folling identifies PKU
1954 – Bickel publishes PKU dietary therapy

9. Courtesy of Harvey L. Levy, MD
TWO SIBLINGS WITH PKU

10. THE FIRST SCREENING TEST FOR PKU
Courtesy of Stephen Cederbaum, MD
The ferric
chloride test

11. Blood filter paper
Bacterial inhibition
assay (Guthrie test)
Universal screening
Advocacy for newborn
screening
Courtesy of Harvey L. Levy, MD
ROBERT GUTHRIE, MD, PhD

12. THE “PKU TEST”
• JFK launches a 20-state trial of the “Guthrie test”
• Massachusetts launches screening for PKU in 1962
• 7 patients are identified in the first six months

13. TIMELINE OF NEWBORN SCREENING
1934 - Folling identifies PKU
1954 – Bickel publishes PKU dietary therapy
1961 – Guthrie
test
1985 – NB screening
begins in Mississippi
1962 – Massachusetts
launches screening for PKU
1990 – States screen for 5-7 disorders

14. NEWBORN SCREENING OVERSIGHT
• Mandated and regulated at the State level
• The Clinical and Laboratory Standards Institute
(CLSI) has proposed voluntary consensus guidelines
• The Centers for Disease Control (CDC) coordinates
and oversees quality assurance for newborn
screening across the country

15. BLOOD FILTER PAPER SPECIMEN
Courtesy of Harvey L. Levy, MD

16. OBTAINING THE SCREEN
• For well infants – screening after 24 hours
• Some states have more than one screen

17. SCREENING COMPLICATED NEWBORNS
• Proposed consensus guidelines by CLSI
• Testing recommended at admission
• If 1st screen < 24 hours – repeat at 48-72 hours
• If < 34 wk, or <2000 gm - repeat at 28 days or at
discharge
• Hemoglobinopathies, galactosemia, biotinidase pre-
transfusion
• If transferred – sending + receiving nurseries send
specimens

18. REPORTING RESULTS
• Most states use two-tier reporting
• Mild abnormality  request a 2nd screen
• Significant abnormality  call the screening MD,
the PCP, and/or the specialty MD
• States report a Primary Marker and
most states a Secondary Marker as well
• For PKU:
• PHE is the primary marker
• PHE/TYR is the secondary marker

19. NON-METABOLIC DISORDERS
• Endocrine disorders:
• Congenital hypothyroidism
• Congenital adrenal hyperplasia
• Hemoglobinopathies
• Severe combined immunodeficiencies
• Cystic fibrosis
• Critical congenital heart disease
• Hearing

20. METABOLIC DISORDERS
• Enzyme assay:
• Galactosemia
• Biotinidase
• Lysosomal storage diseases
• Metabolite measurement:
• Amino acids
• Organic acids
• Fatty acids

21. METABOLIC DISORDERS
One Test
ORIGINAL
METHODOLOGY
NEWEST
METHODOLOGY
One Disease
One Test
Many Diseases

22. NEWEST METHODOLOGY
• Roe and Millington
apply MS/MS to
metabolic disease
• Naylor applies MS/MS
to newborn screening
• ”Expanded NBS”
permits screening for
>50 diseases from a
single specimen
TANDEM MASS
SPECTROMETRY
Many Diseases

23. ORGANIC ACYL–CoA
FATTY ACYL-CoA
CARNITINE
ORGANIC ACYLCARNITINES
FATTY ACYLCARNITINES
GLYCINE
ORGANIC ACYLGLYCINES
FATTY ACYLGLYCINES

25. Normal
newborn
Newborn
with a
screen
positive
for MCAD
344.2 is C8 acylcarnitine
347.2 is internal standard
260.2 is C6 acylcarnitine

26. SECRETARY’S ADVISORY COMMITTEE ON
HERITABLE DISORDERS IN NEWBORNS AND CHILDREN (SACHDNC)

27. RECOMMENDED UNIFORM SCREENING PANEL - 2018
Propionic acidemia
Methylmalonic acidemia
(MMA, mutase)
MMA (cobalamin A+B)
Isovaleric acidemia
Beta-ketothiolase deficiency
Holocarboxylase synthetase def’y
Glutaric acidemia type I
3-MC carboxylase deficiency
Biotinidase deficiency
HMG CoA lyase deficiency
Amino acid disorders Organic acid disorders
PKU
Homocystinuria
Maple syrup urine disease
Tyrosinemia type I
Citrullinemia type I
Argininosuccinic aciduria
MCAD deficiency
VLCAD deficiency
LCHAD deficiency
Trifunctional protein deficiency
Carnitine uptake defect
Congenital hypothyroidism
Congenital adrenal hyperplasia
Hemoglobinopathies (3)
Cystic fibrosis
Severe combined immunodeficiencies
Spinal muscular atrophy
Critical congenital heart disease
Hearing loss
Other disorders
Fatty acid oxidation
defects
Galactosemia
Pompe disease
Hurler disease (MPS I)
X-linked adrenoleukodystrophy
Other Metabolic disorders

28. RUSP – SECONDARY SCREENING PANEL - 2018
Cobalamin C+D defects
Malonic acidemia
Isobutyrylglycinemia
2-methylbutyrylglycinemia
3-methylglutaconic acidemia
2-methyl-3-OH-butyric acidemia
Arginase deficiency
Citrullinemia type II
Hypermethioninemia
Benign hyperphenylalaninemia
Biopterin/synthesis defects
Biopterin/regeneration defects
Tyrosinemia II
Tyrosinemia III
SCAD deficiency
LCHAD/MCHAD deficiency
MAD deficiency (GA II)
MCKAT deficiency
CE RED deficiency
CPT I deficiency
CPT II deficiency
CACT deficiency
Other hemoglobinopathies Galactokinase deficiency
T cell lymphocyte deficiencies Galactoepimerase deficiency
Other disorders

29. THE ISSUE OF
SCAD DEFICIENCY

30. RUSP EXPANSION
Additions since
2006
Pompe disease
Hurler disease (MPS type I)
X-linked adrenoleukodystrophy
Spinal muscular atrophy (specific type)
Hearing loss
Critical congenital heart disease
Severe combined immunodeficiency

31. 1934 - Folling identifies PKU
1954 – Bickel publishes PKU dietary therapy
1961 – Guthrie
test
1985 – NB screening
begins in Mississippi
1962 – Massachusetts
launches screening for PKU
1990 – States screen for 5-7 disorders
1990s – MS/MS  NBS EXPANSION 2006 -
SACHDNC
RUSP

32. NOT ALL DISEASES ARE APPROVED
RUSP rejections Guanidinoacetate methyltransferase
deficiency (2016)
22q11.2 deletion syndromes (2012)
Hemoglobin H (2010)
Krabbe disease (2009-2010)
Fabry disease (2008)
Neimann-Pick disease (2008)

33. THE ISSUE OF
KRABBE DISEASE

34. THE RUSP AND THE STATES
• The RUSP is not followed in some States
• Remember that each State has the authority to
determine the panel of diseases screened within its
jurisdiction

35. 1934 - Folling identifies PKU
1954 – Bickel publishes PKU dietary therapy
1961 – Guthrie
test
1985 – NB screening
begins in Mississippi
1962 – Massachusetts
launches screening for PKU
1990 – States screen for 5-7 disorders
1990s – MS/MS  NBS EXPANSION 2006 -
SACHDNC
RUSP
2018 – 35 Primary, 27 Secondary disorders on the RUSP

36. MOST COMMON OF THE SCREENED CONDITIONS
Disorder Annual # US Cases
(estimate)
Hearing loss 5,073
Primary congenital hypothyroidism 2,156
Sickle cell disease (includes sickle cell anemia, sickle
C disease and hemoglobin S/Beta thalassemia)
1,775
Cystic fibrosis (includes non-classical) 1,248
Medium-chain acyl-CoA dehydrogenase deficiency 239
Classical galactosemia (includes variant) 224
Phenylketonuria (PKU) 215
Congenital adrenal hyperplasia (CAH) 202

37. THE TRAIN HAS LEFT THE STATION…

38. Do parents have a choice?
38

39. What about informed consent?
39

40. ACUTE NEONATAL PRESENTATIONS
Propionic acidemia
Methylmalonic acidemia
(MMA, mutase)
MMA (cobalamin A+B)
Isovaleric acidemia
Beta-ketothiolase deficiency
Holocarboxylase synthetase def’y
Glutaric acidemia type I
3-MC carboxylase deficiency
Biotinidase deficiency
HMG CoA lyase deficiency
Amino acid disorders Organic acid disorders
PKU
Homocystinuria
Maple syrup urine disease
Tyrosinemia type I
Citrullinemia type I
Argininosuccinic aciduria
MCAD deficiency
VLCAD deficiency
LCHAD deficiency
Trifunctional protein deficiency
Carnitine uptake defect
Congenital hypothyroidism
Congenital adrenal hyperplasia
Hemoglobinopathies (3)
Cystic fibrosis
Severe combined immunodeficiencies
Spinal muscular atrophy
Critical congenital heart disease
Hearing loss
Other disorders
Fatty acid oxidation
defects
Galactosemia
Pompe disease
Hurler disease (MPS I)
X-linked adrenoleukodystrophy
Other Metabolic disorders

41. • “Is the abnormal test really
PKU or something else?”
• “Is the call for a repeat
specimen or an emergency referral?”
• PPV for a repeat specimen is lower than for
an emergency referral
• “Is this a medical emergency?”
• This was a concern when the specimen 
now it’s 2-4 days later!
GETTING A CALL
FROM THE NBS
LABORATORY

42. Remember!
• This is a call about a screen, not
a diagnosis
• The call could concern:
• A metabolic emergency
• A false positive
• An effect from TPN or diet
• Carrier status
GETTING A
METABOLIC CALL
FROM THE NBS LAB

43. NEONATAL CONDITIONS CAN IMPACT THE SCREEN
• TPN can raise the levels of certain amino
acids
• MCT oil/supplementation can show up in the
levels of certain fatty acid acylcarnitines, not
unexpectedly
• Liver disease/dysfunction and other disorders
can impact NBS results too

44. ACTING ON THE CALL
• The American College of Medical
Genetics/Genomics (ACMG) website
• A resource for information about genetic
diseases, genetic testing including NBS
• ACT sheets – information about the disease
• Algorithms for diagnostic evaluation
• www.acmg.net

55. • Discuss the screening results and potential
clinical implications
• Assess the need for a repeat specimen
• Discern disease from diet impact from artifact
• Figure out if and how management should
change
HOW A GENETICIST CAN HELP YOU…

56. RESOURCE FOR INFORMATION ABOUT A DISEASE

57. • We will review several problematic NBS cases
together
• Cases are adapted from real situations, and
intended to be practical and relevant to
primary practice
• The session will be an interactive one
NEXT TIME – NEWBORN SCREENING, PART II

58. 58
Get the Most Out of Your Experience
 Use the Q&A Button to submit questions
during today’s session
 Recording and slides will be sent by email
 For further information, contact WILA@chc1.com