Expanded Newborn

Screening:
Public Health
Policy
and
Nutrition 526
October 18,
2010
Clinical
Impact
Beth Ogata, MS, RD, CSP, bogata@uw.edu
Cristine M Trahms, MS, RD, FADA

Newborn Screening
A state mandated public health program
that begins with a heel poke for every
baby before hospital discharge
First screen must be taken 24-48 hours
of life regardless of feeding status or
weight

Blood Sample on Guthrie Filter Paper Car

Who is screened?
Washington State law requires that every
newborn be tested prior to discharge from
the hospital or within five days of age
Second screen strongly recommended
between 7 and 14 days of age)
Third screen recommended for sick and
premature infants

Why do newborn screening?

Screen a presumably
healthy newborn
population
Detect disease before
symptoms present
clinically
Goal: Prevent or reduce
morbidity and mortality

Criteria for Newborn Screening

Important condition
Acceptable treatment available
Facilities for diagnosis and treatment
Difficult to recognize early
Suitable screening test
Natural history known
Cost-effective to diagnose and treat
Wilson & Jungner, 1968

Tandem Mass Spectrometry (MS/MS)

High Impact and High Throughput
One disease, one test is not cost-effective
Many diseases, one test is cost-effective
MS/MS allows for rapid, simultaneous
analysis and detection of many disorders
of amino acid, organic acid, and fatty acid
metabolism

Tandem Mass Spectrometer

(MS/MS)

MS/MS Methodology
Blood spots punched (3/16th inch disc)
Stable isotope internal standards added
(deuterated)
Butyl esters derivatives made
Automatic injection into MS/MS via 96 well
plates
Sample set up determines which masses and
therefore which compounds are detected
2 minute analysis time
Automated data processing for results

MS/MS Methodology continued

Compounds analyzed are amino acids
and acylcarnitines

Amino acids to identify PKU, MSUD,

homocystinuria
Acylcarnitine carnitine (vehicle) + fatty
acid for identification of organic
acidurias and fatty acid oxidation
disorders

MS/MS Plasma Acylcarnitines

*

+
P
re
c(8
5
.1
0
): 0
.4
0
1to1
.2
0
2m
infro
mS
a
m
p
le8(P
A
T
E
)o
fA
C1
0
1
0
0
3D
A
T
A
.w
iff (T
u
rb
oS
p
ra
y
)
1
0
0
%

100%
9
5
%
9
0
%
8
5
%
8
0
%
7
5
%

MCAD

C8

M
a
x
.3
.8
e
4c
p
s
.

7
0
%
6
5
%
6
0
%
5
5
%

Intensity

5
0
%
4
5
%
4
0
%
3
5
%
3
0
%
2
5
%

C2

* *

C6

2
0
%

C10:1

*
C16

1
5
%
1
0
%
5
%
2
6
0

2
8
0

3
0
0

3
2
0

3
4
0

3
6
0

3
8
0
m
/z
,a
m
u

4
0
0

4
2
0

4
4
0

1
0
0
%

100%
9
5
%
9
0
%
8
5
%
8
0
%
7
5
%

Control

4
6
0

+
P
re
c(8
5
.1
0
): 0
.4
0
1to1
.2
0
2m
infro
mS
a
m
p
le9(B
A
D
E
R
)o
fA
C1
0
1
0
0
3D
A
T
A
.w
iff (T
u
rb
oS
p
ra
y
...

4
8
0

5
0
0

M
a
x
.3
.5
e
4c
p
s
.

7
0
%
6
5
%
6
0
%
5
5
%

Intensity

5
0
%
4
5
%
4
0
%

C2

3
5
%
3
0
%
2
5
%

* *

2
0
%
1
5
%
1
0
%
5
%
2
6
0

2
8
0

3
0
0

3
2
0

3
4
0

3
6
0

3
8
0
m
/z
,a
m
u

4
0
0

4
2
0

4
4
0

4
6
0

4
8
0

5
0
0

* internal standards

MS/MS Plasma Amino Acids

What is the scope of newborn screening?

Screen ~80,000 newborns

Receive ~160,000 specimens

Track ~3000 infants with abnormal results

Prevent ~140 babies from death or disability

For example: In WA State

Which disorders should be

identified?
NBS mandates are under state control

Some states screened for 3 diseases, others

40+

2002 Maternal and Child Health Bureau

commissioned ACMG

Analyze literature
Develop consensus on which disorders
Recommend a core panel to create uniform
NBS across all states

Historical Harm (?)

Early PKU screening led to cases of overrestriction and/or implementation of diet
prior to confirmation of diagnosis

Today, diagnosis is quite rapid

40 years ago, it took much longer so more
potential for harm

However, no published evidence of widespread physical/medical harm

BUT the cases do underscore need for
expertise and resources for management

Amino Acid Disorders

AA that are not used to
make proteins are
recycled by their specific
metabolic pathways.

Enzymatic deficiencies in
these pathways lead to
various clinical phenotypes.

Diagnosed by plasma
amino acids, urine amino
acids, and/or urine
organic acids (takes 2-5
days)

PKU: severe, permanent ID

MSUD: ID, hallucinations,
ataxia
HCY: connective tissue
damage (joints, heart), ID,
psychiatric disturbances
CIT: risk of hyperammonemia
ID, coma, death
ASA: brittle hair, liver disease
ID
TYR I: acute or chronic liver
disease, liver cancer,
neurologic pain crises

Organic Acid Disorders

Organic acids are
breakdown products of
protein and fatty acid
metabolism. Defects in
their breakdown lead to
(generally):

Vomiting, metabolic
acidosis, elevated
ammonia in crises
ID, motor delay, ataxia,
cardiac/renal/pancreatic
problems

Diagnosed by urine
organic acids and/or
plasma acylcarnitines

IVA: Isovaleric acidemia

GA I: Glutaric acidemia type I
HMG: 3-OH 3-CH3 glutaric
aciduria
MCD: Multiple carboxylase
deficiency
MUT: Methylmalonic acidemia
(mutase deficiency)
3MCC: 3-Methylcrotonyl-CoA
carboxylase deficiency
Cbl A,B: Methylmalonic
acidemia
PROP: Propionic acidemia
BKT: Beta-ketothiolase
deficiency

Fatty Acid Disorders

Fatty acid disorders lead
to impaired energy
production

Hypoglycemia,
cardiomyopathy, muscle
weakness can be seen

Diagnosed by plasma
acylcarnitines, and urine
organic acids can be
helpful

MCAD: Medium-chain
acyl-CoA dehydrogenase
deficiency
VLCAD: Very long-chain
acyl-CoA dehydrogenase
deficiency
LCHAD: Long-chain L-3OH acyl-CoA
dehydrogenase deficiency
TFP: Trifunctional protein
deficiency
CUD: Carnitine uptake
defect

Who is identified?
1. Patients who need active management

Symptomatic at diagnosis
Strong evidence of pathology if untreated
Examples: PKU, classic galactosemia,
MSUD, PROP, etc.

Who is identified?
2. Patients with disorders known to pose
risk but reduced penetrance

i.e., probably not everyone needs to be

treated
HPHE, MCAD
Both are/have mild ends of the spectrum
that have only been identified through NBS
MCAD mutation c.199 C>T
Never seen in patients picked up clinically

Who is identified?
3. Patients who may not need any
management

Disorders considered extremely rare but

seen in large numbers via NBS programs
Reported cases have significant morbidity
NBS pickups are mostly mild
3MCC, SCAD

Biochemical phenotype

Proceeding with Caution

(Reasons to be Thoughtful)
Proceeding with caution Not screening
Core diseases vs. secondary targets /
unintended targets

What is reported vs. withheld?

Will we pick up untreatable conditions?
What is the impact of false positives on families?

No long-term outcome data consider research

paradigm
Consider infrastructure needed for follow-up

What are we screening for?

9 OA

5 FAO

6 AA

3 Hb Pathies

6 Others

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

Hb SS
Hb S/Th
Hb S/C

CH
BIOT
CAH
GALT
HEAR
CF

How many infants does NBS identify?

2006

2007 Infants Diagnosed

1 Biotinidase deficiency

5 Congenital adrenal hypoplasia (CAH)

45

45 Congenital hypothyroidism (CH)

12

14 Cystic fibrosis

0 Galactosemia

0 Homocystinuria

0 Maple syrup urine disease

6 Medium chain acyl coA dehydrogenase (MCAD) def.

7 Phenylketonuria (PKU)

13

23 Sickle cell and other HG

95

112 TOTAL

Emma
13 months old, healthy
Normal pregnancy and delivery
Normal eating pattern, no allergies or
intolerances
Feb 2008:

Vomited 4-5 times throughout the weekend

No fever
Sleeping for extended periods parents concerned,
but previous fever had same pattern
Parents gave Pedialyte

Emma
4 yo brother, parents sick on
Sunday/Monday; same symptoms
Monday night 9:30 checked on Emma

Raspy breathing thought respiratory

problem but not worried

Tuesday morning 11 am she was found

motionless in her crib and pronounced
dead at the scene

Emma
Autopsy revealed fatty changes to liver
Coroner requested newborn screening
blood spot be sent for acylcarnitine profile
Diagnostic for very long chain acyl-co A
dehydrogenase deficiency (VLCAD)

VLCAD
Disorder of long chain fatty acid
breakdown
C14, C14:1 C16, C18
Normal beta oxidation occurs in
mitochondria

Fatty Acid Oxidation

http://www.genomeknowledge.org/figures/saturatedbetao.jpg

VLCAD Presentations
Hypertrophic cardiomyopathy, with
hypoglycemia and skeletal myopathy, lethargy,
failure to thrive

Usually present birth to 5 months

Hypoglycemia, hepatomegaly, muscle weakness

without cardiac manifestations

Late infancy older childhood

Muscle weakness/pain, rhabdomyolysis with

exercise or illness. No hypoglycemia or cardiac

Teens to adulthood

VLCAD Treatment
Diet low in long-chain fats (Portagen,
Monogen = 87%, 90% of fats as MCT)
Additional medium chain fats (MCT oil,
walnut oil)
Carnitine 100 mg/kg/day
Avoidance of fasting
Treating illness with IV glucose support

VLCAD Diagnosis
Newborn screening
Plasma acylcarnitine profile
Urine organic acids (should be normal)
DNA sequencing

Emmas Family
Family referred to genetics by coroner
Parents requested testing for older brother
(Zach)
Acylcarnitine ordered
DNA sequencing of ACADVL gene
ordered

Acylcarnitine Zach (5 yo)

C14:1
C14

C16 - nl
C16:1- nl

Zach Testing
Reported: mild elevation of C14 and C14:1
with low free carnitine. VLCAD cannot be
ruled out
Recommend supplementing with carnitine
and retest in 1 week
DNA testing results back before AC
repeat: Zachs DNA testing reveals he is
affected
Family seen in clinic, started on treatment

Zach Clinical Picture

5 yo
Healthy
No symptoms of muscle weakness

CPK = 315U/L (35-230)

No hepatomegaly

AST= 49 (5-41)
ALT= 23
Bilirubin conj, unconj = normal (0.0, 0.4)

No evidence of cardiac involvement

Has had several viral illnesses in his lifetime without
difficulty
Once on carnitine, AC profile was classic for VLCAD

Components of Newborn Screening

Sampling

hospital partnerships

Screening

State Lab

Reporting

to health care provider

Referral

to specialty care provider

Short term follow-up

diagnosis

Long term follow-up

ongoing treatment & monitoring

Washington State
Newborn Screening

Birth
Day 1
First Screen

NL

++
Primary
Doctor

2nd Sample

NL

DX

TX

DX

Primary Care
Doctor/ Biochem
Clinic
ASAP

Primary
Care
Doctor
Biochem
Clinic

Long term
Follow up

Timely/urgent
Systematic process

TX

Long term
Follow up

Effective NBS requires a

close working relationship
between hospitals,
newborn screening
program, and follow-up
program

Informed
Consent

Supporting understanding for

families

Nutrition Involvement in NBS

Policy
Diagnostic/coordination
Clinical
Community

Example: infant with galactosemia

Symptoms in newborn, if
untreated

Vomiting, diarrhea
Hyperbilirubinemia, hepatic
dysfunction, hepatomegaly
Renal tubular dysfunction
Cataracts
Encephalopathy
E. coli septicemia result
Death within 6 weeks, if
untreated

Also

Duarte variant
galactokinase deficiency
uridine diphosphate-galactose4-epimerase deficiency
Galactose-1-phosphate uridyl transferase
(GALT) deficiency

Example: infant with galactosemia

Treatment: eliminate all galactose from diet
Primary source is milk
(lactose= galactose +
glucose)
Secondary sources are
legumes
Minor? sources are fruits
and vegetables

Food labels

milk, casein, milk solids,

lactose, whey, hydrolyzed
protein, lactalbumin,
lactostearin, caseinate

Medications (lactose is often

an inactive ingredient)

Dietary supplements
Artificial sweeteners

Monitoring: galactose-1-phosphate levels <3-4 mg/dl

Example: Infant with galactosemia

POLICY

CLINICAL MANAGEMENT

RD participated on
State Advisory
Board to select
disorders,
including
galactosemia

RD provides nutrition care

as member of the
Biochemical Genetics Team:
Initiation of formula
Guidelines for monitoring
intake
Plans for follow-up

DIAGNOSIS &
COOORDINATION
Presumptive positive
RD in contact with family
and local providers to
discuss appropriate feeding
practices and arrange clinic
appointment

RD as case manager
COMMUNITY
RD at local health department
provides ongoing education to
family, local care providers

Nutrition and NBS: Policy

Screening process (disorders, procedures)
RD participated in Advisory Board meetings, providing input about
nutrition-related treatment

Services and reimbursement

Nutrition consultant to state CSHCN Program
RD provides input about relevant state Medicaid policies

Training and education

RD provides information about management of metabolic disorders
to local WIC agencies

Nutrition and NBS: Clinical

Management PKU
Phenylketonuria

Phenylalanine hydroxylase
Dihydropteridine reductase
Biopterin synthetase

Establish diagnosis

Presumptive positive
NBS results
> 3 mg/dL, >24 hrs of age

Differential diagnosis
serum phe, nl tyr
r/o DHPR, biopterin
defects

Current Treatment Guidelines

With effective NBS, children are identified
by 7 days of age
Initiate treatment immediately
Maintain phe levels 1-6 mg/dl (60-360
umol/L)
Lifelong treatment

Outcome Expectations
With NBS and blood
phenylalanine levels
consistently in the
treatment range

Normal IQ and physical

growth are expected

With delayed diagnosis or

consistently elevated
blood levels

IQ is diminished and
physical growth is
compromised

Clinical Management: PKU

Goals of Nutrition Therapy
Normal growth rate
Normal physical
development
Normal cognitive
development
Normal nutritional status

Clinical Management: PKU

Correct substrate
imbalance

Restrict phenylalanine
intake to normalize
plasma concentration

Supply product of
reaction

Supplement tyrosine
to maintain normal
plasma tyrosine levels

Phenylalanine -------------------//----------------------- Tyrosine

(substrate)

phenylalanine hydroxylase

(product)

Phe Levels from NBS to Tx

Diagnostic levels

Equilibrium
achieved by
14 days of age

Blood levels every 2

days
because of rapid growth

Adjustments necessary to maintain

safe blood phe levels
Usual intake of phe

Newborn on formula
20 oz x 22 mg phe/oz = 440 mg phe

1 yo child on regular diet

30 g protein = 1500 mg phe (DRI = 13.5 g)

7 yo child on regular diet

50 g protein = 2500 mg phe (DRI = 19 g)

Phenylalanine requirement

250 mg/d

Management Tools
Specialized formula
provides

80-90% energy intake

89-90% protein intake
tyrosine supplements
no phenylalanine

Phenylalanine to meet
requirement from infant
formula or foods

Food Choices for PKU

Effect of a single amino acid

deficiency on growth

Effective Blood Level Management

in Childhood

Blood levels once per month, or more frequently if needed for good management

PKU
Management
Guidelines
Selfmanagement
Skills

Goal of Lifetime Management of

PKU
To maintain metabolic
balance while providing
adequate nutrients and
energy for normal
physical and intellectual
growth

Maternal PKU Concerns/Outcomes

Women with PKU are at high risk for delivering a
damaged infant

Placenta concentrates phe 2-4x

Microcephaly
Cardiac problems

Infant IQ directly related to maternal blood phe

level
Outcome improved with maternal blood phe <2
mg/dl prior to conception and during pregnancy

Nutrition and NBS: Community

PHN and interpreter make
monthly visits to family of
young child with MSUD.
Through pre-arranged
phone calls, we can discuss
formula composition and
preparation, and solid foods.
This helps provide
information between regular
clinic visits.

Nutrition and NBS: Community

A woman with PKU is enrolled in the First Steps
program (WA State MSS).
The RD with PKU Clinic provides consultation to
the First Steps RD, about management of amino
acid levels.

Metabolic Team
Child

Age-appropriate self-management skills

Parents

Monitoring health status, teaching, advocacy

Nutritionist

Nutrition therapy, feeding skills

Geneticist

Medical monitoring

Social Worker

Family support, counseling

Lab

Laboratory monitoring

Medical Home

Well child care, family support

Psychologist

Developmental monitoring, counseling

PHN, others

Family support in community

School

Educational programs, treatment monitoring

Community

Support of family and friends

Therapists (OT,
PT, SLP, etc.)

Developmental monitoring, intervention

NBS and the Community:

Challenges
Understand the implications of the results
of newborn screening tests
Develop a communication system
between the community providers and the
metabolic team for support of treatment
Interact with PCPs and families as
needed, to support appropriate MNT

NBS and the Community:

What you need to know
Which disorders are identified by NBS in your
state? Where do you find this information?
What is the difference between screening and
diagnostic results?
What is the system for follow-up of presumptive
positive NBS results?
How do you make referrals to regional genetics
clinics and specialty care clinics?

Scenes from the Annals of Reporting

and Acting on NBS Results
A primary care physician telephones are reports
there is a new baby with PKU and asks that you
please start the infant on formula ASAP.

What additional information do

you need?
What would you do?

Scenes from the Annals of Reporting

and Acting on NBS Results
You are on-call for the weekend for your local
hospital and you receive an order from the
newborn nursery on an infant with presumptive
galactosemia and a request for the initiation of
treatment.
What additional information
do you need?
What would you do?

Summary
NBS is the first part of a process
of care that requires strong
partnerships for optimal
outcomes
NBS outcomes are only as good
as the follow-up provided
Families should have access to
the best treatment and care for
their child

Summary
Specific diagnosis must be confirmed

in coordination with the state Newborn Screening

Program

Careful monitoring of medical and nutritional

status must be on-going

by the metabolic team

Nutritional intervention

must be specific to the disorder

specific to the child

Additional Information
Washington State Newborn Screening http://
www.doh.wa.gov/ehsph/phl/newborn/default.htm
National Newborn Screening and Genetics Resource Center
http://genes-r-us.uthscsa.edu
Star G-Screening, Technology, and Research in Genetics
http://newbornscreening.info
Building Block for Life (PNPG)

Expanded NBS 27(1)

Genetics and Expanded NBS 30(3)

Nutrition Focus

Overview nutr assessment of children with metabolic disorders 24(5)

Genetics 22(6)

Journal of Developmental and Behavioral Pediatrics

Levy PA. An overview of newborn screening. 2010;31(7):622.

Why do we do newborn screening?

So Super Girl can be

whoever she wants to
be.