Transcript Newborn Screening

Expanded Newborn
Screening:
Public Health Policy and
Clinical Impact
Nutrition 526
October 18, 2010
Beth Ogata, MS, RD, CSP, [email protected]
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 Card
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
100%
C8
Intensity
*
C2
MCAD
* *
C6
*
C10:1
*
*
C16
100%
Control
Intensity
*
C2
* *
*
*
*
* 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/ßTh
Hb S/C
CH
BIOT
CAH
GALT
HEAR
CF
How many infants does NBS identify?
2006
2007 Infants Diagnosed
2
1 Biotinidase deficiency
5
5 Congenital adrenal hypoplasia (CAH)
45
45 Congenital hypothyroidism (CH)
12
14 Cystic fibrosis
6
0 Galactosemia
1
0 Homocystinuria
0
0 Maple syrup urine disease
3
6 Medium chain acyl coA dehydrogenase (MCAD) def.
7
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
4½ 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
Emma’s 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: Zach’s 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
Primary Care
Doctor/ Biochem
Clinic
ASAP
2nd Sample
DX
NL
TX
+
Primary Care
Doctor
Biochem
Clinic
Long term
Follow up
DX
•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 diphosphategalactose-4-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
Blood levels every 2 days
because of rapid growth
Equilibrium achieved by
14 days of age
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
Age of Child
0-6 months
6 months
6-7 months
8-9 months
10-15 months
2-3 years
4-5 years
PKU
Management
Guidelines
Selfmanagement
Skills
5-6 years
7-10 years
10-12 years
13-14 years
15-17 years
18 years
Tasks for Children and Parents
Parents learn about and adjust to PKU
Start low-protein solid foods
Introduce cup
Introduce finger foods
Consider weaning from bottle (discuss transition with clinic staff)
Learn the concept of “formula first”
Learn to distinguish “yes” and “no” foods
Begin to learn to count foods – “how many”
Begin to use scale – “how much”
Assist in formula preparation
Teach children how to deal with other children’s curiosity about PKU
Prepare formula with decreasing supervision
Choose after school snack
Learn to pack school lunch
Begin to list foods on food record
Begin weighing food regularly on scale
Begin to prepare and consume formula independently each day (with
parental monitoring)
Prepare simple entrees independently
Know what blood levels are ideal
Increasing self-monitoring (with continued parent support) in formula
preparation and consumption
Independently manage total phenylalanine intake for the day
Learn menu planning
Responsible for food records
Responsible for all aspects of self-management
Able to do ‘finger poke’ for blood test
Able to explain basics of PKU – “What is it?”
Responsible for remembering recent blood levels
Continued parent support
Transition to adult-based clinic care
Ready to live independently, including:
-formula preparation and consumption
-food preparation and records
-monthly serum phenylalanine levels
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….