Newborn Screening

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Newborn Screening Powered By Docstoc
					  Expanded Newborn
Public Health Policy and
     Clinical Impact
             Nutrition 526
            October 26, 2011

  Beth Ogata, MS, RD, CSP,
      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

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

Detect disease before
symptoms present

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
Tandem Mass Spectrometer
      MS/MS Methodology
Blood spots punched (3/16th inch disc)
Stable isotope internal standards added
Butyl esters derivatives made
Automatic injection into MS/MS via 96 well
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,
     Acylcarnitine – carnitine (vehicle) + fatty
      acid for identification of organic
      acidurias and fatty acid oxidation
                     MS/MS Plasma Acylcarnitines
                              C8           MCAD        *

                               *            *
              C2   * *   C6        C10:1
                                           Control     *


                               *            *
                   * *

                                                           * 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
NBS mandates are under state control
   Some states screened for 3 diseases, others
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 over-
restriction 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 wide-
spread physical/medical harm
BUT the cases do underscore need for
expertise and resources for management
         Amino Acid Disorders
AA that are not used to            PKU: severe, permanent ID
make proteins are                  MSUD: ID, hallucinations,
recycled by their specific         ataxia
metabolic pathways.                HCY: connective tissue
                                   damage (joints, heart), ID,
   Enzymatic deficiencies in      psychiatric disturbances
    these pathways lead to
    various clinical phenotypes.   CIT: risk of hyperammonemia
                                    ID, coma, death
Diagnosed by plasma                ASA: brittle hair, liver disease
amino acids, urine amino           ID
acids, and/or urine                TYR I: acute or chronic liver
organic acids (takes 2-5           disease, liver cancer,
days)                              neurologic pain crises
       Organic Acid Disorders
Organic acids are              IVA: Isovaleric acidemia
breakdown products of          GA I: Glutaric acidemia type I
protein and fatty acid         HMG: 3-OH 3-CH3 glutaric
metabolism. Defects in         aciduria
their breakdown lead to        MCD: Multiple carboxylase
(generally):                   deficiency
   Vomiting, metabolic        MUT: Methylmalonic acidemia
    acidosis, elevated         (mutase deficiency)
    ammonia in crises          3MCC: 3-Methylcrotonyl-CoA
   ID, motor delay, ataxia,   carboxylase deficiency
    cardiac/renal/pancreatic   Cbl A,B: Methylmalonic
    problems                   acidemia
Diagnosed by urine             PROP: Propionic acidemia
organic acids and/or           BKT: Beta-ketothiolase
plasma acylcarnitines
          Fatty Acid Disorders
Fatty acid disorders lead    MCAD: Medium-chain
to impaired energy           acyl-CoA dehydrogenase
production                   deficiency
   Hypoglycemia,            VLCAD: Very long-chain
    cardiomyopathy, muscle   acyl-CoA dehydrogenase
    weakness can be seen
Diagnosed by plasma
acylcarnitines, and urine    LCHAD: Long-chain L-3-
organic acids can be         OH acyl-CoA
helpful                      dehydrogenase
                             TFP: Trifunctional protein
                             CUD: Carnitine uptake
           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
     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
     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
  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       MCAD      PKU      Hb SS              CH
GA I      VLCAD     MSUD     Hb S/ßTh           BIOT
HMG       LCHAD     HCY      Hb S/C             CAH
MCD       TFP       CIT                         GALT
MUT       CUD       ASA                         HEAR
3MCC                TYR I                       CF
Cbl A,B
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
13 months old, healthy
Normal pregnancy and delivery
Normal eating pattern, no allergies or
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
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
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)
Disorder of long chain fatty acid
C14, C14:1 C16, C18
Normal beta oxidation occurs in
                 Fatty Acid Oxidation
        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
Acylcarnitine ordered
DNA sequencing of ACADVL gene
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
Family seen in clinic, started on treatment
        Zach – Clinical Picture
5 yo
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
Once on carnitine, AC profile was classic for VLCAD
 Components of Newborn Screening
   hospital partnerships
   State Lab
   to health care provider
   to specialty care provider
Short term follow-up
   diagnosis
Long term follow-up
   ongoing treatment & monitoring
Washington State                    Birth

Newborn Screening                   Day 1
                                 First Screen

             NL                      +                           ++
                                             Primary                        Primary Care
                                             Doctor                         Doctor/ Biochem
                    2nd Sample                                              ASAP

             NL                                                   TX
                                                Primary Care
                                                               Long term
                                                               Follow up

                                                               •Systematic process

                                 Long term
                                 Follow up
Effective NBS requires a
close working relationship
between hospitals,
newborn screening
program, and follow-up

Supporting understanding for
Nutrition Involvement in NBS
Example: infant with galactosemia
Symptoms in newborn, if
    Vomiting, diarrhea
    Hyperbilirubinemia, hepatic
     dysfunction, hepatomegaly
    Renal tubular dysfunction
    Cataracts
    Encephalopathy
    E. coli septicemia result
    Death within 6 weeks, if
    Duarte variant
    galactokinase deficiency
    uridine diphosphate-          Galactose-1-phosphate uridyl transferase
     galactose-4-epimerase         (GALT) deficiency
 Example: infant with galactosemia
Treatment: eliminate all galactose from diet
  Primary source is milk      Food labels
  (lactose= galactose +           milk, casein, milk solids,
                                   lactose, whey, hydrolyzed
  glucose)                         protein, lactalbumin,
  Secondary sources are            lactostearin, caseinate
  legumes                     Medications (lactose is often
                              an inactive ingredient)
  Minor? sources are fruits
  and vegetables              Dietary supplements
                              Artificial sweeteners

Monitoring: galactose-1-phosphate levels <3-4 mg/dl
   Example: Infant with galactosemia
POLICY                             CLINICAL MANAGEMENT
RD participated on                 RD provides nutrition care
State Advisory                     as member of the
Board to select                    Biochemical Genetics Team:
                                       •Initiation of formula
galactosemia                           •Guidelines for monitoring
                                       •Plans for follow-up
DIAGNOSIS &                        RD as case manager
“Presumptive positive” 
RD in contact with family
and local providers to         RD at local health department
discuss appropriate feeding    provides ongoing education to
practices and arrange clinic   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
   Phenylalanine hydroxylase
   Dihydropteridine reductase
   Biopterin synthetase
Establish diagnosis
   Presumptive positive
    NBS results
       > 3 mg/dL, >24 hrs of
   Differential diagnosis
        serum phe, nl tyr
       r/o DHPR, biopterin
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
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
    Clinical Management: PKU

Goals of Nutrition Therapy
 Normal growth rate
 Normal physical
 Normal cognitive
 Normal nutritional status
        Clinical Management: PKU
   Correct substrate                  Supply product of
   imbalance                          reaction
       Restrict phenylalanine            Supplement tyrosine
        intake to normalize                to maintain normal
        plasma concentration               plasma tyrosine levels

Phenylalanine -------------------//----------------------- Tyrosine
(substrate)           phenylalanine hydroxylase            (product)
    Phe Levels from NBS to Tx

                                           Equilibrium achieved by
Diagnostic levels
                                           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
   80-90% energy intake
   85-90% 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                          Tasks for Children and Parents
              0-6 months       Parents learn about and adjust to PKU
              6 months         Start low-protein solid foods
              6-7 months       Introduce cup
              8-9 months       Introduce finger foods
              10-15 months     Consider weaning from bottle (discuss transition with clinic staff)
              2-3 years        Learn the concept of “formula first”
                               Learn to distinguish “yes” and “no” foods
              4-5 years        Begin to learn to count foods – “how many”
                               Begin to use scale – “how much”
   PKU        5-6 years        Assist in formula preparation
                               Teach children how to deal with other children’s curiosity about PKU
Management    7-10 years       Prepare formula with decreasing supervision
                               Choose after school snack
 Guidelines                    Learn to pack school lunch
                               Begin to list foods on food record
                               Begin weighing food regularly on scale
              10-12 years      Begin to prepare and consume formula independently each day (with
   Self-                            parental monitoring)
                               Prepare simple entrees independently
management                     Know what blood levels are ideal
              13-14 years      Increasing self-monitoring (with continued parent support) in formula
   Skills                           preparation and consumption
                               Independently manage total phenylalanine intake for the day
                               Learn menu planning
                               Responsible for food records
              15-17 years      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
              18 years         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
To maintain metabolic
balance while providing
adequate nutrients and
energy for normal
physical and intellectual
Maternal PKU Concerns/Outcomes
 Women with PKU are at high risk for delivering a
 damaged infant
    Placenta concentrates phe 2-4x
       Cardiac problems
 Infant IQ directly related to maternal blood phe
 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,   Developmental monitoring, intervention
PT, SLP, etc.)
    NBS and the Community:
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

   What additional information
   do you need?
   What would you do?
NBS is the first part of a process
of care that requires strong
partnerships for optimal
NBS outcomes are only as good
as the follow-up provided
Families should have access to
the best treatment and care for
their child
Specific diagnosis must be confirmed
   in coordination with the state Newborn Screening
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
   National Newborn Screening and Genetics Resource Center
   Star G-Screening, Technology, and Research in Genetics

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

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