1. Expanded Newborn Screening: Public Health Policy and Clinical Impact
Nutrition 526
October 18, 2010
Beth Ogata, MS, RD, CSP,
Cristine M Trahms, MS, RD, FADA

2. 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 hours of life regardless of feeding status or weight
Blood Sample on Guthrie Filter Paper Card

3. 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

4. Why do newborn screening?
Screen a presumably healthy newborn population
Detect disease before symptoms present clinically
Goal: Prevent or reduce morbidity and mortality

5. 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

6. 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

7. Tandem Mass Spectrometer (MS/MS)

8. 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

9. 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

10. MS/MS Plasma Acylcarnitines
Intensity
100% *
MCAD C2
C16 C8
C10:1 C6 *
100%
Control C2
Intensity
* internal standards

11. MS/MS Plasma Amino Acids

12. 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

13. 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

18. 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

19. 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

20. 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

21. 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-3-OH acyl-CoA dehydrogenase deficiency
TFP: Trifunctional protein deficiency
CUD: Carnitine uptake defect

22. Who is identified? Patients who need active management
Symptomatic at diagnosis
Strong evidence of pathology if untreated
Examples: PKU, classic galactosemia, MSUD, PROP, etc.

23. Who is identified?
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

24. Who is identified? 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

25. 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

26. 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

27. How many infants does NBS identify?
2006
2007
Infants Diagnosed 2 1
Biotinidase deficiency 5
Congenital adrenal hypoplasia (CAH) 45
Congenital hypothyroidism (CH) 12 14
Cystic fibrosis 6
Galactosemia
Homocystinuria
Maple syrup urine disease 3
Medium chain acyl coA dehydrogenase (MCAD) def. 7
Phenylketonuria (PKU) 13 23
Sickle cell and other HG 95
112
TOTAL

28. 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

29. 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

30. 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)

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

32. Fatty Acid Oxidation

33. 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

34. 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

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

36. Emma’s Family Family referred to genetics by coroner
Parents requested testing for older brother (Zach)
Acylcarnitine ordered
DNA sequencing of ACADVL gene ordered

37. Acylcarnitine – Zach (5 yo)
C16:1- nl
C14 
C16 - nl

38. 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

39. 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

40. 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

41. Washington State Newborn Screening + ++ Birth NL DX TX
Day 1 First Screen + NL ++ DX TX
Long term Follow up
2nd Sample
Primary Care Doctor/ Biochem Clinic
ASAP
Timely/urgent
Systematic process
Primary Doctor
Primary Care Doctor
Biochem Clinic

42. Effective NBS requires a close working relationship between hospitals, newborn screening program, and follow-up program
Informed Consent

43. Supporting understanding for families

44. Nutrition Involvement in NBS
Policy
Diagnostic/coordination
Clinical
Community

45. 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-galactose-4-epimerase deficiency
Galactose-1-phosphate uridyl transferase (GALT) deficiency

46. 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

47. Example: Infant with galactosemia
POLICY
RD participated on State Advisory Board to select disorders, including galactosemia
CLINICAL MANAGEMENT
RD provides nutrition care as member of the Biochemical Genetics Team:
Initiation of formula
Guidelines for monitoring intake
Plans for follow-up
RD as case manager
DIAGNOSIS & COOORDINATION
“Presumptive positive”  RD in contact with family and local providers to discuss appropriate feeding practices and arrange clinic appointment
COMMUNITY
RD at local health department provides ongoing education to family, local care providers

48. 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

49. 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

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

51. 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

52. Clinical Management: PKU
Goals of Nutrition Therapy
Normal growth rate
Normal physical development
Normal cognitive development
Normal nutritional status

53. 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)

54. Phe Levels from NBS to Tx
Equilibrium achieved by
14 days of age
Diagnostic levels
Blood levels every 2 days
because of rapid growth

55. 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

56. 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

57. Food Choices for PKU

58. Effect of a single amino acid deficiency on growth

59. Effective Blood Level Management in Childhood
Blood levels once per month, or more frequently if needed for good management

60. PKU Management Guidelines Self-management Skills

61. Goal of Lifetime Management of PKU
To maintain metabolic balance while providing adequate nutrients and energy for normal physical and intellectual growth

62. 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

63. 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.

64. 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.

65. 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

66. 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

67. 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?

68. 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?

69. 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?

70. 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

71. 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

72. 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.

73. Why do we do newborn screening?
So Super Girl can be whoever she wants to be….