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The Newborn Screening System. Sheila Weiss, MS, LCGC [email protected]. What is Newborn Screening?. A mandatory public health program designed “to detect, in newborns, congenital disorders leading to developmental impairments or physical disabilities”. - PowerPoint PPT Presentation
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What is Newborn Screening?
A mandatory public health program designed
“to detect, in newborns, congenital disorders leading to
developmental impairments or physical
disabilities”
Why is it Important?
It prevents death and disability to affected infants by providing early treatment
It benefits the public through savings in health care costs and institutional care
Two 6 year old girls with congenital hypothyroidism
WA’s Criteria for Screening
Early identification benefits the newborn
Treatment is available
Nature of the condition justifies population-based screening
A good screening test exists
The benefits justify the costs of screening
A Complete System Includes
Universal screening - all infants
“Appropriate” follow-up response
Diagnosis of affected infants
Appropriate treatment & clinical care
Evaluation of system effectiveness
The Newborn Screening Process
http://www.europaediatrics2008.org http://www2.aap.org
http://www.cdc.gov/ncbddd/jaundice/families
NBS Sequence of Events
recommended window for 1st NBS specimen collection
hospital – blood collection
transit time
NBS lab testing
follow-up
Birth 1Time (days)
2 3 4 5 6 7
When to Screen
Washington State law requires that every newborn be tested “prior to discharge from the hospital or within five days of age”
1st screen should be taken between 18 & 48 hours of life regardless of feeding status (earlier if therapies are administered)
2nd screen strongly recommended between 7 & 14 days of age
Third screen recommended for sick and premature infants at 1 month
Benefits of Repeat Screens
• Maximizes detection of all disorders, particularly milder forms that may benefit from treatment
• May be necessary for detection of some conditions, and is critical for assessment of cystic fibrosis
• Verifies hemoglobin traits, eliminating need for diagnostic lab work
Screening Compliance
Some statistics …
>99.95% of “eligible” infants receive screening (excludes refusals & neonatal deaths)
~94% of infants receive the recommended 2nd screen
~75% of sick & premature receive the recommended 3rd screen
Newborn Screening in WA
~85,000 newborns are screened each year
~170,000 specimens processed
~5,500 results requiring follow-up
170 - 200 true positives
2011 = 188 affected infants prevalence: 1 in 452!
~2,100 false positives
Father of Newborn Screening
“Robert Guthrie, MD, Ph.D. was an American microbiologist,
best known for developing the bacterial inhibition assay used
to screen infants for phenylketonuria at birth, before the development of irreversible
neurological damage.”
Wikipedia
Technology that Enables Expansion
Tandem Mass Spectrometer - MS/MS
MS/MS Plasma Amino Acids
Biotinidase Screening
Hemoglobin Screening
FAE
AE control
FAC
AFSC control
FA normal
Normal Affected
13.0 μM2.12 μM.78 μM 101 μM
100% specificity 100% sensitivity
Screening Results
what we would like …
Screening Results
Normal Affected
200 μM 35 μM 745 μM
Specificity vs. Sensitivity
what we usually get …
Abnormal Screening Results
Response is dependent on disorder, magnitude of result, & demographics of infant
(presumptive, borderline, inconclusive)
Stratifying ResultsCategorization of C3 Cutoffs
Age ≤ 6 days Age > 6 daysC3
mmol/L serum
not all 2° markers* elevated
all 2° markers* elevated
not all 2° markers* elevated
all 2° markers* elevated
< 4.1 normal normal normal normal
4.1 – 4.89 normal normal borderlinea Presumptivec
4.9 – 6.09 normal borderlineb borderlinea Presumptivec
6.1 – 8.39 borderlinea Presumptive c borderlinea Presumptive c
8.4 – 11.99 borderlined Presumptive c borderlined Presumptive c
≥ 12.00 Presumptivec Presumptive c Presumptive Presumptive c
.
* normal ranges for secondary markers: C3/C2 < 0.2 and C3/C16 < 2.2
Follow-up Responses
a - if first screen, wait for routine second; if second screen and previous normal, call health care provider and recommend third screen; if second screen and previous abnormal, call health care provider and recommend immediate diagnostic work-up
b - call health care provider and recommend collecting subsequent screen ASAP
c - call health care provider and recommend immediate diagnostic work-up
d - call health care provider to request second screen ASAP
for abnormal C3 results …
High Urgency !!
• CAH
• Galactosemia
• MSUD
Diagnosis and treatment should be initiated ASAP!
Moderate Urgency!
• Congenital Hypothyroidism
• MCAD deficiency
• PKU
Treatment recommended by 1 - 3 weeks of age
No Medical Urgency
.. can wait over a weekend to notify
• Cystic Fibrosis
• Sickle Cell Disease
Treatment recommended by 2 to 4 weeks of age
Special Issues
for adrenal (CAH) results …
• low birthweight & sick babies
• steroids
• different forms of the disorder - severe (salt-wasting) - non-life threatening (simple virilizing) - other forms
Policy & Program Evaluation
WAs Newborn Screening Timeline1967 Phenylketonuria (PKU)1977 Congenital Hypothyroidism1984 Congenital Adrenal Hyperplasia (CAH)1991 Hemoglobinopathies (includes SCD)2004 Biotinidase deficiency
GalactosemiaHomocystinuriaMaple Syrup Urine Disease (MSUD), Medium Chain Acyl co-A Dehydrogenase (MCAD) deficiency
2006 Cystic Fibrosis2008 3 Amino acid disorders
(ASA, CIT, TYR-1)4 Fatty acid disorders (CUD, LCHAD, TFP, VLCAD)8 Organic acid isorders (HMG, BKT, GA-I, IVA, CblA-B, MUT, MCD, PROP)
# of conditions screened for by state, 2004
Major 2008 Expansion15 Additional Disorders:• 3-OH 3-CH3 glutaric aciduria (HMG) • Argininosuccinic acidemia (ASA) • Beta-Ketothiolase deficiency (BKT) • Carnitine uptake defect (CUD) • Citrullinemia (CIT) • Glutaric acidemia type I (GA 1) • Isovaleric acidemia (IVA) • Long-chain L-3-OH acyl-CoA dehydrogenase deficiency (LCHADD) • Methylmalonic acidemia (Cbl A, B) • Methylmalonic acidemia - mutase deficiency (MUT) • Multiple carboxylase deficiency (MCD) • Propionic acidemia (PROP) • Trifunctional protein deficiency (TFP) • Tyrosinemia type I (TYR I)• Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD)
19 MS/MS disorders 49 markers
What are we screening for?
9 OA 5 FAO 6 AA 3 Hb Pathies 6 Others
CORE PANEL
IVAGA IHMGMCDMMAMUTPROPBKT
3MCC
MCADVLCADLCHADTFPCUD
PKUMSUDHCYCITASATYR I
Hb SSHb S/ßThHb S/C
CHBIOTCAHGALTHEARCF
On seven 1/8 inch blood spots!
3-Methylcrotonyl-CoA carboxylase deficiency (3MCC)
• Without treatment many people have no clinical symptoms.
• Treatment prevents and corrects all problems in symptomatic patients.
• Screening test is very good at detecting affected infants, but not totally specific. Also detects asymptomatic mothers.
• Not evident at birth – a sudden metabolic crisis can bring on severe illness (but in a very small percentage of patients).
Amino Acid Disorders
• Amino acids 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
• 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
Other: 1 ASA, 1 CIT, 1 HCY, 1 TYR
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 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
Fatty Acid Disorders
Objective for an Affected Child
PROMPT DIAGNOSIS & TREATMENT to prevent death and
disability by:
• modifying their feedings• supplementing carnitine• administering hormone
replacement• other therapies
NeoLynx PQ (3.5kV, 25V, 15eV) NL102.1 30-Oct-2004Quattro Micro S/N QAA 709
140 145 150 155 160 165 170 175 180 185 190 195 200 205 210 215 220 225 230 235 240 245 250m/z0
100
%
NL102_MCA_OCT3004_NEWBORN 1 (0.518) Neutral Loss 102ES+ 1.46e7191.08
172.05
145.95149.01
161.97
186.01
182.07
174.05
176.06
227.14
222.07
209.11192.08
212.18
238.15
228.20
240.22
246.04
Ala *Ala
Val
Pro
Ser
Thr
*Val
Tyr
*Met
*Leu
Leu
His
*Phe
Phe
Met
*Tyr
Clinical Management: PKU
• Correct substrate imbalance– Restrict phenylalanine
intake to normalize plasma concentration
• Supply product
– Supplement tyrosine to maintain normal plasma tyrosine levels
Phenylalanine ------------//---------------- Tyrosine
(substrate) phenylalanine hydroxylase (product)
Stabilizing Phe Levels
Blood levels every 2 daysbecause of rapid growth
Equilibrium achieved by 14 days of age
Management Tools
• Specialized formula provides– 80-90% energy intake– 85-90% protein intake– tyrosine supplements– no phenylalanine
• Phenylalanine to meet requirement from infant formula or foods
Effective Phe Level Management
Blood levels once per month, or more frequently if needed for good management
Goals of PKU Management
• Normal growth rate• Normal physical
development• Normal cognitive
development• Normal nutritional status
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
Maternal PKU Syndrome
… and moderate to severe intellectual disability
Other Program Services
Provide metabolic treatment products
Subsidize low-protein foods for low-income families
Contract consultant & clinical services
Evaluate long-term outcomes
On the Horizon
Current National Recommendations
• Severe combined immunodeficiency (SCID)
• (Congenital Heart Defects)
Potential Additions to National List
• Lysosomal storage disorders
• Fragile X
• Spinal Muscular Atrophy
• Muscular dystrophy
Washington State Newborn Screening
www.doh.wa.gov/nbs
(206) 418-5410
or
1-866-660-9050