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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”
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://www.cdc.gov/ncbddd/jaundice/families
http://www2.aap.org
NBS Sequence of Events
follow-up
NBS lab testing
transit time
hospital – blood collection
Time (days)
Birth
1
2
recommended
window for 1st NBS
specimen collection
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
~2,100 false positives
170 - 200 true positives
2011 = 188 affected infants
prevalence: 1 in 452!
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
Screening Results
what we would like …
Normal
Affected
2.12 μM
.78 μM
100% specificity
13.0 μM
101 μM
100% sensitivity
Screening Results
what we usually get …
Normal
35 μM
Affected
200 μM
Specificity vs. Sensitivity
745 μM
Abnormal Screening Results
Response is dependent on disorder,
magnitude of result, & demographics of infant
(presumptive, borderline, inconclusive)
.
Stratifying Results
Categorization of C3 Cutoffs
Age ≤ 6 days
C3
mmol/L
serum
< 4.1
not all 2°
markers*
elevated
normal
4.1 – 4.89
Age > 6 days
normal
not all 2°
markers*
elevated
normal
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
all 2° markers*
elevated
all 2° markers*
elevated
normal
* normal ranges for secondary markers: C3/C2 < 0.2 and C3/C16 < 2.2
Follow-up Responses
for abnormal C3 results …
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
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 Timeline
1967
1977
1984
1991
2004
2006
2008
Phenylketonuria (PKU)
Congenital Hypothyroidism
Congenital Adrenal Hyperplasia (CAH)
Hemoglobinopathies (includes SCD)
Biotinidase deficiency
Galactosemia
Homocystinuria
Maple Syrup Urine Disease (MSUD),
Medium Chain Acyl co-A Dehydrogenase (MCAD) deficiency
Cystic Fibrosis
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 Expansion
15 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
IVA
GA I
HMG
MCD
MMA
MUT
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
3MCC
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
Amino Acid Prevalence
12.0
Per 100,000
10.0
8.0
6.0
4.0
2.0
0.0
PKU
29
MSUD
3
Other
4
All A.A.
36 Pts = 1:9,755
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
Organic Acid Prevalence
4.0
3.5
Per 100,000
3.0
2.5
2.0
1.5
1.0
0.5
0.0
MMA/PA
GA-1
BKT
All O.A.
7
3
2
12 Pts = 1:29,266
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
Fatty Acid Prevalence
10.0
9.0
8.0
Per 100,000
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
MCADD
VLCADD
CUD
All FAOs
22
7
2
31 Pts = 1:11,328
Total MS/MS Prevalence
30.0
Per 100,000
25.0
20.0
15.0
10.0
5.0
0.0
All Panel
All Non-Panel
All Conditons
79
1:4,445
16
1:21,949
95
1:3,696
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
Quattro Micro S/N QAA 709
30-Oct-2004
NL102_MCA_OCT3004_NEWBORN 1 (0.518)
Neutral Loss 102ES+
1.46e7
191.08
100
*Leu
*Phe
227.14
Pro
172.05
%
Leu
Phe
186.01
*Val
222.07
182.07
Tyr
Ala
238.15
*Ala
145.95
149.01
*Met
Ser
192.08
174.05
His
Thr
Met
176.06
145
150
155
160
165
170
240.22
209.11
Val
161.97
0
140
*Tyr
175
180
185
190
195
200
205
228.20
212.18
210
215
220
225
230
246.04
235
240
245
m/z
250
Clinical Management: PKU
• Correct substrate
imbalance
• Supply product
– Restrict phenylalanine
intake to normalize
plasma concentration
– Supplement tyrosine
to maintain normal
plasma tyrosine levels
Phenylalanine ------------//---------------- Tyrosine
(substrate)
phenylalanine hydroxylase
(product)
Stabilizing Phe Levels
Equilibrium achieved by
14 days of age
Blood levels every 2 days
because of rapid growth
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