Title: Newborn Screening
1Newborn Screening
History Increasing Impact on Medical Practice
Dietrich Matern, M.D., FACMG Biochemical Genetics
Laboratory Mayo Clinic College of
Medicine Rochester, MN
2Disclosure
Relevant Financial Relationship(s) None Off
Label Usage None
3Objectives
Demonstrate a deeper understanding of newborn
screening (NBS) Be aware of available tools
to react appropriately to abnormal results.
4Outline
- What is Biochemical Genetics?
- What is Newborn Screening?
- Impact on Medical Practice
- The ACMG uniform panel
- Short-term follow up and confirmation
- Newborn Screening Performance
- Whats next in newborn screening?
American College of Medical Genetics
5What is Biochemical Genetics?
A discipline concerned with
- the evaluation and diagnosis of patients and
families with inherited metabolic disease - monitoring of treatment
- distinguishing heterozygous carriers from
non-carriers by metabolite and enzymatic analysis
of physiological fluids and tissues.
A discipline traditionally practicing and
supporting individualized medicine!
ACMG Standards and guidelines for Clinical
Genetics Laboratories. 2nd ed, 1999
6Biochemical Genetics
- To achieve early detection and prevention of
disease, Biochemical Genetics has a strong
emphasis on screening based upon the analysis and
interpretation of metabolic profiles in body
fluids and tissues - Prenatal diagnosis (at risk patients)
- Newborn screening (pre-symptomatic patients)
- High risk screening (symptomatic patients)
- Postmortem screening (metabolic autopsy)
Rinaldo P, Hahn S, Matern D. Clinical Biochemical
Genetics in the 21st century. Acta Paed 2004
445(Suppl) 1-6
7Outline
- What is Biochemical Genetics?
- What is Newborn Screening?
- Impact on Medical Practice
- The ACMG uniform panel
- Short-term follow up and confirmation
- Newborn Screening Performance
- Whats next in newborn screening?
8Newborn Screening
A public health program
- aimed at identification of conditions for which
early intervention can prevent - - mortality
- - morbidity
- - disabilities
- performed by analysis of diagnostic markers in
blood spots collected on filter paper on the
second day of life
9Phenylketonuria (PKU)
Phenylalanine
Phenylpyruvate
2-Hydroxy- Phenylpyruvate
PAH
Phenyllactate
Tyrosine
2-Hydroxy- Phenylacetate
10Phenylketonuria (PKU)
Incidence 1 15,000 live births in
MN Inheritance autosomal recessive Symptoms
mental retardation (IQ usually
or muscle hypertoni
a 25 of patients
seizures Treatment Phe-restricted
diet Prognosis excellent with initiation of
treatment shortly after birth
11The Traditional NBS Model(Testing as SIMPLE as
Possible)
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13Drivers of Expansion
14MCAD Deficiency
First description of Medium-Chain Acyl-Coenzyme A
Dehydrogenase (MCAD) deficiency by Kolvraa et al
in 1982. Incidence 1 15,000 live
births Gene ACADM (1p31) (common mutation
985A? G) Symptoms - hypoketotic
hypoglycemia - Reye-like syndrome
(hypoglycemia, hyperammonemia, elevated
transaminases, brain edema, fatty liver) -
sudden unexpected death Treatment avoidance
of fasting, IV glucose during stress Prognosis
- excellent when treated before onset of
symptoms - 30-50 of mortality during first
acute episode Diagnosis Acylcarnitine profile
by tandem mass spectrometry
15Drivers of Expansion
- New powerful technology (MS/MS)
16Acylcarnitine Analysis
100
Control
C2
Intensity
17NBS by MS/MS(Multiplex Testing)
18Science 20012542272
19Drivers of Expansion
- New powerful technology (MS/MS)
- Subjective factors
- Public pressure
- Political action
- Scrutiny of mass media (WSJ, 10/30/07, D1)
- Objective evidence and guidelines
- Reports of state experiences
- ACMG uniform panel report
20Outline
- History of Newborn Screening
- Impact on Medical Practice
- The ACMG uniform panel
- Short-term follow up and confirmation
- Newborn Screening Performance
- Whats next in newborn screening?
American College of Medical Genetics
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22Primary Evaluation Criteria of Conditions
Considered for Newborn Screening
- Clinical characteristics (e.g., incidence, burden
of disease if not treated, phenotype in the
newborn) - Analytical characteristics of the screening test
(e.g., availability, features of the platform) - Diagnosis, treatment and management of the
condition in both acute and chronic forms
(includes the availability of health
professionals experienced in diagnosis,
treatment, and management).
23ACMG Panel Final Score
29 Primary Targets
25 Secondary Targets
Not Yet Appropriate
24Uniform Screening Panel
- 29 Core Conditions
- 20 detected by MS/MS (AA, FAO, OA)
- 3 hemoglobinopathies
- 6 others (BIOT, CAH, CF, CH, GAL, HEAR)
- 25 secondary targets
- 22 detected by MS/MS
25HRSA/ACMG Uniform Panel (MS/MS)
Phenylketonuria MSUD Homocystinuria Tyrosinemia
type I Argininosuccinic acidemia Citrullinemia
type I Hyperphenylalaninemia Tyrosinemia type
II Biopterin defects (Bios) Tyrosinemia type
III Biopterin (Reg) Argininemia Hypermethioninemia
Citrullinemia type II
MCAD deficiency VLCAD deficiency LCHAD
deficiency TFP deficiency Carnitine uptake
defect M/SCHAD deficiency SCAD
deficiency MCKAT deficiency CPT-I
deficiency Glutaric acidemia type II CACT
deficiency Dienoyl red. deficiency CPT-II
deficiency
Isovaleric acidemia Glutaric acidemia type I HMG
deficiency 3MCC deficiency BKT deficiency Multiple
carboxylase deficiency Methylmalonic acidemia
(MUT) Methylmalonic acidemia (Cbl A,B) Propionic
acidemia Methylmalonic acidemia (Cbl A,B) 2M3HBA
deficiency IBG deficiency 2MBCAD
deficiency Methylglutaconic acidemia Malonic
acidemia
UNIFORM
PANEL
SECONDARY
TARGETS
22 Secondary targets
20 Primary targets
26Newborn Screening 2008
Number of disorders screened for in the USA
35
35
27Impact on Medical Practice
Pediatrics/Family Medicine only?
28Outline
- What is Biochemical Genetics?
- What is Newborn Screening?
- Impact on Medical Practice
- The ACMG uniform panel
- Short-term follow up and confirmation
- Newborn Screening Performance
- Whats next in newborn screening?
American College of Medical Genetics
29Case Report
- Male born at term (3,320g)
- Normal pregnancy and delivery
- 1st child of non-consanguineous parents
- Newborn screening result
- Propionylcarnitine (C3) 6.6 µmol/L (normal
- C3/C2 Ratio 0.23 (normal
- C3/C16 Ratio 2.55 (normal
What now?
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31http//www.acmg.net/resources/policies/ACT/conditi
on-analyte-links.htm
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35Case Report
- Baby is clinically healthy, feeding well
- Laboratory
- Glucose, Elytes, BGA, NH3, CBC all normal
- Urine organic acids, plasma C3-acylcarnitine,
plasma homocysteine all normal
End of Story? False Positive Newborn Screen?
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37Case Report
- Mother tells you that she is known to have
anemia. - Mother tells you that she had gastric bypass
surgery 2 years ago. - Mother is not aware of ever having been told to
take vitamin B12! - You (recommend) treat(-ing) the mothers
iatrogenic vitamin deficiency
38Maternal Disease Identified by Newborn Screening
39Impact on Medical Practice
- Pediatrics
- Family Medicine
- Internal Medicine
- Obstetrics/Gynecology
- Genetics
Family History!
40Outline
- What is Biochemical Genetics?
- What is Newborn Screening?
- Impact on Medical Practice
- The ACMG uniform panel
- Short-term follow up and confirmation
- Newborn Screening Performance
- Whats next in newborn screening?
American College of Medical Genetics
41What Does Performance Mean to YOU?
Actual PPV 5
42CONCLUSIONS Expanded newborn screening may lead
to improved health outcomes for affected children
and lower stress for their parents. However,
false-positive screening results may place
families at risk for increased stress and
parent-child dysfunction.
43The Minnesota Model
A public-private partnership between The
Minnesota Department of Health (MDH) The
University of Minnesota Mayo Clinic College of
Medicine (established June 2004)
44Birthing Place
45MN Newborn Screening Program
Conditions
AA, OA, FAO (MS/MS) FU
S,2T 21-Hydroxylase deficiency S,FU
2T Congenital hypothyroidism S,FU
Galactosemia S,FU Hemoglobinopathies S
,FU Biotinidase deficiency S,FU
Cystic fibrosis (CF) S,FU AAAmino
Acidopathies OAOrganoacidopathies FAOFatty
Acid Oxidation disorders 2T2nd-tier testing
FUfollow-up Sscreening
462nd Tier Tests
- A cost effective means to implement clinically
defined cutoffs when normal population and
disease range overlap (poor specificity) - Same specimen, no additional patient contact
- Normal result overrules primary screening
472nd Tier Tests
- Steroids (CAH)
- HCY/MMA/MCA/EMA (Met, C3, C4)
- Allo-ILE (BCAA)
48Changing CAH Screening in MN(2007)
w/o 2nd Tier
w/ 2nd Tier
- False positives 710
41 - False () rate 0.97 0.06
- Cost clinical F/U 601,370 38,115
- Cost 2nd tier test 0 24,850
- Total F/U cost 601,370 62,965
Cost clinical F/U 847 per case Cost 2nd tier
test 35 per test
49Birthing Place
MDH Laboratory
Newborn Screening CH GALT CAH SCA
50Changing CAH Screening in MN(2007)
w/o 2nd Tier
w/ 2nd Tier
- False positives 710
41 - False () rate 0.97 0.06
- Cost clinical F/U 601,370 38,115
- Cost 2nd tier test 0 24,850
- Total F/U cost 601,370 62,965
- Cost difference (savings) (89.5)
Cost clinical F/U 847 per case Cost 2nd tier
test 35 per test
51Minnesota NBS Performance
73,013 babies screened in 2007
52NBS Performance in the USA
- False positive rate (MS/MS) 0.07 to 3.0
- True positive rate (MS/MS) 12,000-115,000
53Outline
- What is Biochemical Genetics?
- What is Newborn Screening?
- Impact on Medical Practice
- The ACMG uniform panel
- Short-term follow up and confirmation
- Newborn Screening Performance
- Whats next in newborn screening?
54Partial List of Candidate Conditionsfor
Expansion of Uniform Panel(in alphabetical order)
- ALD (X-linked)
- CDG Ib
- CMV
- Creatine defects
- Duchenne
- G6PD
- Gaucher (LSD)
- HIV
- MPS I/II/IIIa/VI (LSD)
- Fabry (LSD)
- Fam. Hypercholesterol.
- Fragile X
- Friedreich ataxia
- Krabbe (LSD) NY
- Niemann-Pick (LSD)
- Pompe (LSD) Taiwan
- SCID WI
- SLO
- SMA
- Wilson disease
55Late-Onset Dilemma is NOT Unique to LSD Screening
56Familial Hypercholesterolemia
- Heterozygous FH
- Incidence 1500
- Symptoms xanthomata and corneal arcus may
occur already in childhood premature
ischemic heart disease - Homozygous FH
- Incidence 11,000,000
- Symptoms
- tendon and skin xanthomata and corneal arcus in
early childhood intermittent arthralgia
premature arteriosclerosis with evidence of
cardiac dysfunction (e.g. angina) before 10
y/o - fatal myocardial infarction by 2nd or 3rd decade
57NBS for Hypercholesterolemia- Impact on Medical
Practice -
- Confirmation of diagnosis
- Treatment
- Counseling (family, patient)
- Affected family members
- (older) siblings?
- parents!
- aunts, uncles, cousins, etc.
- future children of patient
NBS
?
?
58Conclusions
- In the last 8 years, significant changes have
taken place in newborn screening. - A Uniform Screening Panel was recommended and
endorsed by all stakeholders - Follow up guidelines have been/are being
developed - NBS Performance is highly variable.
- The expansion of NBS will continue.
- The impact of NBS on Medical Practice beyond
Pediatrics will increase.