Newborn Screening

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Newborn Screening
History Increasing Impact on Medical Practice
Dietrich Matern, M.D., FACMG Biochemical Genetics
Laboratory Mayo Clinic College of
Medicine Rochester, MN
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Disclosure
Relevant Financial Relationship(s) None Off
Label Usage None
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Objectives
Demonstrate a deeper understanding of newborn
screening (NBS) Be aware of available tools
to react appropriately to abnormal results.
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Outline

• 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
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What 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
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Biochemical 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
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Outline

• 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?

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Newborn 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

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Phenylketonuria (PKU)
Phenylalanine
Phenylpyruvate
2-Hydroxy- Phenylpyruvate
PAH
Phenyllactate
Tyrosine
2-Hydroxy- Phenylacetate
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Phenylketonuria (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
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The Traditional NBS Model(Testing as SIMPLE as
Possible)

• One disease PKU

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Drivers of Expansion

• New disorders

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MCAD 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
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Drivers of Expansion

• New disorders

• New powerful technology (MS/MS)

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Acylcarnitine Analysis
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Control
C2
Intensity
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NBS by MS/MS(Multiplex Testing)

• Many conditions (IEM)n

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Science 20012542272
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Drivers of Expansion

• New disorders

• 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

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Outline

• 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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Primary 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).

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ACMG Panel Final Score
29 Primary Targets
25 Secondary Targets
Not Yet Appropriate
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Uniform 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

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HRSA/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
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Newborn Screening 2008
Number of disorders screened for in the USA
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35
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Impact on Medical Practice
Pediatrics/Family Medicine only?
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Outline

• 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
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Case 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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http//www.acmg.net/resources/policies/ACT/conditi
on-analyte-links.htm
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Case 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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Case 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

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Maternal Disease Identified by Newborn Screening
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Impact on Medical Practice

• Pediatrics
• Family Medicine
• Internal Medicine
• Obstetrics/Gynecology
• Genetics

Family History!
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Outline

• 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
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What Does Performance Mean to YOU?
Actual PPV 5
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CONCLUSIONS 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.
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The 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)
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Birthing Place
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MN 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
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2nd 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

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2nd Tier Tests

• Steroids (CAH)
• HCY/MMA/MCA/EMA (Met, C3, C4)
• Allo-ILE (BCAA)

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Changing CAH Screening in MN(2007)
w/o 2nd Tier
w/ 2nd Tier

• False positives 710
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• 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
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Birthing Place
MDH Laboratory
Newborn Screening CH GALT CAH SCA
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Changing CAH Screening in MN(2007)
w/o 2nd Tier
w/ 2nd Tier

• False positives 710
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• 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
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Minnesota NBS Performance
73,013 babies screened in 2007
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NBS Performance in the USA

• False positive rate (MS/MS) 0.07 to 3.0
• True positive rate (MS/MS) 12,000-115,000

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Outline

• 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?

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Partial 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

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Late-Onset Dilemma is NOT Unique to LSD Screening
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Familial 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

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NBS 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
?
?
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Conclusions

• 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.