Newborn Screening:
Ontario’s Expanded Screening Program
Prepared by:
June C. Carroll, MD, CCFP, FCFP
Sydney G. Frankfort Chair in Family Medicine
Associate Professor, Department of Family Medicine
Mount Sinai Hospital, University of Toronto
Andrea L. Rideout, MS, CCGC, CGC
Project Manager / Genetic Counsellor
The Genetics Education Project
Funded by:
Ontario Women’s Health Council
Version: August 2007
The Genetics Education Project
 Reviewers:
Members of The Genetics Education Project
Ontario Newborn Screening Program: Dr. Michael
Geraghty, Mireille Cloutier MSC., Christina Honeywell
MSc., Sari Zelenietz MSc.
 Funded by:
Ontario Women’s Health Council as part of its funding to
The Genetics Education Project
* Health care providers must use their own clinical judgment in addition to the
information presented herein. The authors assume no responsibility or
liability resulting from the use of information in this presentation.
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Newborn Screening – What’s new?
 Previously:
– PKU, congenital hypothyroidism, hearing loss
 Beginning April 2006:
– Progressive expansion to 29 disorders by the
end of 2008
– NBS includes hearing screening but, the focus of
this module will be on metabolic, endocrine and
hematologic conditions
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Expanded NBS – 29 conditions
 20 inborn errors of metabolism
– 9 organic acid disorders
– 5 fatty acid oxidation disorders
– 6 amino acid disorders
 3 hemoglobinopathies
– Sickle cell and related disorders
 2 endocrine disorders
 3 other metabolic disorders
 1 hearing loss
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Benefits of NBS
 Identification
 Early intervention
 Reduced morbidity and mortality
 Family planning
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Risks of NBS
Parental anxiety (false positives)
Missed diagnosis (false negatives)
The right ‘not to know’
Unanticipated outcomes
Labelling – diagnosis of benign conditions
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Public’s attitude to NBS
 Study of 200 Australian new mothers
» Quinlivan 2006 J Pscyhosomatic Ob/Gyn
Supported NBS where outcomes used to prevent
or reduce severity of disease (85%)
Less support if screening used for future family
planning (65%)
Parental consent should be mandatory (86%)
Majority concerned re discrimination, difficulty
getting insurance/employment for those with
genetic condition
1/3 had similar concerns for carriers
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Why Changes to NBS now?
Reagent for PKU test unavailable
Tandem Mass Spectrometry more efficient
2 infants diagnosed post-mortem with MCAD
Ombudsman’s report 2005
Consumer lobbying
Geneticist lobbying
Political will
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NBS: What’s NOT changing?
 Heel prick method for sample collection
NBS: What’s changing?
 New screening card
 Location: Children’s Hospital of Eastern Ontario
 Transportation – sample cards are sent via
Canada Post courier service to Ontario NBS
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Timing of Testing
 Acceptable samples
– between 1 day (24 hours) and 7 days after birth
 Best time for sample:
– between 2 days (48 hours) and 3 days (72 hours) after
 If tested before 1 day (24 hours) of age, REPEAT
the test within 5 days*
 If the baby is >5 days, screening is still available
– Contact Ontario NBS program for details
* Repeat sample within 5 days has been the Ontario
standard of care since 2001
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Special Considerations
 Prematurity or illness
– If <37 weeks - collect specimen at 5-7 days old
– Indicate this on NBS card
– i.e. associated with false +ve congenital hypothyroidism
 Total Parenteral Nutrition (TPN)
– Certain amino acids and organic acids will be elevated
– Indicate this on NBS card
 Transfusion
– Disorders may be missed
– Ideally complete card before transfusion
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The Heel Test
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What makes
a good
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NBS: What’s New?
 Location
– Children’s Hospital of Eastern Ontario (CHEO)
 Tandem Mass Spectrometry
Allows to screen for multiple conditions concurrently
Same cost to screen for one condition as multiple
Increased sensitivity and specificity
Screening for some metabolites can give information
about several diseases
 Educational materials
– MOH & CHEO have developed materials for the
public and healthcare providers
Parents will ask you about
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NBS Report
 Cystic fibrosis
- 2008
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Screen Positive Results
 Screen positive means:
– Further testing is required to confirm the diagnosis
– Does NOT mean that the infant is affected
 NBS laboratory will immediately notify regional
treatment centre
 Regional treatment centre will notify the infant’s
healthcare provider and parents and arrange
confirmatory testing
 If diagnosis is confirmed, regional treatment centre will
provide management counselling & follow up
 Report will be mailed to referring hospital and HCP,
provided that correct information is completed on the
screening card.
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Results of Expanded NBS by MS/MS
Schulze et al. Pediatrics 2003
 250,000 neonates screened for 23 IEM
– 106 newborns with confirmed metabolic disorder
 70 required treatment
Overall prevalence of metabolic disorder = 1/2400
825 false positives (0.33% false positive rate)
Overall specificity = 99.67% (PPV = 11.3%)
Overall sensitivity = 100% for classic forms of disorders
= 92.6% for variants
– 61 /106 were judged to have benefited from screening
and treatment
 58% of true positives
 1/4100 newborns
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 Results will go to:
– Submitting health care professional /hospital
– Infant’s health care professional – if this information is
completed on the screening card
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Expanded NBS – 29 conditions
 20 inborn errors of metabolism
– 9 organic acid disorders
– 5 fatty acid oxidation disorders
– 6 amino acid disorders
 3 hemoglobinopathies
– Sickle cell and related disorders
 2 endocrine disorders
 3 other metabolic disorders
 1 hearing loss
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Inborn errors of metabolism
 Rare
 Usually autosomal recessive inheritance
– consanguinity is more common
 Symptoms secondary to a problem in the
metabolic pathway
 Usually not significant dysmorphism
 Early recognition and intervention can be
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Frequency of Inborn Errors of Metabolism
using MS/MS Tandem Mass Spectrometry
 Amino Acid Disorders
 Organic Acid Disorders
 Fatty Acid Oxidation Defects
 IEM combined frequency
 All NBS: IEM, CF, CAH,
biotinidase, galactosemia
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Organic Acid Disorders
Isovaleric acidemia (IVA)
Glutaric acidemia type 1 (GA1)
Hydrodroxymethylglutaric acidemia (HMG)
Multiple carboxylase deficiency (MCD)
Methylmalonic acidemia (MUT)
Methylmalonic acidemia (Cbl A, B)
3-methylcrotonyl glycinuria (3MCG)
Propionic acidemia (PROP)
Β-ketothiolase deficiency (BKT)
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Organic Acid Disorders
 What are organic acid disorders?
– Body cannot metabolize certain amino acids and fats
– Accumulation of organic acids in blood and urine
– Serious potentially preventable effects on health and
development, including death
 Symptoms
– acute encephalopathy, vomiting, metabolic acidosis,
ketosis, hyperammonemia, hypoglycemia, coma
– dehydration, failure to thrive, hypotonia, GDD
– sepsis, death
 Treatment
– Low protein diet / restrict amino acids,
– Supplements: carnitine, biotin, riboflavin, glycine
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– Avoid fasting
Fatty Acid Oxidation Disorders
 Medium-chain acyl-CoA dehydrogenase
(MCAD) deficiency
 Very long-chain acyl-CoA dehydrogenase
deficiency (VLCAD)
 Long-chain L-3-OH acyl-CoA dehydrogenase
deficiency (LCHAD)
 Trifunctional protein deficiency (TFP)
– catalyzes 3 steps in mitochondrial beta-oxidation of
fatty acids
 Carnitine uptake defect (CUD)
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Disorders of Fatty Acid Oxidation
 What are disorders of fatty acid oxidation?
– Breakdown of fatty acids in mitochondria is essential
part of body’s ability to produce energy
– Disorder: inability to break down fatty acids
 Symptoms
– Decompensate with any catabolic stress
 fever, fasting, intercurrent illness
– Hypoketotic hypoglycemia, liver, muscle, heart disease
– Lethargy, seizures, coma, sudden death (SIDS)
 Treatment
– Avoid fasting
– Frequent feeding
– IV glucose when ill to prevent hypoglycemia
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Amino Acid Disorders
 Phenylketonuria (PKU)
 Maple syrup urine disease (MSUD)
 Tyrosinemia type 1 (TYR 1)
– Common in French Canadians
 Homocystinuria (HCY)
 Citrullinemia (CIT)
 Argininosuccinic aciduria (ASA)
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Amino Acid Disorders
 What are Amino acid disorders?
– Occur when the body cannot either metabolize or
produce certain amino acids
– Results in toxic accumulation of substances
– Serious potentially preventable effects on health and
development including death
 Symptoms -example PKU
– Hyperphenylalaninemia (neurotoxic)
– Microcephaly, epilepsy, MR, behaviour problems
 Treatment
– Diet: reduce phenylalanine, low protein, supplement
cofactors or essential amino acids
– Avoid fasting
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Endocrine Disorders: CH
Congenital Hypothyroidism (CH)
 What is CH?
– inadequate thyroid hormone production
– Anatomic defect in gland, IEM, iodine deficiency
 Symptoms
– MR, ↓ growth & bone maturation, neurologic problems:
spasticity, gait abn, dysarthria, autistic behaviour
 Treatment
– Thyroid hormone replacement
– Diagnosis made before 13 days to prevent symptoms
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Endocrine Disorders: CAH
Congenital Adrenal Hyperplasia (CAH)
 What is CAH?
– Impaired synthesis of cortisol by the adrenal cortex leads to ↑↑↑
androgen biosynthesis
– Inability to maintain adequate energy & blood glucose level to
meet stress of injury & illness
 Symptoms
– Virilization (♀ ambiguous genitalia), precocious puberty,
infertility, short stature
– Renal salt wasting leads to FTT, vomiting, dehydration,
hypotension, hyponatremia, & hyperkalemia
 Treatment
– Glucocorticoid replacement therapy
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 Sickle cell disease (Hb SS)
 Hemoglobin SC disease
 Sickle-β thalassemia (Hb S/β-thal)
 Other hemoglobin variants may be
picked up as variants
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Sickle Cell Disease
 What is sickle cell disease? (Hb SS)
– Change in the shape of the betaglobin component of the
hemoglobin molecule that interferes with hemoglobin’s ability to
carry oxygen
 Symptoms
– Painful vaso-occlusive crises, hemolytic anemia, frequent
infections, tissue ischemia, chronic organ dysfunction
 Diagnosis
– Quantitative hemoglobin electrophoresis
– Do not rely on solubility testing methods (Sickledex etc)
 Treatment
– Prophylactic penicillin (84% reduction in infection)
– Vaccinations (pneumococcal, influenza)
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Other Hemoglobinopathies
 Hemoglobin C disease (Hb-CC)
– ‘benign’ hemoglobinopathy
– mild hemolytic anemia, retinopathy & dental
infarctions, gallstones, splenomegaly, joint pain
 Sickle cell and C trait (carriers) (Hb AS, Hb AC)
– > 50% normal hemoglobin – generally asymptomatic
no clinical symptoms
 Other hemoglobin variants
 Autosomal recessive inheritance
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Other Disorders:
Biotinidase deficiency
 What is biotinidase deficiency?
– Biotinidase is responsible for recycling biotin – a
cofactor for 4 dependant carboxylases
 Symptoms
– Metabolic ketoacidosis, organic aciduria, mild
– Seizures, hypotonia, ataxia, developmental delay, vision
problems, hearing loss, cutaneous abnormalities
 Treatment
– 5-10mg of oral biotin per day, long term treatment
prevents all symptoms
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Other Disorders: Galactosemia
 What is galactosemia?
– Lactose is main sugar in breast milk & infant formulas
– Metabolized into glucose and galactose in the intestine
– Unable to break down galactose
 Symptoms
– Feeding problems, FTT, bleeding, infection, liver failure,
cataracts, MR
 Treatment
– Lactose-galactose-restricted diet
 must be started in first 10 days of life to prevent symptoms
– Even with treatment - ↑ developmental delay, speech
problems, abn motor function, premature ovarian failure
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Other Disorders: Cystic fibrosis
 What is cystic fibrosis?
– Due to mutations in the CFTR gene which is responsible for
chloride regulation and other transport pathways.
 Symptoms
Chronic sinopulmonary disease
Gastrointestinal/nutritional abnormalities
Azoospermia (males)
Salt loss syndrome
Shortened life span – but improving with treatment
 Treatment
– Pulmonary: oral, inhaled, or IV antibiotics, bronchodilators, antiinflammatory agents, mucolytic agents, chest physiotherapy
– Gastrointestinal: Nutritional therapy special formulas for weight
gain via improved intestinal absorption, and additional fat-soluble
vitamins & zinc to prevent deficiencies
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Case 1
 Carmen and George bring Amy into your office
for 1 week visit
 Healthy 1 week old
 Parents worried re risk of SIDS
 First daughter died of SIDS 5 years earlier
 Carmen’s cousin died of SIDS at 18 months
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Case 1: Amy – 5 days old
 You receive a call that Amy has screened
positive for MCAD deficiency
– Medium chain acyl-CoA dehydrogenase deficiency
 You ask Carmen and George to bring her in that
 Healthy 5 day old
 Parents worried about risk of SIDS
 First daughter died of SIDS 5 years earlier
 Carmen’s cousin died of SIDS at 13 months
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Case 1
British / French
Irish / German
MI – died 69
A&W Schizophrenic
Prost Ca Dx 74
13 months
1 wk
8 months
A& W
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Case 1
 Amy’s expanded newborn screening
report is the following:
– Screen positive for medium chain acylCoA deficiency
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MCAD (medium chain acyl-CoA deficiency)
 Incidence
– 1 in 4,900 – 1 in 17,000
– most prevalent in North Europeans
 Inheritance
– Autosomal recessive (Gene: ACADM)
 Enzyme
– Medium-chain acyl-coenzyme A dehydrogenase
 Function
– Mitochrondrial fatty acid β-oxidation
– Energy source once hepatic glycogen stores become
– Important during prolonged fasting
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MCAD: Symptoms
 Usually presents at 3 to 24 months
 Triggered by fever, illness, or fasting
 Symptoms:
– Hypoglycemia, vomiting
– Lethargy → coma → death
– Encephalopathy, respiratory arrest, hepatomegaly,
 Long term outcomes: developmental &
behavioural disabilities, chronic muscle
weakness, seizures, cerebral palsy, ADD
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MCAD: a preventable cause of SIDS
 Sudden death is the first symptom in 25% of
MCAD cases
 Early diagnosis and treatment of MCAD can
prevent sudden death
 MCAD responsible for ~1% of SIDS cases, all
FAO disorders ~4%
– Opdal et al. Pediatrics 2004;114:506-512
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MCAD: Management
 Infants require frequent feedings
– Formulas containing medium chain triglycerides as
the primary source of fat should be avoided
 Toddlers: 2g/kg of uncooked cornstarch at
bedtime to ensure sufficient glucose overnight
 High carbohydrate, low fat diet
 Carnitine supplementation
 Avoid fasting, hypoglycemia
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Case 2
 Peter and Tina come to your office for a routine
newborn visit
 Kechia is a healthy 1 week old newborn
 Her NBS results show that she is a carrier of
hemoglobin S - sickle cell trait
How would you proceed?
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Hemoglobin S Carriers
 Carriers of sickle cell trait (HbAS)
– no clinical symptoms
– should they be notified?
 Benefits
– Sequential testing and identification of carriers/ affected in family
– Reproductive counselling/prenatal diagnosis
 Risks
Exposure of non-paternity
Fear of chronic illness
Fear of sickle cell disease in future pregnancies
Diminished self esteem
Potential discrimination
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HbAS- Sickle
cell trait
HbSS – Sickle
cell disease
Case 2 – sequential testing
of family members
Hb - AA
Hb - AA
Hb - AS
Hb - AS
Hb - AS
Hb - AS
Hb - AS Hb - AA
Hb - AS
Hb - AA
Hb - AA
Hb - AA
Hb - AA
1 week
Hb - AS
Hb - AA
Hb - SS
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Prevalence : Hemoglobinopathies
Hb S trait
Hb C trait β thal trait
1/30 -50
1/20 – 30
African American
1/50 -75
West African
Hispanic Caribbean
Mexican, Central
1/20 *
Southeast Asian
Asian subcontinent
Middle Eastern
*In cis – 2 α thal deletions on same chromosome
Source: March of Dimes
α thal trait
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NBS – Bottom Line
Offer newborn screening
Discuss the benefits
Discuss how testing is done
Discuss timing
Repeat sample sometimes required
Discuss difference between screening and
diagnostic test
 Discuss possible results
 Answer questions/brochure
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MOH Educational Materials
 MOHLTC INFOline at 1-866-532-3161 / TTY: 1-800-3875559
 Contact the Ontario Newborn Screening Program at:
Department of Genetics
Children’s Hospital of Eastern Ontario
Room 3127, 401 Smyth Road
Ottawa, ON K1H 8L1
(613) 738-3222
 Educational materials are available free-of-charge and
can be ordered through or by
calling 1-877-844-1944
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Disorder Fact
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 CHEO’s Newborn Screening Website:
 March of Dimes:
 Genetests:
 National Newborn Screening & Genetics
Resource Center:
 Pediatrix – US private lab offering NBS
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 June Carroll MD CCFP
 Judith Allanson MD FRCP
 Sean Blaine MD CCFP
 Mary Jane Esplen PhD RN
 Sandra Farrell MD FRCPC
 Judy Fiddes
 Gail Graham MD FRCPC
 Jennifer MacKenzie MD
 Wendy Meschino MD FRCPC
 Fiona Miller PhD
 Ms. Joanne Miyazaki
 Andrea Rideout MS CGC
 Linda Spooner RN BScN
 Cheryl Shuman MS CGC
 Anne Summers MD FCCMG
 Sherry Taylor PhD FCCMG
 Brenda Wilson BSc MB ChB
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Ontario Ministry of Health and Long Term Care, News release November
2, 2005: Ontario becomes national leader in newborn screening, New
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Ontario Ministry of Health and Long Term Care, News release November
23, 2006: McGuinty government expands newborn screening, Screening
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The Genetics Education Project

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