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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

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Newborn Screening: Ontario’s Expanded Screening Program

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newborn screening ontario s expanded screening program
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

  • 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.

newborn screening what s new
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
expanded nbs 29 conditions
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
benefits of nbs
Benefits of NBS
  • Identification
  • Early intervention
  • Reduced morbidity and mortality
  • Family planning
risks of nbs
Risks of NBS
  • Parental anxiety (false positives)
  • Missed diagnosis (false negatives)
  • The right ‘not to know’
  • Unanticipated outcomes
  • Labelling – diagnosis of benign conditions
public s attitude to nbs
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
why changes to nbs now
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
nbs what s not changing
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 Program
timing of testing
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 birth
  • 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

special considerations
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 screens
  • 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
nbs what s new
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 NBS

nbs report
NBS Report
  • Cystic fibrosis
    • 2008
screen positive results
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.
results of expanded nbs by ms ms schulze et al pediatrics 2003
Results of Expanded NBS by MS/MSSchulze 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
  • Results will go to:
    • Submitting health care professional /hospital
    • Infant’s health care professional – if this information is completed on the screening card
expanded nbs 29 conditions19
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
inborn errors of metabolism
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 lifesaving
frequency of inborn errors of metabolism using ms ms tandem mass spectrometry
Frequency of Inborn Errors of Metabolism using MS/MS Tandem Mass Spectrometry
  • Amino Acid Disorders 1/5,100
  • Organic Acid Disorders 1/20,000
  • Fatty Acid Oxidation Defects 1/12,500
  • IEM combined frequency ~1/4,000
  • All NBS: IEM, CF, CAH, ~1/1,500

biotinidase, galactosemia

organic acid disorders
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)
organic acid disorders23
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
    • Avoid fasting
fatty acid oxidation disorders
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)
disorders of fatty acid oxidation
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
amino acid disorders
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)
amino acid disorders27
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
endocrine disorders ch
Congenital Hypothyroidism (CH)

What is CH?

inadequate thyroid hormone production

Anatomic defect in gland, IEM, iodine deficiency


MR, ↓ growth & bone maturation, neurologic problems: spasticity, gait abn, dysarthria, autistic behaviour


Thyroid hormone replacement

Diagnosis made before 13 days to prevent symptoms

Endocrine Disorders: CH
endocrine disorders cah
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
  • Sickle cell disease (Hb SS)
  • Hemoglobin SC disease
  • Sickle-β thalassemia (Hb S/β-thal)
  • Other hemoglobin variants may be picked up as variants
sickle cell disease
Sickle Cell Disease
  • What is sickle cell disease? (Hb SS)
    • Change in the shape of the betaglobin component of the hemoglobin moleculethat 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)
other hemoglobinopathies
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
other disorders biotinidase deficiency
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 hyperammonemia
    • 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
other disorders galactosemia
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
other disorders cystic fibrosis
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, anti-inflammatory 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
case 1
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
case 1 amy 5 days old
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 day
  • 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
case 139








Case 1

British / French

Irish / German




Prost Ca Dx 74





MI – died 69
















13 months

1 wk


A& W

7 5



8 months

case 140
Case 1
  • Amy’s expanded newborn screening report is the following:
    • Screen positive for medium chain acyl-CoA deficiency
mcad medium chain acyl coa deficiency
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 depleted
    • Important during prolonged fasting
mcad symptoms
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, seizures
  • Long term outcomes: developmental & behavioural disabilities, chronic muscle weakness, seizures, cerebral palsy, ADD
mcad a preventable cause of sids
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
mcad management
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
case 2
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?

hemoglobin s carriers
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
    • Stigmatization
    • Diminished self esteem
    • Potential discrimination
    • Misdiagnosis
case 2 sequential testing of family members


HbAS- Sickle

cell trait

HbSS – Sickle

cell disease

Case 2 – sequential testing of family members



Hb - AA


Hb - AS


Hb - AS

Hb - AA

Hb - AS

Hb - AA

Hb - AS

Hb - AS

Hb - AA

Hb - AS



Hb - SS

1 week

Hb - AS

Hb - AA

Hb - AA

Hb - AA

Hb - AA

prevalence hemoglobinopathies
Prevalence : Hemoglobinopathies

*In cis – 2 α thal deletions on same chromosome

Source: March of Dimes

nbs bottom line
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
moh educational materials
MOH Educational Materials
  • MOHLTC INFOline at 1-866-532-3161 / TTY: 1-800-387-5559
  • 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

Disorder Fact Sheets

  • CHEO’s Newborn Screening Website:

  • March of Dimes:

  • Genetests:

  • National Newborn Screening & Genetics Resource Center:

  • Pediatrix – US private lab offering NBS
the genetics education project committee
June Carroll MD CCFP


Sean Blaine MD CCFP

Mary Jane Esplen PhD RN

Sandra Farrell MD FRCPC FCCMG

Judy Fiddes


Jennifer MacKenzie MD FRCPC FAAP FCCMG

Wendy Meschino MD FRCPC FCCMG

Fiona Miller PhD

Ms. Joanne Miyazaki

Andrea Rideout MS CGC CCGC

Linda Spooner RN BScN

Cheryl Shuman MS CGC


Sherry Taylor PhD FCCMG

Brenda Wilson BSc MB ChB MSc MRCP(UK) FFPH

The Genetics Education Project Committee
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