Newborn Screening:
Ontario’s Expanded Screening Program
Prepared by:
June C Carroll MD, CCFP, FCFP
Sydney G. Frankfort Chair in Family Medicine
Mount Sinai Hospital, University of Toronto
Andrea Rideout MS, CGC, CCGC
Certified Genetic Counsellor
Project Manager – The Genetics Education Project
Funded by:
Ontario Women’s Health Council
Version: January 2010
Acknowledgments
Reviewers:
 Members of The Genetics Education Project
 Ontario Newborn Screening Program: Dr.
Michael Geraghty, Mireille Cloutier MSc.,
Christina Honeywell MSc., Sari Zelenietz MSc,
Shelley Kennedy 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?
 Previously:
 PKU, congenital hypothyroidism, hearing loss
 Beginning April 2006:
 Progressive expansion to 29 primary disorders
 NBS includes hearing screening but, the focus of
this module will be on metabolic, endocrine and
hematologic conditions
Expanded NBS – 29 conditions
 20 inborn errors of metabolism
 3 hemoglobinopathies
 2 endocrine disorders
 Congenital hypothyroidism
 Congenital adrenal hypoplasia
 3 other metabolic disorders
 Cystic fibrosis
 Galactosemia
 Biotinidase deficiency
 Hearing loss
Benefits of NBS
 Identification
 Early intervention
 Reduced morbidity & mortality
 Family planning
Risks of NBS
 Parental anxiety (false positives)
 Missed diagnosis (false negatives)
 The right ‘not to know’
 Unanticipated outcomes
 Labelling – diagnosis of benign
conditions
NBS: how & where is it done?
 Method:
Heel prick
 Sample collection: newborn screening
card
 Testing Location: Ontario Newborn
Screening Program at Children’s
Hospital of Eastern Ontario (CHEO)
 Transportation: NBS cards are sent
via courier service
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
 Prematurity or illness
 If <37 weeks - collect specimen at 5-7 days old
 Indicate this on NBS card
 May have false positive test results
 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 and obtain sample before transfusion
 Early discharge
 If prior to 24 hours, parents should be informed that a repeat
sample must be done
The Heel Test
What makes
a good spot?
See Ontario NBS Program
website – educational
resource for blood spot
collection:
http://www.newbornscreen
ing.on.ca
NBS: For your information
 Location
 Ontario Newborn Screening Program (ONSP) at
CHEO http://www.newbornscreening.on.ca
 Tandem Mass Spectrometry




Allows screening 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 & ONSP have developed materials for the
public and healthcare providers
Parents will ask you about NBS
NBS
Report
Screen Positive Results
 Screen positive means:
 Further testing is required to confirm the diagnosis
 Does NOT mean that the infant is affected
 ONSP will immediately notify regional treatment centre
 Regional treatment centre will notify the infant’s
healthcare provider and/or 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, provided that
correct information is completed on the screening card.
Results of Expanded NBS by MS/MS
Schulze et al. Pediatrics 2003
 250,000 neonates screened for 23 inborn errors of
metabolism
 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
Negative Results
 Results will go to:
 Submitting health care professional/hospital
 If you suspect that an infant or child has symptoms
of a screened condition and their NBS results are
negative – please refer to the appropriate specialist
for evaluation
 NBS panel does not screen for every metabolic condition
 NBS is a screening test – not diagnostic
Expanded NBS – 29 conditions
 20 inborn errors of metabolism
 9 organic acid disorders
 5 fatty acid oxidation disorders
 6 amino acid disorders




3 hemoglobinopathies
2 endocrine disorders
3 other metabolic disorders
Hearing loss
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 (IEM)
using MS/MS Tandem Mass Spectrometry
Disorders:
Germany
2003
USA
2006
Amino Acid Disorders (*)
1/3,800
1/14,600
Organic Acid Disorders
1/14,700
1/15,900
Fatty Acid Oxidation
1/10,400
Disorders
IEM combined frequency(*) ~1/4,300
1/10,100
~1/2,400
All NBS: IEM, CF, CAH,
~1/1,500 Not
biotinidase, galactosemia
reported
(*) Does not include tyrosinemia type 1 and 2
Organic Acid Disorders









Isovaleric acidemia (IVA)
Glutaric acidemia type 1 (GA1)
Hydrodroxymethylglutaric acidemia (HMG)
Multiple carboxylase deficiency (MCD)
Methylmalonic acidemias (MMA)
Methylmalonic acidemia (Cbl A, B)
3-methylcrotonyl glycinuria (3MCC)
Propionic acidemia (PA)
Β-ketothiolase deficiency (BKT)
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, global
developmental delay
 sepsis, death
 Treatment
 Low protein diet / restrict amino acids,
 Supplements: carnitine, biotin, riboflavin, glycine
 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 betaoxidation of fatty acids
 Carnitine uptake defect (CUD)
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 betaoxidation of fatty acids
 Carnitine uptake defect (CUD)
Disorders of Fatty Acid Oxidation
 What are disorders of fatty acid oxidation?
 Breakdown of fatty acids in mitochondria is an 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
 IV glucose when ill to prevent hypoglycemia
 Frequent feeding
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)
Disorders of Fatty Acid Oxidation
 What are disorders of fatty acid oxidation?
 Breakdown of fatty acids in mitochondria is an 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
 IV glucose when ill to prevent hypoglycemia
 Frequent feeding
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 Disorders
 What are amino acid disorders?
 Occur when the body cannot either metabolize or
produce certain amino acids
 Result in toxic accumulation of substances
 Serious potentially preventable effects on health and
development including death
 Symptoms (untreated) example PKU
 Hyperphenylalaninemia (neurotoxic)
 Microcephaly, epilepsy, mental retardation, behaviour
problems
 Treatment
 Diet: reduce phenylalanine, low protein, supplement
cofactors or essential amino acids
Expanded NBS – 29 conditions
 20 inborn errors of metabolism
 3 hemoglobinopathies
 2 endocrine disorders
 Congenital hypothyroidism
 Congenital adrenal hyperplasia
 3 other metabolic disorders
 Hearing loss
Endocrine Disorders: CH
Congenital Hypothyroidism (CH)
 What is CH?
 inadequate thyroid hormone production
 Anatomic defect in gland, dyshormogenesis, iodine
deficiency
 Symptoms
 MR, ↓ growth & bone maturation, neurologic
problems: spasticity, gait abn, dysarthria, autistic
behaviour
 Treatment
 Diagnosis made before 13 days to prevent symptoms
 Thyroid hormone replacement
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
Expanded NBS – 29 conditions
 20 inborn errors of metabolism
 3 hemoglobinopathies




Sickle cell disease (Hb-SS)
SC disease (Hb-SC)
Sickle beta thalassemia
Other hemoglobinopathies may reported if
clinically significant
 2 endocrine disorders
 3 other metabolic disorders
 Hearing loss
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 and/or Molecular analysis
 Do not rely on solubility testing methods (Sickledex etc)
 Treatment
 Prophylactic penicillin (84% reduction in infection)
 Vaccinations (pneumococcal, influenza)
 Aggressive treatment of fever and dehydration
Expanded NBS – 29 conditions




20 inborn errors of metabolism
3 hemoglobinopathies
2 endocrine disorders
3 other metabolic disorders
 Biontinidase deficiency
 Galactosemia
 Cystic fibrosis
 Hearing loss
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
 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, mental retardation, death
 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
 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
Cases
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
 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 months
Case 1
Legend
Prostate
cancer
SIDS
British / French
Irish / German
79
Prost Ca Dx 74
MI  died 6569
A&W
39
A&W
37
Schizophrenic
35
George
A&W
32
Carmen
A&W
P
S
7
A&W
5
A&W
29
A&W
11 wk
SIDS
Amy
A& W
72
A&W
25
A&W
S
49
Accident
SIDS
13 months
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)
 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
 Required for energy and ketone body production
 Important during prolonged fasting
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 after a clinical episode:
developmental & behavioural disabilities, chronic
muscle weakness, seizures, cerebral palsy, ADD
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
 Infants require frequent feedings
 Formulas containing medium chain triglycerides as
the primary source of fat should be avoided
 Avoid prolonged fasting, hypoglycemia
 Aggressive treatment of illness often with
IV fluids especially when vomiting
Case 2
 Angela receives a call from the Ontario
Newborn Screening Program for a repeat
NBS sample for her newborn, Liam.
 Angela comes to your office for a routine
newborn visit.
 Liam’s newborn screening report:
 Positive, for cystic fibrosis
 Category B
 IRT>96%
 DeltaF508 (one mutation identified)
What are the next steps?
 ~1 in 40 chance of being affected with CF
 Sweat chloride test is next step
 3 possible results:
 Abnormal – affected with CF
 Borderline – inconclusive, follow up with specialist
 Normal – unaffected, but carrier of CF
 Blood work:
 Confirmatory genetic testing
 Genetic counselling is recommended
NBS for cystic fibrosis
 Some evidence that early identification leads to
better outcomes
 Lower incidence of malnutrition
 Improved growth (height, weight)
 Better lung function parameters at 10 years of age
 no evidence of difference in adulthood
 ?improved survival by 10 years of age
 ?reduced mortality
 Identification enables family planning
Liam’s results




Sweat test results – Normal
Liam is a carrier of CF
He will not develop CF
Parents Angela and James have genetic
counselling…
 Angela – carrier of CF deltaF508 mutation + normal gene
 James – carrier of CF R553X mutation + normal gene
 Risk to have a child affected with CF
 25% with each pregnancy
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
Provincial Educational Materials
 www.health.gov.on.ca/newbornscreening
 MOHLTC INFOline at 1-866-532-3161/TTY: 1800-387-5559
 Contact the Ontario Newborn Screening Program:
 Telephone: 613-738-3222
 www.newbornscreening.on.ca
 Educational materials are available free-of-charge
and can be ordered through www.health.gov.on.ca
or by calling 1-877-844-1944
Education:
http://www.health.gov.on.ca
Disorder Fact
Sheets
www.health.gov.on.ca/ne
wbornscreening
Parent Fact Sheets
www.newbornscreening.
on.ca
Resources
 ONSP Newborn Screening Website:
http://www.newbornscreening.on.ca/bins/index.asp
 March of Dimes:
www.marchofdimes.com
 Genetests:
www.genetests.org
 National Newborn Screening & Genetics
Resource Center:
genes-r-us.uthscsa.edu
 Pediatrix – US private lab offering NBS
www.pediatrix.com
Resources
 American College of Medical Genetics – fact
sheets
http://www.acmg.net/resources/policies/NBS/NBSsections.htm
 American Academy of Pediatrics – fact sheets
http://aappolicy.aappublications.org/cgi/content/abstra
ct/pediatrics;118/3/e934
 American Academy of Family Physicians –
Information & resources
http://www.aafp.org/afp/2008/0401/p987.html
 Ontario Medical Association – Important
changes to NBS in Ontario
http://www.oma.org/Health/newborn/06newborn.asp
The Genetics Education Project
Committee
 June C Carroll MD CCFP
 Judith Allanson MD
FRCP FRCP(C) FCCMG
FABMG
 Sean Blaine MD CCFP
 Mary Jane Esplen PhD
RN
 Sandra Farrell MD
FRCPC FCCMG
 Judy Fiddes
 Gail Graham MD FRCPC
FCCMG
 Jennifer MacKenzie MD
FRCPC FAAP FCCMG
 Wendy Meschino MD
FRCPC FCCMG
 Fiona Miller PhD
 Joanne Miyazaki
 Andrea L. Rideout MS
CGC CCGC
 Linda Spooner RN BScN
 Cheryl Shuman MS CGC
 Anne Summers MD
FCCMG FRCPC
 Sherry Taylor PhD
FCCMG
 Brenda Wilson BSc MB
ChB MSc MRCP(UK)
FFPH
References
1.
2.
3.
4.
Ontario Ministry of Health and Long Term Care, News release
November 2, 2005: Ontario becomes national leader in newborn
screening, New state-of-the-art testing program means that
children will have a better start on life
http://www.health.gov.on.ca/english/media/news_releases/archive
s/nr_05/nr_110205.html
Ontario Ministry of Health and Long Term Care, News release
November 23, 2006: McGuinty government expands newborn
screening, Screening for cystic fibrosis brings total number of
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http://www.health.gov.on.ca/english/media/news_releases/archive
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Bellis MA, Hughes K, Hughes S, Aston JR. Measuring parent
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