Newborn Screening: Ontario

1
Newborn Screening Ontarios 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 Womens Health Council
• Version January 2010

2
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 Womens 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.

3
Newborn Screening Whats 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

4
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

5
Benefits of NBS

• Identification
• Early intervention
• Reduced morbidity mortality
• Family planning

6
Risks of NBS

• Parental anxiety (false positives)
• Missed diagnosis (false negatives)
• The right not to know
• Unanticipated outcomes
• Labelling diagnosis of benign conditions

7
NBS how where is it done?

• Method Heel prick
• Sample collection newborn screening card
• Testing Location Ontario Newborn Screening
  Program at Childrens Hospital of Eastern Ontario
  (CHEO)
• Transportation NBS cards are sent via courier
  service

8
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 gt5 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

9
Special Considerations

• Prematurity or illness
• If lt37 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

10
The Heel Test
11
What makes a good spot?See Ontario NBS Program
website educational resource for blood spot
collectionhttp//www.newbornscreening.on.ca
12
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

13
NBS Report
14
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
  infants 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.

15
Results of Expanded NBS by MS/MSSchulze 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

16
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

17
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

18
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

19
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 Disorders 1/10,400 1/10,100
IEM combined frequency() 1/4,300 1/2,400
All NBS IEM, CF, CAH, biotinidase, galactosemia 1/1,500 Not reported
() Does not include tyrosinemia type 1 and 2
20
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)
• ?-ketothiolase deficiency (BKT)

21
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

22
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)

23
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)

24
Disorders of Fatty Acid Oxidation

• What are disorders of fatty acid oxidation?
• Breakdown of fatty acids in mitochondria is an
  essential part of bodys 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

25
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)

26
Disorders of Fatty Acid Oxidation

• What are disorders of fatty acid oxidation?
• Breakdown of fatty acids in mitochondria is an
  essential part of bodys 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

27
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)

28
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

29
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

30
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

31
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

32
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

33
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
  hemoglobins 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

34
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

35
Other DisordersBiotinidase 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

36
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

37
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

38
Cases
39
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
• Carmens cousin died of SIDS at 18 months

40
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
• Carmens cousin died of SIDS months

41
Case 1
British / French
Irish / German
79 Prost Ca Dx 74
72 AW
49 Accident
65 AW
MI died 69
25 AW
32 Carmen AW
37 Schizophrenic
39 AW
29 AW
35 George AW
SIDS 13 months
11 wk Amy A W
7 5 AW AW
SIDS
42
Case 1

• Amys expanded newborn screening report is the
  following
• Screen positive for medium chain acyl-CoA
  deficiency

43
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 ß-oxidation
• Required for energy and ketone body production
• Important during prolonged fasting

44
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

45
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 2004114506-512

46
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

47
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.
• Liams newborn screening report
• Positive, for cystic fibrosis
• Category B
• IRTgt96
• DeltaF508 (one mutation identified)

48
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

49
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

50
Liams 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

51
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

52
Provincial Educational Materials

• www.health.gov.on.ca/newbornscreening
• MOHLTC INFOline at 1-866-532-3161/TTY
  1-800-387-5559
• Contact the Ontario Newborn Screening Program
• Telephone [phone]
• 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

53
Educationhttp//www.health.gov.on.ca
54

• Disorder Fact Sheets
• www.health.gov.on.ca/newbornscreening
• Parent Fact Sheets www.newbornscreening.on.ca

55
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

56
Resources

• American College of Medical Genetics fact
  sheets
• http//www.acmg.net/resources/policies/NBS/NBS-se
  ctions.htm
• American Academy of Pediatrics fact sheets
• http//aappolicy.aappublications.org/cgi/content/
  abstract/pediatrics118/3/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

57
The Genetics Education Project Committee

• 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

• 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

58
References

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   News release November 2, 2005 Ontario becomes
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2. Ontario Ministry of Health and Long Term Care,
   News release November 23, 2006 McGuinty
   government expands newborn screening, Screening
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59
References

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