Newborn Screening: Ontario’s Expanded Screening Program

1
Newborn Screening Ontarios 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 Womens Health Council Version
August 2007
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.
• 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 disorders by the end
  of 2008
• 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
• 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

5
Benefits of NBS

• Identification
• Early intervention
• Reduced morbidity and 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
Publics 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

8
Why Changes to NBS now?

• Reagent for PKU test unavailable
• Tandem Mass Spectrometry more efficient
• 2 infants diagnosed post-mortem with MCAD
• Ombudsmans report 2005
• Consumer lobbying
• Geneticist lobbying
• Political will

9
NBS Whats NOT changing?

• Heel prick method for sample collection

NBS Whats changing?

• New screening card
• Location Childrens Hospital of Eastern Ontario
• Transportation sample cards are sent via Canada
  Post courier service to Ontario NBS Program

10
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

11
Special Considerations

• Prematurity or illness
• If lt37 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

12
The Heel Test
13
What makes a good spot?
14
NBS Whats New?

• Location
• Childrens 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

15
NBS Report

• Cystic fibrosis
• 2008

16
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
  infants 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.

17
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

18
Results

• Results will go to
• Submitting health care professional /hospital
• Infants health care professional if this
  information is completed on the screening card

19
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

20
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

21
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

22
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)
• ?-ketothiolase deficiency (BKT)

23
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

24
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)

25
Disorders of Fatty Acid Oxidation

• What are disorders of fatty acid oxidation?
• Breakdown of fatty acids in mitochondria is
  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
• Frequent feeding
• IV glucose when ill to prevent hypoglycemia

26
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)

27
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

28
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

29
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

30
Hemoglobinopathies

• Sickle cell disease (Hb SS)
• Hemoglobin SC disease
• Sickle-ß thalassemia (Hb S/ß-thal)
• Other hemoglobin variants may be picked up as
  variants

31
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
• Do not rely on solubility testing methods
  (Sickledex etc)
• Treatment
• Prophylactic penicillin (84 reduction in
  infection)
• Vaccinations (pneumococcal, influenza)

32
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)
• gt 50 normal hemoglobin generally asymptomatic
  no clinical symptoms
• Other hemoglobin variants
• Autosomal recessive inheritance

33
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

34
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

35
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

36
Cases
37
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

38
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 at 13 months

39
Case 1
British / French
Irish / German
72 AW
79 Prost Ca Dx 74
49 Accident
65 AW
MI died 69
25 AW
29 AW
37 Schizophrenic
32 Carmen AW
39 AW
35 George AW
SIDS 13 months
1 wk Amy A W
7 5 AW
AW
SIDS 8 months
40
Case 1

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

41
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
• Energy source once hepatic glycogen stores become
  depleted
• Important during prolonged fasting

42
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

43
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

44
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

45
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?

46
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

47
Case 2 sequential testing of family members
Barbados
Jamaica
Hb - AA
22 Hb - AS
24 Hb - AS
Hb - AA
Hb - AS
Hb - AA
Hb - AS
Hb - AS
Hb - AA
Hb - AS
P
3months Hb - SS
1 week Hb - AS
Hb - AA
Hb - AA
Hb - AA
Hb - AA
48
Prevalence Hemoglobinopathies
In cis 2 a thal deletions on same chromosome
Source March of Dimes
49
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

50
MOH 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 at
• Department of Genetics
• Childrens Hospital of Eastern Ontario
• Room 3127, 401 Smyth Road
• Ottawa, ON K1H 8L1
• [phone]
• Educational materials are available
  free-of-charge and can be ordered through
  www.health.gov.on.ca or by calling 1-877-844-1944

51
Educationhttp//www.health.gov.on.ca
52

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

53
Resources

• CHEOs 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

54
The Genetics Education Project Committee

• June 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
• Ms. Joanne Miyazaki
• Andrea 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

55
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