1. 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: May 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 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.

3. 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

4. Expanded NBS – 29 conditions  20 inborn errors of metabolism  3 hemoglobinopathies  2 endocrine disorders  Congenital hypothyroidism  Congenital adrenal hyperplasia  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: Newborn Screening Ontario (NSO) at Children’s 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 >5 days, screening is still available  Contact NSO program for details * Repeat sample within 5 days has been the Ontario standard of care since 2001

9. 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

10. The Heel Test

11. What makes a good spot? See Newborn Screening Ontario website – educational resource for blood spot collection: http://www.newbornscreen ing.on.ca http://www.newbornscreen ing.on.ca

12. NBS: For your information  Location  Newborn Screening Ontario at CHEO http://www.newbornscreening.on.ca 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 & NSO 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  NSO 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.

15. 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

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. Disorders: Germany 2003 USA 2006 Amino Acid Disorders (*)1/3,8001/14,600 Organic Acid Disorders1/14,7001/15,900 Fatty Acid Oxidation Disorders 1/10,4001/10,100 IEM combined frequency(*)~1/4,300~1/2,400 All NBS: IEM, CF, CAH, biotinidase, galactosemia ~1/1,500Not reported Frequency of Inborn Errors of Metabolism (IEM) using MS/MS Tandem Mass Spectrometry (*) Does not include tyrosinemia type 1 and 2

20. Organic Acid Disorders  Isovaleric acidemia (IVA)  Glutaric acidemia type 1 (GA1)  HMG-CoA lyase deficiency (HMG)  Multiple carboxylase deficiency (MCD)  Methylmalonic acidemia (MMA)  Methylmalonic acidemia (MUT, Cbl)  3-methylcrotonyl-CoA carboxylase (3MCC) deficiency  Propionic acidemia (PA)  Β-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. 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

24. Amino Acid Disorders  Phenylketonuria (PKU)  Maple syrup urine disease (MSUD)  Tyrosinemia type 1 (TYR 1)  Common in French Canadians  Homocystinuria (HCY)  Citrullinemia (CIT)  Argininosuccinic acidemia (ASA)

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. Cases

36. 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

37. 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

38. Case 1  –   39 A&W 37 Schizophrenic  35 George A&W  25 A&W     29 A&W  11 wk Amy A& W SIDS  79 Prost Ca Dx 74  72 A&W 32 Carmen A&W British / French Irish / German SIDS 13 months 49 Accident   7 5 A&W P S S Legend Prostate cancer SIDS

39. Case 1  Amy’s expanded newborn screening report is the following:  Screen positive for medium chain acyl-CoA deficiency

40. 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

41. 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

42. 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

43. 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

44. Case 2  Angela receives a call from Newborn Screening Ontario 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)

45. 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

46. 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

47. 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

48. 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

49. Provincial Educational Materials  www.health.gov.on.ca/newbornscreening  MOHLTC INFOline at 1-866-532-3161/TTY: 1- 800-387-5559  Contact Newborn Screening Ontario:  Telephone: 613-738-3222  www.newbornscreening.on.ca www.newbornscreening.on.ca  Educational materials are available free-of-charge and can be ordered through www.health.gov.on.ca or by calling 1-877-844-1944www.health.gov.on.ca

50. Education : http://www.health.gov.on.ca

51. Disorder Fact Sheets www.health.gov.on.ca/ne wbornscreening Parent Fact Sheets www.newbornscreening. on.ca www.newbornscreening. on.ca

52. Resources  Newborn Screening Ontario 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

53. Resources  American College of Medical Genetics – fact sheets http://www.acmg.net/resources/policies/NBS/NBS- sections.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

54. 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

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