Newborn Screening Ontarios Expanded Screening Program Prepared by

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

Acknowledgments Reviewers: n Members of The Genetics Education Project n Ontario Newborn Screening Program: Dr. Michael Geraghty, Mireille Cloutier MSc. , Christina Honeywell MSc. , Sari Zelenietz MSc, Shelley Kennedy MSc. n 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? n Previously: ¨ PKU, n 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 n n n 20 inborn errors of metabolism 3 hemoglobinopathies 2 endocrine disorders ¨ Congenital hypothyroidism ¨ Congenital adrenal hyperplasia n 3 other metabolic disorders ¨ Cystic fibrosis ¨ Galactosemia ¨ Biotinidase deficiency n Hearing loss

Benefits of NBS n Identification n Early intervention n Reduced morbidity & mortality n Family planning

Risks of NBS n Parental anxiety (false positives) n Missed diagnosis (false negatives) n The right ‘not to know’ n Unanticipated outcomes n Labelling – diagnosis of benign conditions

NBS: how & where is it done? n Method: Heel prick n Sample collection: newborn screening card n Testing Location: Newborn Screening Ontario (NSO) at Children’s Hospital of Eastern Ontario (CHEO) n Transportation: NBS cards are sent via courier service

Timing of Testing n Acceptable samples ¨ between n Best time for sample: ¨ between birth n n 2 days (48 hours) and 3 days (72 hours) after 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 * 1 day (24 hours) and 7 days after birth NSO program for details Repeat sample within 5 days has been the Ontario standard of care since 2001

Special Considerations n Prematurity or illness ¨ ¨ ¨ n Total Parenteral Nutrition (TPN) ¨ ¨ n Certain amino acids and organic acids will be elevated Indicate this on NBS card Transfusion ¨ ¨ n If <37 weeks - collect specimen at 5 -7 days old Indicate this on NBS card May have false positive test results 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 Newborn Screening Ontario website – educational resource for blood spot collection: http: //www. newbornscreen ing. on. ca

NBS: For your information n Location ¨ Newborn Screening Ontario at CHEO http: //www. newbornscreening. on. ca n 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 n Educational materials ¨ MOH & NSO have developed materials for the public and healthcare providers Parents will ask you about NBS

NBS Report

Screen Positive Results n Screen positive means: Further testing is required to confirm the diagnosis ¨ Does NOT mean that the infant is affected ¨ n n 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.

Results of Expanded NBS by MS/MS Schulze et al. Pediatrics 2003 n 250, 000 neonates screened for 23 inborn errors of metabolism ¨ 106 newborns with confirmed n 70 required treatment metabolic disorder 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 ¨ Overall § = 92. 6% for variants ¨ 61 /106 were judged to have benefited from screening and treatment n 58% of true positives n 1/4100 newborns

Negative Results n Results will go to: ¨ Submitting n 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 is a screening test – not diagnostic

Expanded NBS – 29 conditions n 20 inborn errors of metabolism ¨ 9 organic acid disorders ¨ 5 fatty acid oxidation disorders ¨ 6 amino acid disorders 3 hemoglobinopathies n 2 endocrine disorders n 3 other metabolic disorders n Hearing loss n

Inborn errors of metabolism Rare n Usually autosomal recessive inheritance ¨consanguinity is more common n Symptoms secondary to a problem in the metabolic pathway n Usually not significant dysmorphism n Early recognition and intervention can be lifesaving n

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 n n n n n Isovaleric acidemia (IVA) Glutaric acidemia type 1 (GA 1) HMG-Co. A lyase deficiency (HMG) Multiple carboxylase deficiency (MCD) Methylmalonic acidemia (MMA) Methylmalonic acidemia (MUT, Cbl) 3 -methylcrotonyl-Co. A carboxylase (3 MCC) deficiency Propionic acidemia (PA) Β-ketothiolase deficiency (BKT)

Organic Acid Disorders n 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 n Symptoms ¨ acute encephalopathy, vomiting, metabolic acidosis, ketosis, hyperammonemia, hypoglycemia, coma ¨ dehydration, failure to thrive, hypotonia, global developmental delay ¨ sepsis, death n Treatment ¨ Low protein diet / restrict amino acids, ¨ Supplements: carnitine, biotin, riboflavin, ¨ Avoid fasting glycine

Fatty Acid Oxidation Disorders Medium-chain acyl-Co. A dehydrogenase (MCAD) deficiency n Very long-chain acyl-Co. A dehydrogenase deficiency (VLCAD) n Long-chain L-3 -OH acyl-Co. A dehydrogenase deficiency (LCHAD) n Trifunctional protein deficiency (TFP) n ¨ catalyzes 3 steps in mitochondrial betaoxidation of fatty acids n Carnitine uptake defect (CUD)

Disorders of Fatty Acid Oxidation n 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 n Symptoms ¨ Decompensate with any catabolic n fever, fasting, intercurrent illness stress ¨ Hypoketotic hypoglycemia, liver, muscle, heart disease ¨ Lethargy, seizures, coma, sudden death (SIDS) n Treatment ¨ Avoid fasting ¨ IV glucose when ill to prevent hypoglycemia ¨ Frequent feeding

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

Amino Acid Disorders n 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 n Symptoms (untreated) example PKU ¨ Hyperphenylalaninemia (neurotoxic) ¨ Microcephaly, epilepsy, mental retardation, behaviour problems n Treatment ¨ Diet: reduce phenylalanine, low protein, supplement cofactors or essential amino acids

Expanded NBS – 29 conditions 20 inborn errors of metabolism n 3 hemoglobinopathies n 2 endocrine disorders n ¨ Congenital hypothyroidism ¨ Congenital adrenal hyperplasia 3 other metabolic disorders n Hearing loss n

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) n 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 ¨ n Symptoms Virilization (♀ ambiguous genitalia), precocious puberty, infertility, short stature ¨ Renal salt wasting leads to FTT, vomiting, dehydration, hypotension, hyponatremia, & hyperkalemia ¨ n Treatment ¨ Glucocorticoid replacement therapy

Expanded NBS – 29 conditions 20 inborn errors of metabolism n 3 hemoglobinopathies n ¨ Sickle cell disease (Hb-SS) ¨ SC disease (Hb-SC) ¨ Sickle beta thalassemia ¨ Other hemoglobinopathies may reported if clinically significant 2 endocrine disorders n 3 other metabolic disorders n Hearing loss n

Sickle Cell Disease n What is sickle cell disease? (Hb SS) ¨ n Symptoms ¨ n Change in the shape of the betaglobin component of the hemoglobin molecule that interferes with hemoglobin’s ability to carry oxygen 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) ¨ n 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 n 3 hemoglobinopathies n 2 endocrine disorders n 3 other metabolic disorders n ¨ Biontinidase deficiency ¨ Galactosemia ¨ Cystic fibrosis n Hearing loss

Other Disorders: Biotinidase deficiency n What is biotinidase deficiency? ¨ Biotinidase is responsible for recycling biotin – a cofactor for 4 dependant carboxylases n Symptoms ¨ Metabolic ketoacidosis, organic aciduria, mild hyperammonemia ¨ Seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, cutaneous abnormalities n Treatment ¨ 5 -10 mg of oral biotin per day, long term treatment prevents all symptoms

Other Disorders: Galactosemia n 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 n Symptoms ¨ Feeding problems, FTT, bleeding, infection, liver failure, cataracts, mental retardation, death n Treatment ¨ Lactose-galactose-restricted diet n 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 n What is cystic fibrosis? ¨ n Symptoms ¨ ¨ ¨ n Due to mutations in the CFTR gene which is responsible for chloride regulation and other transport pathways. 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 n Healthy 1 week old n Parents worried re risk of SIDS n First daughter died of SIDS 5 years earlier n Carmen’s cousin died of SIDS at 18 months n

Case 1: Amy – 5 days old n You receive a call that Amy has screened positive for MCAD deficiency ¨ Medium n n n chain acyl-Co. A 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 MI British / French Irish / German – 39 A&W 79 Prost Ca Dx 74 died 65 69 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 n Amy’s expanded newborn screening report is the following: ¨Screen positive for medium chain acyl-Co. A deficiency

MCAD (medium chain acyl-Co. A deficiency) n Incidence ¨ 1 in 4, 900 – 1 in 17, 000 ¨ most prevalent in North Europeans n Inheritance ¨ Autosomal n recessive (Gene: ACADM) Enzyme ¨ Medium-chain n acyl-coenzyme A dehydrogenase Function ¨ Mitochrondrial fatty acid β-oxidation ¨ Required for energy and ketone body ¨ Important during prolonged fasting production

MCAD: Symptoms n n n Usually presents at 3 to 24 months Triggered by fever, illness, or fasting Symptoms: ¨ Hypoglycemia, vomiting ¨ Lethargy → coma → death ¨ Encephalopathy, respiratory arrest, hepatomegaly, seizures n 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 n Early diagnosis and treatment of MCAD can prevent sudden death n MCAD responsible for ~1% of SIDS cases, all FAO disorders ~4% n ¨ Opdal et al. Pediatrics 2004; 114: 506 -512

MCAD: Management n Infants require frequent feedings ¨ Formulas containing medium chain triglycerides as the primary source of fat should be avoided Avoid prolonged fasting, hypoglycemia n Aggressive treatment of illness often with IV fluids especially when vomiting n

Case 2 Angela receives a call from Newborn Screening Ontario for a repeat NBS sample for her newborn, Liam. n Angela comes to your office for a routine newborn visit. n Liam’s newborn screening report: n ¨ Positive, for cystic fibrosis ¨ Category B IRT>96% n Delta. F 508 (one mutation identified) n

What are the next steps? ~1 in 40 chance of being affected with CF n Sweat chloride test is next step n ¨ 3 possible results: Abnormal – affected with CF n Borderline – inconclusive, follow up with specialist n Normal – unaffected, but carrier of CF n n Blood work: ¨ Confirmatory n genetic testing Genetic counselling is recommended

NBS for cystic fibrosis n 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 n no evidence of difference in adulthood ¨ ? improved survival by 10 years of age ¨ ? reduced mortality n Identification enables family planning

Liam’s results n n 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 delta. F 508 mutation + normal gene ¨ James – carrier of CF R 553 X mutation + normal gene ¨ Risk to have a child affected with CF n 25% with each pregnancy

NBS – Bottom Line Offer newborn screening n Discuss the benefits n Discuss how testing is done n Discuss timing n Repeat sample sometimes required n Discuss difference between screening and diagnostic test n Discuss possible results n Answer questions/brochure n

Provincial Educational Materials n n n 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 n 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 n Newborn Screening Ontario Website: http: //www. newbornscreening. on. ca/bins/index. asp n n 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 n American College of Medical Genetics – fact sheets http: //www. acmg. net/resources/policies/NBSsections. htm n American Academy of Pediatrics – fact sheets http: //aappolicy. aappublications. org/cgi/content/abstra ct/pediatrics; 118/3/e 934 n American Academy of Family Physicians – Information & resources http: //www. aafp. org/afp/2008/0401/p 987. html n Ontario Medical Association – Important changes to NBS in Ontario http: //www. oma. org/Health/newborn/06 newborn. asp

The Genetics Education Project Committee § § § § § June C Carroll MD CCFP Judith Allanson MD FRCP(C) FCCMG FABMG Sean Blaine MD CCFP Mary Jane Esplen Ph. D RN Sandra Farrell MD FRCPC FCCMG Judy Fiddes Gail Graham MD FRCPC FCCMG Jennifer Mac. Kenzie MD FRCPC FAAP FCCMG Wendy Meschino MD FRCPC FCCMG § § § § Fiona Miller Ph. D Joanne Miyazaki Andrea L. Rideout MS CGC CCGC Linda Spooner RN BSc. N Cheryl Shuman MS CGC Anne Summers MD FCCMG FRCPC Sherry Taylor Ph. D FCCMG Brenda Wilson BSc MB Ch. B MSc MRCP(UK) FFPH

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