Newborn Screening: Ontario’s Expanded Screening Program

Prepared by: June C Carroll MD, CCFP, FCFPSydney G. Frankfort Chair in Family MedicineMount Sinai Hospital, University of Toronto

Andrea Rideout MS, CGC, CCGCCertified Genetic CounsellorProject 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.newbornscreening.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/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

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

Disorders: Germany2003

USA2006

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

Frequency of Inborn Errors of Metabolism (IEM) using MS/MS Tandem Mass Spectrometry

(*) 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 beta-oxidation 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 beta-oxidation 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: CHCongenital 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, 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

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

–

39

A&W

37

Schizophrenic

35GeorgeA&W

25

A&W

29

A&W

11 wkAmy A& W

SIDS

79Prost Ca Dx 74

72

A&W

32CarmenA&W

British / FrenchIrish / German

SIDS13 months

49Accident

7 5

A&W A&W

PS S

Legend

Prostatecancer

SIDS

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: 1-

800-387-5559 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 Sheetswww.health.gov.on.ca/newbornscreening

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

sheetshttp://www.acmg.net/resources/policies/NBS/NBS-sections.htm

American Academy of Pediatrics – fact sheetshttp://aappolicy.aappublications.org/cgi/content/abstract/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 Ontariohttp://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

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