The Genetics Education Project Prepared by: June C. Carroll, MD, CCFP, FCFP Sydney G. Frankfort...

The Genetics Education ProjectThe Genetics Education Project

Prepared by: June C. Carroll, MD, CCFP, FCFPSydney G. Frankfort Chair in Family Medicine

Associate Professor, Department of Family Medicine Mount Sinai Hospital, University of Toronto

Andrea L. Rideout, MS, CCGC, CGCProject Manager / Genetic Counsellor

The Genetics Education Project

Funded by: Ontario Women’s Health Council

Version: August 2007

Newborn Screening: Ontario’s Expanded Screening Program


Acknowledgments Reviewers:

Members of The Genetics Education ProjectOntario Newborn Screening Program: Dr. Michael Geraghty, Mireille Cloutier MSC., Christina Honeywell MSc., Sari Zelenietz 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 disorders by the

end of 2008

– 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– 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


Benefits of NBS

Identification Early intervention Reduced morbidity and 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


Public’s 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


Why Changes to NBS now?

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


NBS: What’s NOT changing?

Heel prick method for sample collection

NBS: What’s changing? New screening card Location: Children’s Hospital of Eastern Ontario Transportation – sample cards are sent via

Canada Post courier service to Ontario NBS Program


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– 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


The Heel Test


What makes a good spot?


NBS: What’s New? Location

– Children’s 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


NBS Report

Cystic fibrosis- 2008


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 infant’s 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.


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


Results

Results will go to:– Submitting health care professional /hospital– Infant’s health care professional – if this information is

completed on the screening card


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


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


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


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) 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, GDD– 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)


Disorders of Fatty Acid Oxidation What are disorders of fatty acid oxidation?

– Breakdown of fatty acids in mitochondria is 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– Frequent feeding– IV glucose when ill to prevent hypoglycemia


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

– 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


Endocrine Disorders: CHCongenital 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


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


Hemoglobinopathies

Sickle cell disease (Hb SS) Hemoglobin SC disease Sickle-β thalassemia (Hb S/β-thal) Other hemoglobin variants may be

picked up as variants


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– Do not rely on solubility testing methods (Sickledex etc)

Treatment– Prophylactic penicillin (84% reduction in infection)– Vaccinations (pneumococcal, influenza)


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)– > 50% normal hemoglobin – generally asymptomatic

no clinical symptoms

Other hemoglobin variants Autosomal recessive inheritance


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, 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


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 at 13 months


Case 1

MI – died 69

39

A&W

37

Schizophrenic

35GeorgeA&W

25

A&W

65

A&W

29

A&W

1 wkAmy A& W

SIDS

8 months

79

Prost Ca Dx 74

72

A&W

32CarmenA&W

British / FrenchIrish / German

SIDS13 months

49Accident

7 5

A&W A&W

PC 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– Energy source once hepatic glycogen stores become

depleted– 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: 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

Toddlers: 2g/kg of uncooked cornstarch at bedtime to ensure sufficient glucose overnight

High carbohydrate, low fat diet Carnitine supplementation Avoid fasting, hypoglycemia


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?


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


Case 2 – sequential testing of family members

P

Hb - AA Hb - AS Hb - AS Hb - AS

3monthsHb - SS

22Hb - AS Hb - AS

1 weekHb - AS

24Hb - AS

Hb - AA

Hb - AA Hb - AA

Hb - AA

Hb - AAHb - AAHb - AA

Jamaica Barbados

HbAS- Sickle cell trait

HbSS – Sicklecell disease

Legend


Prevalence : HemoglobinopathiesEthnicity Hb S trait Hb C trait β thal trait α thal trait

Mediterranean 1/30 -50 Rare 1/20 – 30 1/30-50

African American 1/12 1/50 1/75 1/30

Non-Hispanic Caribbean

1/12 1/30 1/50 -75 1/30

West African 1/6 1/20-30 1/50 1/30

Hispanic Caribbean 1/30 Rare 1/75 Variable

Mexican, Central American

1/30-200 Rare 1/30-50 Variable

Asian Rare Rare 1/50 1/20 *

Southeast Asian Rare Rare 1/30 >1/20*

Asian subcontinent 1/50–100 Rare 1/30-50 Variable

Middle Eastern 1/50-100 Rare 1/50 variable

*In cis – 2 α thal deletions on same chromosome Source: March of Dimes


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


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 Children’s Hospital of Eastern Ontario Room 3127, 401 Smyth Road Ottawa, ON K1H 8L1

(613) 738-3222

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


Resources CHEO’s 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


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


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