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  • Newborn Screening: Ontarios Expanded Screening ProgramPrepared 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 Womens Health Council

    Version: May 2010

  • AcknowledgmentsReviewers: Members of The Genetics Education ProjectOntario Newborn Screening Program: Dr. Michael Geraghty, Mireille Cloutier MSc., Christina Honeywell MSc., Sari Zelenietz MSc, Shelley Kennedy 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.

  • Newborn Screening Whats new?Previously: PKU, congenital hypothyroidism, hearing lossBeginning 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 conditions20 inborn errors of metabolism3 hemoglobinopathies2 endocrine disordersCongenital hypothyroidismCongenital adrenal hyperplasia3 other metabolic disordersCystic fibrosisGalactosemiaBiotinidase deficiency Hearing loss

  • Benefits of NBSIdentification Early interventionReduced morbidity & mortality Family planning

  • Risks of NBSParental anxiety (false positives)Missed diagnosis (false negatives)The right not to knowUnanticipated outcomesLabelling diagnosis of benign conditions

  • NBS: how & where is it done?Method: Heel prickSample collection: newborn screening cardTesting Location: Newborn Screening Ontario (NSO) at Childrens Hospital of Eastern Ontario (CHEO)Transportation: NBS cards are sent via courier service

  • Timing of TestingAcceptable samplesbetween 1 day (24 hours) and 7 days after birthBest time for sample:between 2 days (48 hours) and 3 days (72 hours) after birthIf tested before 1 day (24 hours) of age, REPEAT the test within 5 days*If the baby is >5 days, screening is still availableContact NSO program for details

    *Repeat sample within 5 days has been the Ontario standard of care since 2001

  • Special ConsiderationsPrematurity or illnessIf
  • The Heel Test

  • What makes a good spot?

    See Newborn Screening Ontario website educational resource for blood spot collection:http://www.newbornscreening.on.ca

  • NBS: For your informationLocationNewborn Screening Ontario at CHEO http://www.newbornscreening.on.ca Tandem Mass SpectrometryAllows screening for multiple conditions concurrentlySame cost to screen for one condition as multipleIncreased sensitivity and specificityScreening for some metabolites can give information about several diseasesEducational materialsMOH & NSO have developed materials for the public and healthcare providers

    Parents will ask you about NBS

  • NBS Report

  • Screen Positive ResultsScreen positive means:Further testing is required to confirm the diagnosisDoes NOT mean that the infant is affectedNSO will immediately notify regional treatment centreRegional treatment centre will notify the infants healthcare provider and/or parents and arrange confirmatory testingIf diagnosis is confirmed, regional treatment centre will provide management counselling & follow upReport 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 2003250,000 neonates screened for 23 inborn errors of metabolism106 newborns with confirmed metabolic disorder70 required treatmentOverall prevalence of metabolic disorder = 1/2400825 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 variants61 /106 were judged to have benefited from screening and treatment58% of true positives1/4100 newborns

  • Negative ResultsResults 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 evaluationNBS panel does not screen for every metabolic conditionNBS is a screening test not diagnostic

  • Expanded NBS 29 conditions20 inborn errors of metabolism 9 organic acid disorders5 fatty acid oxidation disorders6 amino acid disorders3 hemoglobinopathies2 endocrine disorders3 other metabolic disordersHearing loss

  • Inborn errors of metabolismRareUsually autosomal recessive inheritanceconsanguinity is more commonSymptoms secondary to a problem in the metabolic pathwayUsually not significant dysmorphismEarly recognition and intervention can be lifesaving

  • Frequency of Inborn Errors of Metabolism (IEM) using MS/MS Tandem Mass Spectrometry(*) Does not include tyrosinemia type 1 and 2

    Disorders:Germany2003USA2006Amino Acid Disorders (*)1/3,8001/14,600Organic Acid Disorders1/14,7001/15,900Fatty Acid Oxidation Disorders1/10,4001/10,100IEM combined frequency(*)~1/4,300~1/2,400All NBS: IEM, CF, CAH, biotinidase, galactosemia~1/1,500Not reported

  • Organic Acid DisordersIsovaleric 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)-ketothiolase deficiency (BKT)

  • Organic Acid DisordersWhat are organic acid disorders?Body cannot metabolize certain amino acids and fatsAccumulation of organic acids in blood and urineSerious potentially preventable effects on health and development, including deathSymptomsacute encephalopathy, vomiting, metabolic acidosis, ketosis, hyperammonemia, hypoglycemia, comadehydration, failure to thrive, hypotonia, global developmental delaysepsis, death TreatmentLow protein diet / restrict amino acids, Supplements: carnitine, biotin, riboflavin, glycineAvoid fasting

  • Fatty Acid Oxidation DisordersMedium-chain acyl-CoA dehydrogenase (MCAD) deficiencyVery 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 OxidationWhat are disorders of fatty acid oxidation?Breakdown of fatty acids in mitochondria is an essential part of bodys ability to produce energy Disorder: inability to break down fatty acidsSymptomsDecompensate with any catabolic stressfever, fasting, intercurrent illness Hypoketotic hypoglycemia, liver, muscle, heart diseaseLethargy, seizures, coma, sudden death (SIDS)TreatmentAvoid fastingIV glucose when ill to prevent hypoglycemiaFrequent feeding

  • Amino Acid DisordersPhenylketonuria (PKU)Maple syrup urine disease (MSUD)Tyrosinemia type 1 (TYR 1)Common in French CanadiansHomocystinuria (HCY)Citrullinemia (CIT)Argininosuccinic acidemia (ASA)

  • Amino Acid DisordersWhat are amino acid disorders?Occur when the body cannot either metabolize or produce certain amino acidsResult in toxic accumulation of substancesSerious potentially preventable effects on health and development including deathSymptoms (untreated) example PKU Hyperphenylalaninemia (neurotoxic)Microcephaly, epilepsy, mental retardation, behaviour problems TreatmentDiet: reduce phenylalanine, low protein, supplement cofactors or essential amino acids

  • Expanded NBS 29 conditions20 inborn errors of metabolism 3 hemoglobinopathies2 endocrine disordersCongenital hypothyroidismCongenital adrenal hyperplasia3 other metabolic disordersHearing loss

  • Endocrine Disorders: CHCongenital Hypothyroidism (CH) What is CH?inadequate thyroid hormone productionAnatomic defect in gland, dyshormogenesis, iodine deficiencySymptomsMR, growth & bone maturation, neurologic problems: spasticity, gait abn, dysarthria, autistic behaviour TreatmentDiagnosis made before 13 days to prevent symptoms Thyroid hormone replacement

  • Endocrine Disorders: CAHCongenital Adrenal Hyperplasia (CAH)

    What is CAH?Impaired synthesis of cortisol by the adrenal cortex leads to androgen biosynthesisInability to maintain adequate energy & blood glucose level to meet stress of injury & illnessSymptomsVirilization ( ambiguous genitalia), precocious puberty, infertility, short stature Renal salt wasting leads to FTT, vomiting, dehydration, hypotension, hyponatremia, & hyperkalemia TreatmentGlucocorticoid replacement therapy

  • Expanded NBS 29 conditions20 inborn errors of metabolism 3 hemoglobinopathiesSickle cell disease (Hb-SS)SC disease (Hb-SC)Sickle beta thalassemiaOther hemoglobinopathies may reported if clinically significant2 endocrine disorders3 other metabolic disordersHearing loss

  • Sickle Cell DiseaseWhat 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 oxygenSymptomsPainful vaso-occlusive crises, hemolytic anemia, frequent infections, tissue ischemia, chronic organ dysfunctionDiagnosisQuantitative hemoglobin electrophoresis and/or Molecular analysisDo not rely on solubility testing methods (Sickledex etc)TreatmentProphylactic penicillin (84% reduction in infection)Vaccinations (pneumococcal, influenza)Aggressive treatment of fever and dehydration

  • Expanded NBS 29 conditions20 inborn errors of metabolism 3 hemoglobinopathies2 endocrine disorders3 other metabolic disordersBiontinidase deficiencyGalactosemiaCystic fibrosisHearing loss

  • Other Disorders:Biotinidase deficiencyWhat is biotinidase deficiency?Biotinidase is responsible for recycling biotin a cofactor for 4 dependant carboxylasesSymptomsMetabolic ketoacidosis, organic aciduria, mild hyperammonemiaSeizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, cutaneous abnormalitiesTreatment5-10mg of oral biotin per day, long term treatment prevents all symptoms

  • Other Disorders: GalactosemiaWhat is galactosemia?Lactose is main sugar in breast milk & infant formulasMetabolized into glucose and galactose in the intestineUnable to break down galactoseSymptoms Feeding problems, FTT, bleeding, infection, liver failure, cataracts, mental retardation, death TreatmentLactose-galactose-restricted diet must be started in first 10 days of life to prevent symptomsEven with treatment - developmental delay, speech problems, abn motor function, premature ovarian failure

  • Other Disorders: Cystic fibrosisWhat is cystic fibrosis?Due to mutations in the CFTR gene which is responsible for chloride regulation and other transport pathways.Symptoms Chronic sinopulmonary diseaseGastrointestinal/nutritional abnormalitiesAzoospermia (males)Salt loss syndromeShortened life span but improving with treatmentTreatmentPulmonary: 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 1Carmen and George bring Amy into your office for 1 week visitHealthy 1 week oldParents worried re risk of SIDSFirst daughter died of SIDS 5 years earlierCarmens cousin died of SIDS at 18 months

  • Case 1: Amy 5 days oldYou receive a call that Amy has screened positive for MCAD deficiencyMedium chain acyl-CoA dehydrogenase deficiencyYou ask Carmen and George to bring her in that dayHealthy 5 day oldParents worried about risk of SIDSFirst daughter died of SIDS 5 years earlierCarmens cousin died of SIDS months

  • Case 1MI died 69 39A&W 37Schizophrenic 35GeorgeA&W 25A&W 65A&W 29A&W 11 wkAmy A& WSIDS 79 Prost Ca Dx 74 72A&W 32CarmenA&WBritish / FrenchIrish / GermanSIDS13 months 49Accident 7 5A&W A&W

  • Case 1Amys expanded newborn screening report is the following:

    Screen positive for medium chain acyl-CoA deficiency

  • MCAD (medium chain acyl-CoA deficiency)Incidence1 in 4,900 1 in 17,000 most prevalent in North EuropeansInheritanceAutosomal recessive (Gene: ACADM)EnzymeMedium-chain acyl-coenzyme A dehydrogenaseFunctionMitochrondrial fatty acid -oxidationRequired for energy and ketone body productionImportant during prolonged fasting

  • MCAD: SymptomsUsually presents at 3 to 24 monthsTriggered by fever, illness, or fastingSymptoms:Hypoglycemia, vomitingLethargy coma deathEncephalopathy, respiratory arrest, hepatomegaly, seizuresLong 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 casesEarly diagnosis and treatment of MCAD can prevent sudden deathMCAD responsible for ~1% of SIDS cases, all FAO disorders ~4%Opdal et al. Pediatrics 2004;114:506-512

  • MCAD: ManagementInfants require frequent feedingsFormulas containing medium chain triglycerides as the primary source of fat should be avoidedAvoid prolonged fasting, hypoglycemiaAggressive treatment of illness often with IV fluids especially when vomiting

  • Case 2Angela 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.Liams newborn screening report:Positive, for cystic fibrosisCategory BIRT>96%DeltaF508 (one mutation identified)

  • What are the next steps?~1 in 40 chance of being affected with CFSweat chloride test is next step3 possible results:Abnormal affected with CFBorderline inconclusive, follow up with specialist Normal unaffected, but carrier of CFBlood work:Confirmatory genetic testingGenetic counselling is recommended

  • NBS for cystic fibrosisSome evidence that early identification leads to better outcomesLower incidence of malnutritionImproved growth (height, weight)Better lung function parameters at 10 years of ageno evidence of difference in adulthood?improved survival by 10 years of age?reduced mortalityIdentification enables family planning

  • Liams resultsSweat test results NormalLiam is a carrier of CFHe will not develop CF Parents Angela and James have genetic counsellingAngela carrier of CF deltaF508 mutation + normal geneJames carrier of CF R553X mutation + normal geneRisk to have a child affected with CF25% with each pregnancy

  • NBS Bottom LineOffer newborn screeningDiscuss the benefitsDiscuss how testing is doneDiscuss timingRepeat sample sometimes requiredDiscuss difference between screening and diagnostic testDiscuss possible resultsAnswer questions/brochure

  • Provincial Educational Materialswww.health.gov.on.ca/newbornscreeningMOHLTC INFOline at 1-866-532-3161/TTY: 1-800-387-5559Contact Newborn Screening Ontario: Telephone: 613-738-3222www.newbornscreening.on.caEducational 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

  • ResourcesNewborn Screening Ontario Website:http://www.newbornscreening.on.ca/bins/index.aspMarch of Dimes:www.marchofdimes.comGenetests:www.genetests.orgNational Newborn Screening & Genetics Resource Center:genes-r-us.uthscsa.eduPediatrix US private lab offering NBSwww.pediatrix.com

  • ResourcesAmerican College of Medical Genetics fact sheetshttp://www.acmg.net/resources/policies/NBS/NBS-sections.htmAmerican Academy of Pediatrics fact sheetshttp://aappolicy.aappublications.org/cgi/content/abstract/pediatrics;118/3/e934 American Academy of Family Physicians Information & resourceshttp://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 CommitteeJune C Carroll MD CCFPJudith Allanson MD FRCP FRCP(C) FCCMG FABMGSean Blaine MD CCFPMary Jane Esplen PhD RNSandra Farrell MD FRCPC FCCMG Judy FiddesGail Graham MD FRCPC FCCMG Jennifer MacKenzie MD FRCPC FAAP FCCMGWendy Meschino MD FRCPC FCCMGFiona Miller PhDJoanne Miyazaki Andrea L. Rideout MS CGC CCGCLinda Spooner RN BScNCheryl Shuman MS CGC Anne Summers MD FCCMG FRCPC Sherry Taylor PhD FCCMGBrenda Wilson BSc MB ChB MSc MRCP(UK) FFPH

  • ReferencesOntario Ministry of Health and Long Term Care, News release November 2, 2005: Ontario becomes national leader in newborn screening, New state-of-the-art testing program means that children will have a better start on life http://www.health.gov.on.ca/english/media/news_releases/archives/nr_05/nr_110205.html Ontario Ministry of Health and Long Term Care, News release November 23, 2006: McGuinty government expands newborn screening, Screening for cystic fibrosis brings total number of tests to 28. http://www.health.gov.on.ca/english/media/news_releases/archives/nr_06/nov/nr_112306.htmlBellis MA, Hughes K, Hughes S, Aston JR. Measuring parent discrepancy and its public health consequences. J Epidemiol Community Health 2005; 59: 749-754.Ontario Ministry of Health and Long Term Care, Newborn Screening website: http://www.health.gov.on.ca/english/providers/program/child/screening/screen_sum.html www.health.gov.on.ca/english/providers/program/child/screening/screen_sum.html

  • ReferencesNCCLS (National Committee for Clinical Laboratory Standards now known as CLSI Clinical Laboratory Standards Institute) LAR-A3 Blood collection on filter paper for neonatal screening programs: approved standard, third edition.Simple Spot Check 04/03/02 Lit. #718 produced by Schleicher & Schuell BioScience Inc. 10 Optical Ave, Keene NH 03431 USA. Scheicher & Schuell BioScience GmbH P.O. Box 1160, D-37582 Dassel, Germany. Waston MS, Mann MY, Lloyd-Puryear MA, Rinaldo P, Howell RR. Executive summary: Newborn screening panel and system. Genet Med 2006; 8 (5, supplement): 1s-11s. Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: Results, outcome and implications. Pediatrics 2003; 111:1399-1406.

  • ReferencesApplegarth Da, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969 1996. Pediatrics 2000: 105:e10-e16.Frazier DM, Millington DS, McCandless SE, Keoberl DD, Weavil Sd, Chaing SH, Muenzer J. The tandem mass spectrometry newborn screening experience in North Carolina: 1997-2005. J Inhert Metab Dis 2006; 29:76-85.Marsden D, Larson C, Levy Hl. Newborn screening for metabolic disorders. J Pediatr 2006; 148:577-584.Centers for Disease Control and Prevention. Impact of expanded newborn screening United States 2006 Morbidity and Mortality Weekly Report. 2008;57:1012-1015.

  • ReferencesSeashore MA. Genetest Reviews: The organic acidemias: An overview. Last updated 03 July 2007. www.genetests.org. Ogier de Baulny HO, Saudubray JM. Branched-chain organic acidurias. Semin Neonatol. 2002; 7:65-74.Venditti CP. Genetests Reviews: Methylmalonic Acidemia. Last updated 18 January 2007. www.genetests.org. Korman SH. Inborn errors of isoleucine degradation: A review. Mol Genet Metab. 1006: 89:289-299.Gibson KM, Breuer J, Kiaser K, Nylan WL, McCoy EE, Ferreira P, Greene CL, Blitzer MG, Shapira E, Reverte F, Conde C, Bagnell P, Cole DEC. 3-hydroy-3-methylglutaryl-coenzyme A lyase deficiency: Report of five new patients. J Inhert Metab Dis 1988; 11:76-87.Roth KS. Holocarboxylase Deficiency. Last updated 31 August 2007. http://www.emedicine.com/ped/topic1020.htm

  • ReferencesAngelini C, Federico A, Reichmann H, Lombes, Chinnery P, Turnbull D. Task force guidelines handbook: EFNS guidelines on diagnosis and management of fatty acid mitochondrial disorders. Eur J Neurol. 2006; 13:923-929.Saudubray JM, Martin D, deLonlay P, Touati G, Poggi-Travert F, bonnet D, Jouvet P, Boutron M, Slama A, Vianey-saban C, Bonnefont JP, Rabier, Kamoun P, Brivet M. Recognition and management of fatty acid oxidation defects: A series of 107 patients. J Inherit Metabo Dis. 1999; 22:488-502.Hellekson KL; National Institutes of Health. Am Fam Physician. 2001 63:1430 1432. National Institutes of Health Consensus Development Panel. National institutes of Health consensus development conference statement: Phenylketonuria screening and management, October 16-18 2000. Pediatrics 2001; 108: 972-982.Mitchell JJ, Scriver CR. Genetests Reviews: Phenylalanine hydroxylase deficiency. Last updated 29 march 2007. www.genetests.org. Morton DH, Strauss KA, Robinson DL, Puffenberger EG, Kelley RI. Diagnosis and treatment of maple syrup urine disease: A study of 36 patients. Pediatrics 2002; 109:999-1008.

  • ReferencesLe Roux C, Murphy E, Liblurn M. The longest surviving patient with classical maple syrup urine disease. J Inherit Metab Dis 2006; 29:190-194.Strauss KA, Puffenberger EG, Morton DH. Genetests Reviews: Maple Syrup Urine Disease. Last updated 30 January 2006. www.genetests.org. Scott CR. The genetic tyrosinemias. Am J Med Genet Part C Semin Med Genet 2006; 142C:121-126.Russo PA, Mitchell GA, Tanguay RM. Tyrosinemia: a review. Pediatr Dev Pathol. 2001; 4:212-221.Sniderman King L, Trahms C Scott R. Genetests Reviews: Tyrosinemia Type I. Last updated 31 October 2008. www.genetests.org.Walter JH, Wraith JE, White FJ, Bridge C, Till J. Strategies for the treatment of cystathionine -synthase deficiency: the experience of the Wilink Biochemical Genetics Unit over the past 30 years. Eur J Pediatr. 1998; 157(Suppl 2):s71-s76.

  • ReferencesDe Franchis R, Sperendeo MP, Sebastio G, Andria G. The Italian Study group on Homocystinuria. Clinical aspects of the cynstathionine -synthase deficiency: how wide is the clinical spectrum? Eur J Pediatr. 1998; 157(Suppl 2):s67-s70.Picker JD. Levy HL. Genetests Reviews: Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. Last updated 29 March 2006. www.genetests.org. Summar M, Tuchman M. Proceeding of a consensus conference for the management of patients with urea acid cycle disorders. J Pediatr. 2001; 138(Suppl1):s6-s10.The Urea Cycle Disorders Conference Group. Consensus statement from a conference for the management of patients with urea cycle disorders. J Pediatr. 2001; 138(Suppl1):s1-s5.Summar, ML. Genetests Reviews: Urea Cycle Disorders Overview. Last updated 11 August 2005. www.genetests.org. Thoene, JG. Genetests Reviews: Citrullinemia Type I. Last updated 02 June 2009. www.genetests.org

  • ReferencesRoth KS. Argininosuccinate Lyase Deficiency. Last Updated 24 March 2009. www.emedicine.com - free registration is required. If you are already registered the direct link is: http://emedicine.medscape.com/article/950752-overview American Academy of Pediatrics; Rose SR; Section on Endocrinology and Committee on Genetics, American Thyroid Association; Brown RS; Public Health Committee, Lawson Wilkins Pediatric Endocrine Society; Foley T, Kaplowitz PB, Kaye CI, Sundararajan S, Varma SK. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics. 2006 Jun;117:2290-2303.Postellon D, Bourgeois MJ, Varma S. eMedicine: Congenital Hypothyroidism. Last Updated: 23 August 2006 http://www.emedicine.com/ped/topic501.htmMerke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005; 365: 2125-2136.

  • ReferencesNew MI, Nimkarn S. GeneTests Reviews: Congenital Adrenal Hyperplasia, last update 7 September 2006. http://www.genetests.org.Wethers DL. Sickle cell disease in childhood: Part II. Diagnosis and treatment of major complications and recent advances in treatment. Am Fam Physician. 2000; 62: 1309-1314.Bender MA. GeneTests Reviews: Sickle cell Disease, last update 7 March 2006. http://www.genetests.orgWolf B. Worldwide survey of neonatal screening for biotinidase deficiency. J Inherit Metab Dis. 1991; 14:923-927.Wolf B. GeneTests Reviews: Biotinidase Deficiency, last update 25 September 2008. http://www.genetests.org.Bosch AM. Classical galatosemia revisited. J Inherit. Metab. Dis. 2006; 29:516-529.

  • ReferencesSchweitzer-Krantz S. Early diagnosis of inherited metabolic disorders improving outcome: the controversial issue of galactosemia. Eur J Pediatr. 2003; 162:s50-s503.Elsas LJ. GeneTests Reviews: Galactosemia, last update 27 September 2007. http://www.genetests.orgMoskowitz SM, Gibson RL, Sternen DL, Cutting GR. Genetests Reviews: CFTR-Related Disorders. Last updated 19 February 2008. www.genetests.org.Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodman D. Cystic fibrosis adult care: Consensus conference report. Chest 2004;125:s1-s39.Saiman L, Siegel J. Infection control recommendations for patients with cystic fibrosis: Microbiology, important pathogens and infection control to prevent patient to patient transmission, Cystic fibrosis consensus conference on infection control participants. Am J Infection Control 2003; 31:s1-s62.

  • ReferencesCystic Fibrosis Trust Clinical Standards and Accreditation Group. Standards of care for children and adults with cystic fibrosis in the UK. May 2001.Matern D, Rinaldo P. GeneTests Reviews: Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. Last update 3 February 2005. http://www.genetests.orgOpdal SH, Rognum TO. The sudden infant death gene: does it exist? Pediatrics 2004; 114:506-512.Grosse SD, Rosenfeld M, Devine OJ, Lai HJ, Farrell PM. Potential impact of newborn screening for cystic fibrosis on child survival: A systematic review and analysis. J Pediatr 2006;149:362-366.Dankert-Roelse JE, Merelle ME.Review of outcomes neonatal screening for cystic fibrosis verses non-screening in Europe. J Pediatr 2005; 147:s15-20.Southern KW, Mrelle MME, Dankert-Roelse JE, Nagelkerke A. Newborn screening for cystic fibrosis (Review). Cochrane Database of Systematic Reviews, Issue 1, 2009.

  • *Slide 1: Title*Slide 2: Acknowledgements 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.*Slide 3: Newborn Screening Whats New?Prior to April 2006, all babies born in Ontario were screened for 3 conditions:Phenylalanine hydroxylase deficiency (PKU)Congenital hypothyroidism (CH)Congenital hearing loss Metabolic, endocrine and haematological disorders are the focus of this educational module hearing screening will not be discussed.Beginning in April 2006, Ontario started the gradual expansion of the newborn screening program to include 29 disorders (including cystic fibrosis), plus screening for congenital hearing loss.1,2Tandem mass spectrometry will pick up an additional 20 disorders as variants (variants include disorders for which there is no known effective treatment and benign disorders which do not need treatment). Carrier status is reported for cystic fibrosis.

    *Slide 4: Expanded 29 conditionsInborn errors of metabolism, also known as inherited metabolic diseases, comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to genetic defects in genes that code for enzymes which facilitate conversion of various substances into other products. In the majority of these disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds.Hemoglobinopathies refer to diseases resulting from genetic alterations in the amount of, and/or structure of the alpha and/or beta chain components of hemoglobin. The clinical picture of hemoglobinopathies varies; ranging from benign (carriers) to transfusion-dependent anemia or lethal in some cases.Endocrine disorders refer to diseases involving the production or metabolism of hormones. Other conditions: galactosemia, biotinidase deficiency, cystic fibrosis and hearing loss. Galactosemia and biotinidase deficiency are both metabolic disorders that are not amino acid, organic acid or fatty acid disorders.Hearing loss will not be discussed in this module.*Slide 5: Benefits of NBSIdentification Early intervention:Start treatment before symptoms present Diagnosis while newborn is in crisis earlier, targeted treatment Reduction in unnecessary investigationsCost-savingReduced morbidity and mortality:Prevent metabolic crisis, metal retardation, SIDS, deathNot all developmental delay/symptoms can be prevented, but with early treatment, affected children can reach their full potentialFamily Planning:Parents can be informed of diagnosis and managementFamily members can be counselled about their own risk (if any) and the risk for future childrenResources and support groups for parents*Slide 6: Risks of NBSParental anxiety:There are concerns that parents may become anxious when they are informed of their childs initial screen positive result. Some of these parents may have persisting concerns about their childs health in spite of the negative confirmatory test. Other parents may express relief that the initial screening result was false.Missed diagnosis:False negatives. No screening test is perfect and some cases may be missed by NBS. The sensitivity and specificity of NBS for classic forms of inborn errors of metabolism are high; this may not be true for the variant or less severe forms of these conditions.The right not to know:Some parents would prefer not to know this information at birth and would prefer to wait until their child manifests symptoms of the disease, though with most of these conditions, the goal is to prevent and reduce symptoms before irreversible damage occurs.Unanticipated outcomes:Misattributed paternity: When an infant is identified with a condition on the NBS panel, sequential testing of the parents and other family members can identify previously unknown non-paternity.The misattributed paternity rate is ~4% per a recent meta-analysis, the literature ranges from 2 to 10% depending on the study. 3Labelling:There is concern that particularly when children are identified as carriers of disorders through NBS (i.e. hemoglobinopathy or cystic fibrosis) they may experience the negative consequences of labelling. This may include discrimination or different treatment by family, teachers etc. *Slide 7: NBS: how & where it is done?*Slide 8: Timing of testing4Samples should be collected between 24 hours (one day) to seven days after birthIdeal time for sample is 24 hours (one day) to 72 hours (three days) after birthSample cards should be sent to the NBS laboratory when the sample is dry, about four to six hours after collection, and no later than 24 hours after collection.Why is timing important? The levels of the various compounds in the blood spot change with the babys age. Analysis takes the age of the infant into consideration. Individual interpretation must be made by the lab director when an infant is tested outside of the one to seven day time frame. If infants are screened before 24 hours, the recommendation is to repeat these samples within 5 days. The goal is to conduct NBS within the first 7 days of life so that infants with these disorders can be identified and treated before serious problems such as brain damage have occurred.If the baby is >5 days, screening is still available. Contact Newborn Screening Ontario for details

    *Slide 9: Special considerations4Prematurity, total parenteral nutrition, and transfusion should be indicated on the NBS specimen collection card.Prematurity >37 weeks gestation: collect sample between five to seven days after birth. Premature infants can have false positive test results.Total parenteral nutrition (hyperalimentation): certain compounds (amino and organic acids) can be elevated in these cases and need to be taken into consideration when analyzing the sample.Transfusion: ideally a specimen card should be completed before transfusion. When completed after transfusion, the donors blood may normalize abnormal analyte levels (i.e. congenital hypothyroidism, biotinidase deficiency) and affected infants may be missed. Donor haemoglobin may also produce a false negative for sickle cell disease. Early discharge: A sample should be collected from every infant prior to discharge. If the infant is discharged before 24 hours of age, parents should be informed that a repeat sample after 24 hours of age must be done.*Slide 10: The Heel Test 5Acceptable samples:Heel prickDorsal hand veinPeripheral or central line unless this line is used for hyperalimentationUnacceptable samples:Cord bloodSamples that have been in contact with EDTA and citrate anticoagulants these can cause false negative results (CH, CAH, CF)Samples that have been contaminated with water, urine, feeding formulas, antiseptic solutions, powder from gloves Milking or squeezing puncture may cause hemolysis and an admixture of tissue fluidsHow to collect a specimen:To prevent contamination, do not touch any part of the filter paper circles before, during or after collection. Disposable gloves and powder lactose residue can contaminate the sample.Hold the infants heel lower than the heart, warm with water or a towel if necessary. Heat pack not to exceed 42 degrees C.Select puncture site. In the photograph, this is the shaded area.Cleanse puncture site with alcohol and NOT iodine. Allow puncture site to air dry.Puncture heel with sterile lancet, depth 98% of newborns screened were Caucasian. In the USA the proportion of Caucasians would be significantly less. The prevalence of some conditions varies by ethnic background.

    *Slide 20: Organic Acid DisordersThe nine disorders listed are core disorders recommended for screening by the Ontario NBS Advisory Committee following review of several reports and NBS programs including the ACMG NBS report. Below is a list of the core organic acid disorders including the secondary organic acid disorders or variants which can be detected when screening for these core disorders:Isovaleric acidemia (IVA)secondary target:2-Methylbutyryl-CoA dehydrogenase deficiency (2MBG)Glutaric acidemia type 1 (GA1)HMG-CoA lyase deficiency (HMG)secondary targets:3-Methylcrotonyl-CoA carboxylase deficiency (3MCC)2-Methyl 3-hydroxy butyric aciduria (2M3HBA)3-Methylglutaconic aciduria (3MGA)-ketothiolase deficiency (BKT)Multiple carboxylase deficiency (MCD)Methylmalonic acidemia (MMA) Methylmalonic acidemia (MUT, Cbl A,B)secondary targets:Methylmalonic acidemia (Cbl C, D)3-methylcrotonyl-CoA carboxylase (3MCG) deficiencyPropionic acidemia (PA)

    *Slide 21: Organic Acid DisordersFor a general overview of organic acid disorders see: (13) Seashore MA. Genetest Reviews: The organic acidemias: An overview. Last updated 03 July 2007. www.genetests.org. For a review of methylmalonic acidemia, propionic acidemia and isovaleric acidemia see: (14) Ogier de Baulny HO, Saudubray JM. Branched-chain organic acidurias. Semin Neonatol. 2002; 7:65-74.For more information about methylmalonic acidemia see: (15) Venditti CP. Genetests Reviews: Methylmalonic Acidemia. Last updated 18 January 2007. www.genetests.org. For more information about -ketothiolase deficiency, 2-Methylbutyryl-CoA dehydrogenase deficiency, 2-Methyl 3-hydroxy butyric aciduria see: (16) Korman SH. Inborn errors of isoleucine degradation: A review. Mol Genet Metab. 1006: 89:289-299.For more information about Hydrodroxymethylglutaric acidemia see: (17) Gibson KM, Breuer J, Kiaser K, Nylan WL, McCoy EE, Ferreira P, Greene CL, Blitzer MG, Shapira E, Reverte F, Conde C, Bagnell P, Cole DEC. 3-hydroy-3-methylglutaryl-coenzyme A lyase deficiency: Report of five new patients. For more information about multiple carboxylase deficiency see (18) Roth KS. Holocarboxylase Deficiency. Last updated 31 August 2007. http://www.emedicine.com/ped/topic1020.htm. *Slide 22: Fatty Acid Oxidation DisordersThe five disorders listed are core disorders recommended for screening by the Ontario NBS Advisory Committee following review of several reports and NBS programs including the ACMG NBS report. Below is a list of core fatty acid oxidation disorders and secondary fatty acid oxidation disorders which can be detected when screening for these core disorders:Medium-chain acyl-CoA dehydrogenase (MCAD) deficiencysecondary targets:Glutaric acidemia type 2 (GA2)Medium-chain ketoacyl-CoA thiolase deficiency (MCKAT)Medium/short-chain (L-3-OH acyl) hydroxyacyl-CoA dehydrogenase deficiency (M/SCHAD)Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD)secondary targets:Carnitine palmitoytransferase deficiency type 2 (CPT II)Carnitine acylcarnitine translocase deficiency (CACAT)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)secondary targets:Carnitine palmitoyltransferase deficiency type 1 (CPT I)*Slide 23: Fatty Acid Oxidation DisordersFor a review of Fatty Acid Oxidation disorders see: (19) Angelini C, Federico A, Reichmann H, Lombes, Chinnery P, Turnbull D. Task force guidelines handbook: EFNS guidelines on diagnosis and management of fatty acid mitochondrial disorders. Eur J Neurol. 2006; 13:923-929.(20) Saudubray JM, Martin D, deLonlay P, Touati G, Poggi-Travert F, bonnet D, Jouvet P, Boutron M, Slama A, Vianey-saban C, Bonnefont JP, Rabier, Kamoun P, Brivet M. Recognition and management of fatty acid oxidation defects: A series of 107 patients. J Inherit Metabo Dis. 1999; 22:488-502.*Slide 24: Amnio Acid DisordersThe five disorders listed are core disorders recommended for screening by the Ontario NBS Advisory Committee following review of several reports and NBS programs including the ACMG NBS report. Below is a list of core amino acid oxidation disorders and secondary or variant amino acid oxidation disorders which can be detected when screening for these core disorders:Phenylketonuria (PKU)secondary targets:Defects of Biopterin cofactor biosynthesis (BIOPT (BS))Defects of Biopterin cofactor regeneration (BIOPT (Reg))Benign hyperphenylalaninemia (H-PHE)Maple syrup urine disease (MSUD)Tyrosinemia type 1 (TYR 1)secondary targetsTyrosinemia type 2 (TYR 2)Tyrosinemia type 3 (TYR 3)Homocystinuria (HCY)secondary targetsHypermetioninemia (MET)Citrullinemia (CIT)secondary targetsCitrullinemia type 2 (CIT II)Argininosuccinic acidemia (ASA)

    *Slide 25: Amnio Acid DisordersFor more information about phenylketonuria see: (21)Hellekson KL; National Institutes of Health. Am Fam Physician. 2001 63:1430 1432. (22) National Institutes of Health Consensus Development Panel. National institutes of Health consensus development conference statement: Phenylketonuria screening and management, October 16-18 2000. Pediatrics 2001; 108: 972-982.(23) Mitchell JJ, Scriver CR. Genetests Reviews: Phenylalanine hydroxylase deficiency Phenylalanine hydroxylase deficiency. Last updated 29 March 2007. www.genetests.org. For more information about maple syrup urine disease see: (24) Morton DH, Strauss KA, Robinson DL, Puffenberger EG, Kelley RI. Diagnosis and treatment of maple syrup urine disease: A study of 36 patients. Pediatrics 2002; 109:999-1008.(25) Le Roux C, Murphy E, Liblurn M. The longest surviving patient with classical maple syrup urine disease. J Inherit Metab Dis 2006; 29:190-194(26) Strauss KA, Puffenberger EG, Morton DH. Genetests Reviews: Maple Syrup Urine Disease. Last updated 30 January 2006. www.genetests.org. For more information about tyrosinemias see: (27) Scott CR. The genetic tyrosinemias. Am J Med Genet Part C Semin Med Genet 2006; 142C:121-126.(28) Russo PA, Mitchell GA, Tanguay RM. Tyrosinemia: a review. Pediatr Dev Pathol. 2001; 4:212-221.(29) Sniderman King L, Trahms C Scott R. Genetests Reviews: Tyrosinemia Type I. Last updated 31 October 2008. www.genetests.org.For more information about homocystinuria see: (30) Walter JH, Wraith JE, White FJ, Bridge C, Till J. Strategies for the treatment of cystathionine -synthase deficiency: the experience of the Wilink Biochemical Genetics Unit over the past 30 years. Eur J Pediatr. 1998; 157(Suppl 2):s71-s76.(31) De Franchis R, Sperendeo MP, Sebastio G, Andria G. The Italian Study group on Homocystinuria. Clinical aspects of the cynstathionine -synthase deficiency: how wide is the clinical spectrum? Eur J Pediatr. 1998; 157(Suppl 2):s67-s70(32) Picker JD. Levy HL. Genetests Reviews: Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. Last updated 29 March 2006. www.genetests.org. Citrullinemia and argininosuccinic aciduria are both urea cycle disorders; for more information about urea acid cycle disorders see: (33) Summar M, Tuchman M. Proceeding of a consensus conference for the management of patients with urea acid cycle disorders. J Pediatr. 2001; 138(Suppl1):s6-s10.(34) The Urea Cycle Disorders Conference Group. Consensus statement from a conference for the management of patients with urea cycle disorders. J Pediatr. 2001; 138(Suppl1):s1-s5.(35) Summar, ML. Genetests Reviews: Urea Cycle Disorders Overview. Last updated 11 August 2005. www.genetests.org.(36) Thoene, JG. Genetests Reviews: Citrullinemia Type I. Last updated 02 June 2009. www.genetests.org.(37) Roth KS. Argininosuccinate Lyase Deficiency Argininosuccinate Lyase Deficiency. Last Updated 24 March 2009. www.emedicine.com Free registration, direct link: http://emedicine.medscape.com/article/950752-overview. *Slide 26: Expanded NBS 29 Conditions*Slide 27: Endocrine DisordersCongenital hypothyroidism for a review see:(38) American Academy of Pediatrics; Rose SR; Section on Endocrinology and Committee on Genetics, American Thyroid Association; Brown RS; Public Health Committee, Lawson Wilkins Pediatric Endocrine Society; Foley T, Kaplowitz PB, Kaye CI, Sundararajan S, Varma SK. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics. 2006 Jun;117:2290-2303.(39) Postellon D, Bourgeois MJ, Varma S. eMedicine: Congenital Hypothyroidism. Last Updated: 28 May 2008 http://emedicine.medscape.com/article/919758-overview. *Slide 28: Endocrine DisordersCongenital Adrenal Hyperplasia for a review see:(40) Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005; 365: 2125-2136.(41) New MI, Nimkarn S. GeneTests Reviews: Congenital Adrenal Hyperplasia, last update 7 September 2006. http://www.genetests.org

    *Slide 29: Expanded NBS 29 ConditionsSickle cell disease (Hb SS), variants includeHemoglobin SC disease (Hb SC)Sickle- thalassemia (Hb S/-thal)Variants may have similar symptoms and treatments as classical sickle cell disease.

    *Slide 30: Sickle Cell DiseaseFor a review of sickle disease in primary care see: (42) Wethers DL. Sickle cell disease in childhood: Part II. Diagnosis and treatment of major complications and recent advances in treatment. Am Fam Physician. 2000; 62: 1309-1314.(43) Vichinsky E, Schlis K. GeneTests Reviews: Sickle cell disease, last update 7 March 2006. http://www.genetests.org*Slide 31: Expanded NBS 29 Conditions*Slide 32 Other Disorders: Biotinidase DeficiencyFor more information about biotinidase deficiency see: (43)Moslinger D, Stockler-ipsiroglu S, Scheibenreiter S, Tiefenthaler M, Muhl A, Seidl R, Strobl W, Plecko B, Suormala T, Baumgartner ER. Clinical and neuropsychological outcome in 33 patients with biotinidase deficiency ascertained by nationwide newborn screening and family studies in Austria. Eur J Pediatr. 2001;160:277-82.(44) Wolf B. Worldwide survey of neonatal screening for biotinidase deficiency. J Inherit Metab Dis. 1991; 14:923-927.(45) Wolf B. GeneTests Reviews: Biotinidase Deficiency, last update 25 September 2008. http://www.genetests.org *Slide 33: Other Disorders: GalactosemiaClassical galactosemia (transferase deficient galactosemia) (GALT)Variants: Galactokinase deficiency (GALK)Galactose epimerase deficiency (GALE) For a review of galactosemia see: (46) Bosch AM. Classical galactosemia revisited. J Inherit. Metab. Dis. 2006; 29:516-529.(47) Schweitzer-Krantz S. Early diagnosis of inherited metabolic disorders improving outcome: the controversial issue of galactosemia. Eur J Pediatr. 2003; 162:s50-s503.(48) Elsas LJ. GeneTests Reviews: Galactosemia, last update 27 September 2007. http://www.genetests.org*Slide 34: Other Disorders: Cystic Fibrosis

    CFTR gene CFTR stand for Cystic Fibrosis Transmembrane conductance Regulator. The CFTR gene product functions as a chloride channel and controls the regulation of other transport pathwaysHelpful references for the management of cystic fibrosis:Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodman D. Cystic fibrosis adult care: Consensus conference report. Chest 2004;125:s1-s39.Saiman L, Siegel J. Infection control recommendations for patients with cystic fibrosis: Microbiology, important pathogens and infection control to prevent patient to patient transmission, Cystic fibrosis consensus conference on infection control participants. Am J Infection Control 2003; 31:s1-s62.Cystic Fibrosis Trust Clinical Standards and Accreditation Group. Standards of care for children and adults with cystic fibrosis in the UK. May 2001.

    *Slide 35: Cases*Slide 36: Case 1*Slide 37: Case 1 Amy -5 days old*Slide 38: Case 1

    *Slide 39: Case 1*Slide 40: MCAD (medium chain acyl-CoA deficiency)*Slide 41: MCAD: SymptomsFor a review of MCAD:Reference (53) Matern D, Rinaldo P. GeneTests Reviews: Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. Last update 3 February 2005. http://www.genetests.org *Slide 42: MCAD: a preventable cause of SIDSReference: (54) Opdal SH The sudden infant death syndrome gene: does it exist? Pediatrics 2004; 114:506-512*Slide 43: MCAD: Management

    *Slide 44: Case 2*Slide 45: What are the next steps?*Slide 46: NBS for cystic fibrosis

    References:Grosse SD, Rosenfeld M, Devine OJ, Lai HJ, Farrell PM. Potential impact of newborn screening for cystic fibrosis on child survival: A systematic review and analysis. J Pediatr 2006;149:362-366.Dankert-Roelse JE, Merelle ME.Review of outcomes neonatal screening for cystic fibrosis verses non-screening in Europe. J Pediatr 2005; 147:s15-20.Southern KW, Mrelle MME, Dankert-Roelse JE, Nagelkerke A. Newborn screening for cystic fibrosis (Review). Cochrane Database of Systematic Reviews, Issue 1, 2009.*Slide 47: Liams results

    *Slide 48: NBS Bottom line*Slide 49: MOH Educational Materials*Slide 50: Education*Slide 51: Disorder Fact Sheets*Slide 52: ResourcesReview articles:Pass K A, Lane PA, Fernhoff PM, Hinton CF, Panny SR, parks JS, Pelias MZ, Rhead WJ, Ross SI, Wethers DL, Elsas LJ for CORN. US newborn screening system guidelines II: Follow-up of children, diagnosis, management and evaluation. Statement of the council of regional networks for genetic services (CORN). Pediatrics 2000; 137(4):s1-s46.

    Slide 53: ResourcesWatson MS, Mann MY, Lloyd-Puryear MA, Rinaldo P, Newborn Screening: Toward a Uniform Screening Panel and System. Genet Med 2006:8(5, Supplement)American Academy of Pediatrics, Newborn Screening Fact Sheets Kaye CL and the Committee on Genetics. Newborn screening fact sheets. Pediatrics 2006; 118:e934-e963.Clarke JTR, Geraghty MT, Hudak AP, Chakraborty P. Important changes to newborn screening in Ontario. Ontario Medical Review. April 1, 2006. Waisbren SE. Expanded newborn screening: information and resources for the family physician. Am Fam Physician. 2008 Apr 1;77(7):987-94. Review.

    *Slide 54: The Genetics Education Project CommitteeCommittee Members

    *Slide 55: References 1*Slide 56: References 2

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    *Slide 66: The Genetics Education Project Logo