Download - Click here to get the file
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
The Genetics Education ProjectThe Genetics Education Project
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.
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
Benefits of NBS
Identification Early intervention Reduced morbidity and mortality Family planning
The Genetics Education ProjectThe Genetics Education Project
Risks of NBS
Parental anxiety (false positives) Missed diagnosis (false negatives) The right ‘not to know’ Unanticipated outcomes Labelling – diagnosis of benign conditions
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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 Genetics Education ProjectThe Genetics Education Project
The Heel Test
The Genetics Education ProjectThe Genetics Education Project
What makes a good spot?
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
NBS Report
Cystic fibrosis- 2008
The Genetics Education ProjectThe Genetics Education Project
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.
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
Results
Results will go to:– Submitting health care professional /hospital– Infant’s health care professional – if this information is
completed on the screening card
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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)
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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)
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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)
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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)
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
Cases
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
Case 1
Amy’s expanded newborn screening report is the following:
– Screen positive for medium chain acyl-CoA deficiency
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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?
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
Education:http://www.health.gov.on.ca
The Genetics Education ProjectThe Genetics Education Project
Disorder Fact Sheetswww.health.gov.on.ca/newbornscreening
The Genetics Education ProjectThe Genetics Education Project
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 ProjectThe Genetics Education Project
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
The Genetics Education ProjectThe Genetics Education Project
References1. Ontario 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
2. 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.html
3. Bellis MA, Hughes K, Hughes S, Aston JR. Measuring parent discrepancy and its public health consequences. J Epidemiol Community Health 2005; 59: 749-754.
4. Quinlivan 2006 J Pscyhosomatic Ob/Gyn 5. Holtzman NA, Faden R, Chwalow AJ, Horn SD. Effect of informed
parental consent on mothers' knowledge of newborn screening. Pediatrics. 1983; 72:807-812.
The Genetics Education ProjectThe Genetics Education Project
References6. Tymstra T. False positive results in screening tests: experiences
of parents of children screened for congenital hypothyroidism. Fam Pract. 1986; 3:92-96.
7. Tluczek A, Mischler EH, Bowers B, Peterson NM, Morris ME, Farrell PM, Bruns WT, Colby H, McCarthy C, Fost N, et al. Psychological impact of false-positive results when screening for cystic fibrosis. Pediatr Pulmonol Suppl. 1991;7:29-37.
8. Waisbren SE, Albers S, Amato S, Ampola M, Brewster TG, Demmer L, Eaton RB, Greenstein R, Korson M, Larson C, Marsden D, Msall M, Naylor EW, Pueschel S, Seashore M, Shih VE, Levy HL. Effect of expanded newborn screening for biochemical genetic disorders on child outcomes and parental stress. JAMA. 2003;290:2564-2572.
9. Tluczek A, Koscik RL, Farrell PM, Rock MJ. Psychosocial risk associated with newborn screening for cystic fibrosis: parents' experience while awaiting the sweat-test appointment. Pediatrics. 2005;115:1692-1703.
The Genetics Education ProjectThe Genetics Education Project
References10. Mischler EH, Wilfond BS, Fost N, Laxova A, Reiser C, Sauer CM,
Makholm LM, Shen G, Feenan L, McCarthy C, Farrell PM. Cystic fibrosis newborn screening: impact on reproductive behavior and implications for genetic counseling. Pediatrics. 1998; 102:44-52.
11. Dudding T, Wilcken B, Burgess B, Hambly J, Turner G. Reproductive decisions after neonatal screening identifies cystic fibrosis. Arch Dis Child Fetal Neonatal Ed. 2000; 82:F124-127.
12. Martin, A. Ontario Ombudsman Report: The Right to be impatient. September 2005.
13. 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
14. NCCLS (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.”
The Genetics Education ProjectThe Genetics Education Project
References15. “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.
16. 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.
17. 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.
18. Applegarth Da, Toone JR, Lowry RB. Incvidence of inborn errors of metabolism in British Columbia, 1969 – 1996. Pediatrics 2000: 105:e10-e16.
19. 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.
20. Marsden D, Larson C, Levy Hl. Newborn screening for metabolic disorders. J Pediatr 2006; 148:577-584.
The Genetics Education ProjectThe Genetics Education Project
References
21. Seashore MA. Genetest Reviews: The organic acidemias: An overview. Last updated 27 december 2006. www.genetests.org.
22. Ogier de Baulny HO, Saudubray JM. Branched-chain organic acidurias. Semin Neonatol. 2002; 7:65-74.
23. Venditti CP. Genetests Reviews: Methylmalonic Acidemia. Last updated 18 January 2007. www.genetests.org.
24. Korman SH. Inborn errors of isoleucine degradation: A review. Mol Genet Metab. 1006: 89:289-299.
25. 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.
26. Roth KS. Holocarboxylase Deficiency. Last updated 22 September 2005. http://www.emedicine.com/ped/topic1020.htm
The Genetics Education ProjectThe Genetics Education Project
References27. 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.
28. 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.
29. Hellekson KL; National Institutes of Health. Am Fam Physician. 2001 63:1430 1432.
30. 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.
31. Mitchell JJ, Scriver CR. Genetests Reviews: Phenylalanine hydroxylase deficiency. Last updated 19 July 2005. www.genetests.org.
32. 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.
The Genetics Education ProjectThe Genetics Education Project
References33. 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.
34. Strauss KA, Puffenberger EG, Morton DH. Genetests Reviews: Maple Syrup Urine Disease. Last updated 30 January 2006. www.genetests.org.
35. Scott CR. The genetic tyrosinemias. Am J Med Genet Part C Semin Med Genet 2006; 142C:121-126.
36. Russo PA, Mitchell GA, Tanguay RM. Tyrosinemia: a review. Pediatr Dev Pathol. 2001; 4:212-221.
37. Sniderman King L, Trahms C Scott R. Genetests Reviews: Tyrosinemia Type I. Last updated 24 July 2006. www.genetests.org.
38. Walter JH, Wraith JE, White FJ, Bridge C, Till J. Strategies for the treatment of cystathionine β-synthase deficiency: the experience of the Wilink Biochemical Genetics Unit over the past 30 years. Eur J Pediatr. 1998; 157(Suppl 2):s71-s76.
The Genetics Education ProjectThe Genetics Education Project
References39. De Franchis R, Sperendeo MP, Sebastio G, Andria G. The Italian
Study group on Homocystinuria. Clinical aspects of the cynstathionine β-synthase deficiency: how wide is the clinical spectrum? Eur J Pediatr. 1998; 157(Suppl 2):s67-s70.
40. Picker JD. Levy HL. Genetests Reviews: Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. Last updated 29 March 2006. www.genetests.org.
41. 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.
42. 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.
43. Summar, ML. Genetests Reviews: Urea Cycle Disorders Overview. Last updated 11 August 2005. www.genetests.org.
44. Thoene, JG. Genetests Reviews: Citrullinemia Type I. Last updated 22 December 2006. www.genetests.org
The Genetics Education ProjectThe Genetics Education Project
References45. Roth KS. Argininosuccinate Lyase Deficiency. Last Updated 7 July
2005. www.emedicine.com - free registration is required. If you are already registered the direct link is: http://www.emedicine.com/ped/topic2745.htm
46. 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.
47. Postellon D, Bourgeois MJ, Varma S. eMedicine: Congenital Hypothyroidism. Last Updated: 23 August 2006 http://www.emedicine.com/ped/topic501.htm
48. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005; 365: 2125-2136.
The Genetics Education ProjectThe Genetics Education Project
References
49. New MI, Nimkarn S. GeneTests Reviews: Congenital Adrenal Hyperplasia, last update 7 September 2006. http://www.genetests.org.
50. 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.
51. Bender MA. GeneTests Reviews: Sickle cell Disease, last update 7 March 2006. http://www.genetests.org
52. Wolf B. Worldwide survey of neonatal screening for biotinidase deficiency. J Inherit Metab Dis. 1991; 14:923-927.
53. Wolf B. GeneTests Reviews: Biotinidase Deficiency, last update 2 March 2006. http://www.genetests.org.
54. Bosch AM. Classical galatosemia revisited. J Inherit. Metab. Dis. 2006; 29:516-529.
The Genetics Education ProjectThe Genetics Education Project
References55. Schweitzer-Krantz S. Early diagnosis of inherited metabolic
disorders improving outcome: the controversial issue of galactosemia. Eur J Pediatr. 2003; 162:s50-s503.
56. Elsas LJ. GeneTests Reviews: Galactosemia, last update 2 May 2005. http://www.genetests.org
57. Moskowitz SM, Gibson RL, Sternen DL, Cutting GR. Genetests Reviews: CFTR-Related Disorders. Last updated 24 August 2005. www.genetests.org.
58. Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodman D. Cystic fibrosis adult care: Consensus conference report. Chest 2004;125:s1-s39.
59. 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.
The Genetics Education ProjectThe Genetics Education Project
References60. Cystic Fibrosis Trust Clinical Standards and Accreditation Group.
Standards of care for children and adults with cystic fibrosis in the UK. May 2001.
61. Matern D, Rinaldo P. GeneTests Reviews: Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. Last update 3 February 2005. http://www.genetests.org
62. Opdal SH, Rognum TO. The sudden infant death gene: does it exist? Pediatrics 2004; 114:506-512.
63. American Academy of Pediatrics, Newborn Screening Fact Sheets Kaye CL and the Committee on Genetics. Newborn screening fact sheets. Pediatrics 2006; 118:e934-e963.
64. 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 councilof regional networks for genetic services (CORN). Pediatrics 2000; 137(4):s1-s46.
The Genetics Education ProjectThe Genetics Education Project