Transcript Ontario`s Expanded Screening Program

Newborn Screening:
Ontario’s Expanded Screening Program
Prepared by:
June C Carroll MD, CCFP, FCFP
Sydney G. Frankfort Chair in Family Medicine
Mount Sinai Hospital, University of Toronto
Andrea Rideout MS, CGC, CCGC
Certified Genetic Counsellor
Project Manager – The Genetics Education Project
Funded by:
Ontario Women’s Health Council
Version: January 2010
Acknowledgments
Reviewers:
 Members of The Genetics Education Project
 Ontario Newborn Screening Program: Dr.
Michael Geraghty, Mireille Cloutier MSc.,
Christina Honeywell MSc., Sari Zelenietz MSc,
Shelley Kennedy MSc.
 Funded by:
Ontario Women’s Health Council as part of its
funding to The Genetics Education Project
* Health care providers must use their own clinical judgment in addition
to the information presented herein. The authors assume no
responsibility or liability resulting from the use of information in this
presentation.
Newborn Screening – What’s new?
 Previously:
 PKU, congenital hypothyroidism, hearing loss
 Beginning April 2006:
 Progressive expansion to 29 primary disorders
 NBS includes hearing screening but, the focus of
this module will be on metabolic, endocrine and
hematologic conditions
Expanded NBS – 29 conditions
 20 inborn errors of metabolism
 3 hemoglobinopathies
 2 endocrine disorders
 Congenital hypothyroidism
 Congenital adrenal hypoplasia
 3 other metabolic disorders
 Cystic fibrosis
 Galactosemia
 Biotinidase deficiency
 Hearing loss
Benefits of NBS
 Identification
 Early intervention
 Reduced morbidity & mortality
 Family planning
Risks of NBS
 Parental anxiety (false positives)
 Missed diagnosis (false negatives)
 The right ‘not to know’
 Unanticipated outcomes
 Labelling – diagnosis of benign
conditions
NBS: how & where is it done?
 Method:
Heel prick
 Sample collection: newborn screening
card
 Testing Location: Ontario Newborn
Screening Program at Children’s
Hospital of Eastern Ontario (CHEO)
 Transportation: NBS cards are sent
via courier service
Timing of Testing
 Acceptable samples
 between 1 day (24 hours) and 7 days after birth
 Best time for sample:
 between 2 days (48 hours) and 3 days (72 hours) after
birth
 If tested before 1 day (24 hours) of age, REPEAT
the test within 5 days*
 If the baby is >5 days, screening is still available
 Contact Ontario NBS program for details
* Repeat sample within 5 days has been the Ontario
standard of care since 2001
Special Considerations
 Prematurity or illness
 If <37 weeks - collect specimen at 5-7 days old
 Indicate this on NBS card
 May have false positive test results
 Total Parenteral Nutrition (TPN)
 Certain amino acids and organic acids will be elevated
 Indicate this on NBS card
 Transfusion
 Disorders may be missed
 Ideally complete card and obtain sample before transfusion
 Early discharge
 If prior to 24 hours, parents should be informed that a repeat
sample must be done
The Heel Test
What makes
a good spot?
See Ontario NBS Program
website – educational
resource for blood spot
collection:
http://www.newbornscreen
ing.on.ca
NBS: For your information
 Location
 Ontario Newborn Screening Program (ONSP) at
CHEO http://www.newbornscreening.on.ca
 Tandem Mass Spectrometry
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Allows screening for multiple conditions concurrently
Same cost to screen for one condition as multiple
Increased sensitivity and specificity
Screening for some metabolites can give information
about several diseases
 Educational materials
 MOH & ONSP have developed materials for the
public and healthcare providers
Parents will ask you about NBS
NBS
Report
Screen Positive Results
 Screen positive means:
 Further testing is required to confirm the diagnosis
 Does NOT mean that the infant is affected
 ONSP will immediately notify regional treatment centre
 Regional treatment centre will notify the infant’s
healthcare provider and/or parents and arrange
confirmatory testing
 If diagnosis is confirmed, regional treatment centre will
provide management counselling & follow up
 Report will be mailed to referring hospital, provided that
correct information is completed on the screening card.
Results of Expanded NBS by MS/MS
Schulze et al. Pediatrics 2003
 250,000 neonates screened for 23 inborn errors of
metabolism
 106 newborns with confirmed metabolic disorder
 70 required treatment
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Overall prevalence of metabolic disorder = 1/2400
825 false positives (0.33% false positive rate)
Overall specificity = 99.67% (PPV = 11.3%)
Overall sensitivity = 100% for classic forms of disorders
 =
92.6% for variants
 61 /106 were judged to have benefited from screening
and treatment
 58% of true positives
 1/4100 newborns
Negative Results
 Results will go to:
 Submitting health care professional/hospital
 If you suspect that an infant or child has symptoms
of a screened condition and their NBS results are
negative – please refer to the appropriate specialist
for evaluation
 NBS panel does not screen for every metabolic condition
 NBS is a screening test – not diagnostic
Expanded NBS – 29 conditions
 20 inborn errors of metabolism
 9 organic acid disorders
 5 fatty acid oxidation disorders
 6 amino acid disorders
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3 hemoglobinopathies
2 endocrine disorders
3 other metabolic disorders
Hearing loss
Inborn errors of metabolism
 Rare
 Usually autosomal recessive inheritance
 consanguinity is more common
 Symptoms secondary to a problem in the
metabolic pathway
 Usually not significant dysmorphism
 Early recognition and intervention can be
lifesaving
Frequency of Inborn Errors of Metabolism (IEM)
using MS/MS Tandem Mass Spectrometry
Disorders:
Germany
2003
USA
2006
Amino Acid Disorders (*)
1/3,800
1/14,600
Organic Acid Disorders
1/14,700
1/15,900
Fatty Acid Oxidation
1/10,400
Disorders
IEM combined frequency(*) ~1/4,300
1/10,100
~1/2,400
All NBS: IEM, CF, CAH,
~1/1,500 Not
biotinidase, galactosemia
reported
(*) Does not include tyrosinemia type 1 and 2
Organic Acid Disorders
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Isovaleric acidemia (IVA)
Glutaric acidemia type 1 (GA1)
Hydrodroxymethylglutaric acidemia (HMG)
Multiple carboxylase deficiency (MCD)
Methylmalonic acidemias (MMA)
Methylmalonic acidemia (Cbl A, B)
3-methylcrotonyl glycinuria (3MCC)
Propionic acidemia (PA)
Β-ketothiolase deficiency (BKT)
Organic Acid Disorders
 What are organic acid disorders?
 Body cannot metabolize certain amino acids and fats
 Accumulation of organic acids in blood and urine
 Serious potentially preventable effects on health and
development, including death
 Symptoms
 acute encephalopathy, vomiting, metabolic acidosis,
ketosis, hyperammonemia, hypoglycemia, coma
 dehydration, failure to thrive, hypotonia, global
developmental delay
 sepsis, death
 Treatment
 Low protein diet / restrict amino acids,
 Supplements: carnitine, biotin, riboflavin, glycine
 Avoid fasting
Fatty Acid Oxidation Disorders
 Medium-chain acyl-CoA dehydrogenase
(MCAD) deficiency
 Very long-chain acyl-CoA dehydrogenase
deficiency (VLCAD)
 Long-chain L-3-OH acyl-CoA
dehydrogenase deficiency (LCHAD)
 Trifunctional protein deficiency (TFP)
 catalyzes 3 steps in mitochondrial betaoxidation of fatty acids
 Carnitine uptake defect (CUD)
Fatty Acid Oxidation Disorders
 Medium-chain acyl-CoA dehydrogenase
(MCAD) deficiency
 Very long-chain acyl-CoA dehydrogenase
deficiency (VLCAD)
 Long-chain L-3-OH acyl-CoA
dehydrogenase deficiency (LCHAD)
 Trifunctional protein deficiency (TFP)
 catalyzes 3 steps in mitochondrial betaoxidation of fatty acids
 Carnitine uptake defect (CUD)
Disorders of Fatty Acid Oxidation
 What are disorders of fatty acid oxidation?
 Breakdown of fatty acids in mitochondria is an essential
part of body’s ability to produce energy
 Disorder: inability to break down fatty acids
 Symptoms
 Decompensate with any catabolic stress
 fever, fasting, intercurrent illness
 Hypoketotic hypoglycemia, liver, muscle, heart disease
 Lethargy, seizures, coma, sudden death (SIDS)
 Treatment
 Avoid fasting
 IV glucose when ill to prevent hypoglycemia
 Frequent feeding
Amino Acid Disorders
 Phenylketonuria (PKU)
 Maple syrup urine disease (MSUD)
 Tyrosinemia type 1 (TYR 1)
 Common in French Canadians
 Homocystinuria (HCY)
 Citrullinemia (CIT)
 Argininosuccinic aciduria (ASA)
Disorders of Fatty Acid Oxidation
 What are disorders of fatty acid oxidation?
 Breakdown of fatty acids in mitochondria is an essential
part of body’s ability to produce energy
 Disorder: inability to break down fatty acids
 Symptoms
 Decompensate with any catabolic stress
 fever, fasting, intercurrent illness
 Hypoketotic hypoglycemia, liver, muscle, heart disease
 Lethargy, seizures, coma, sudden death (SIDS)
 Treatment
 Avoid fasting
 IV glucose when ill to prevent hypoglycemia
 Frequent feeding
Amino Acid Disorders
 Phenylketonuria (PKU)
 Maple syrup urine disease (MSUD)
 Tyrosinemia type 1 (TYR 1)
 Common in French Canadians
 Homocystinuria (HCY)
 Citrullinemia (CIT)
 Argininosuccinic aciduria (ASA)
Amino Acid Disorders
 What are amino acid disorders?
 Occur when the body cannot either metabolize or
produce certain amino acids
 Result in toxic accumulation of substances
 Serious potentially preventable effects on health and
development including death
 Symptoms (untreated) example PKU
 Hyperphenylalaninemia (neurotoxic)
 Microcephaly, epilepsy, mental retardation, behaviour
problems
 Treatment
 Diet: reduce phenylalanine, low protein, supplement
cofactors or essential amino acids
Expanded NBS – 29 conditions
 20 inborn errors of metabolism
 3 hemoglobinopathies
 2 endocrine disorders
 Congenital hypothyroidism
 Congenital adrenal hyperplasia
 3 other metabolic disorders
 Hearing loss
Endocrine Disorders: CH
Congenital Hypothyroidism (CH)
 What is CH?
 inadequate thyroid hormone production
 Anatomic defect in gland, dyshormogenesis, iodine
deficiency
 Symptoms
 MR, ↓ growth & bone maturation, neurologic
problems: spasticity, gait abn, dysarthria, autistic
behaviour
 Treatment
 Diagnosis made before 13 days to prevent symptoms
 Thyroid hormone replacement
Endocrine Disorders: CAH
Congenital Adrenal Hyperplasia (CAH)
 What is CAH?
 Impaired synthesis of cortisol by the adrenal cortex leads to ↑↑↑
androgen biosynthesis
 Inability to maintain adequate energy & blood glucose level to
meet stress of injury & illness
 Symptoms
 Virilization (♀ ambiguous genitalia), precocious puberty,
infertility, short stature
 Renal salt wasting leads to FTT, vomiting, dehydration,
hypotension, hyponatremia, & hyperkalemia
 Treatment
 Glucocorticoid replacement therapy
Expanded NBS – 29 conditions
 20 inborn errors of metabolism
 3 hemoglobinopathies
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Sickle cell disease (Hb-SS)
SC disease (Hb-SC)
Sickle beta thalassemia
Other hemoglobinopathies may reported if
clinically significant
 2 endocrine disorders
 3 other metabolic disorders
 Hearing loss
Sickle Cell Disease
 What is sickle cell disease? (Hb SS)
 Change in the shape of the betaglobin component of the
hemoglobin molecule that interferes with hemoglobin’s ability to
carry oxygen
 Symptoms
 Painful vaso-occlusive crises, hemolytic anemia, frequent
infections, tissue ischemia, chronic organ dysfunction
 Diagnosis
 Quantitative hemoglobin electrophoresis and/or Molecular analysis
 Do not rely on solubility testing methods (Sickledex etc)
 Treatment
 Prophylactic penicillin (84% reduction in infection)
 Vaccinations (pneumococcal, influenza)
 Aggressive treatment of fever and dehydration
Expanded NBS – 29 conditions
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20 inborn errors of metabolism
3 hemoglobinopathies
2 endocrine disorders
3 other metabolic disorders
 Biontinidase deficiency
 Galactosemia
 Cystic fibrosis
 Hearing loss
Other Disorders:
Biotinidase deficiency
 What is biotinidase deficiency?
 Biotinidase is responsible for recycling biotin – a
cofactor for 4 dependant carboxylases
 Symptoms
 Metabolic ketoacidosis, organic aciduria, mild
hyperammonemia
 Seizures, hypotonia, ataxia, developmental delay, vision
problems, hearing loss, cutaneous abnormalities
 Treatment
 5-10mg of oral biotin per day, long term treatment
prevents all symptoms
Other Disorders: Galactosemia
 What is galactosemia?
 Lactose is main sugar in breast milk & infant formulas
 Metabolized into glucose and galactose in the intestine
 Unable to break down galactose
 Symptoms
 Feeding problems, FTT, bleeding, infection, liver failure,
cataracts, mental retardation, death
 Treatment
 Lactose-galactose-restricted diet
 must be started in first 10 days of life to prevent symptoms
 Even with treatment - ↑ developmental delay, speech
problems, abn motor function, premature ovarian failure
Other Disorders: Cystic fibrosis
 What is cystic fibrosis?
 Due to mutations in the CFTR gene which is responsible for
chloride regulation and other transport pathways.
 Symptoms
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Chronic sinopulmonary disease
Gastrointestinal/nutritional abnormalities
Azoospermia (males)
Salt loss syndrome
Shortened life span – but improving with treatment
 Treatment
 Pulmonary: oral, inhaled, or IV antibiotics, bronchodilators, antiinflammatory agents, mucolytic agents, chest physiotherapy
 Gastrointestinal: Nutritional therapy special formulas for weight
gain via improved intestinal absorption, and additional fat-soluble
vitamins & zinc to prevent deficiencies
Cases
Case 1
 Carmen and George bring Amy into your
office for 1 week visit
 Healthy 1 week old
 Parents worried re risk of SIDS
 First daughter died of SIDS 5 years earlier
 Carmen’s cousin died of SIDS at 18
months
Case 1: Amy – 5 days old
 You receive a call that Amy has screened
positive for MCAD deficiency
 Medium chain acyl-CoA dehydrogenase deficiency
 You ask Carmen and George to bring her in that
day
 Healthy 5 day old
 Parents worried about risk of SIDS
 First daughter died of SIDS 5 years earlier
 Carmen’s cousin died of SIDS months
Case 1
Legend
Prostate
cancer
SIDS
British / French
Irish / German
79
Prost Ca Dx 74
MI  died 6569
A&W
39
A&W
37
Schizophrenic
35
George
A&W
32
Carmen
A&W
P
S
7
A&W
5
A&W
29
A&W
11 wk
SIDS
Amy
A& W
72
A&W
25
A&W
S
49
Accident
SIDS
13 months
Case 1
 Amy’s expanded newborn
screening report is the following:
 Screen positive for medium chain
acyl-CoA deficiency
MCAD (medium chain acyl-CoA deficiency)
 Incidence
 1 in 4,900 – 1 in 17,000
 most prevalent in North Europeans
 Inheritance
 Autosomal recessive (Gene: ACADM)
 Enzyme
 Medium-chain acyl-coenzyme A dehydrogenase
 Function
 Mitochrondrial fatty acid β-oxidation
 Required for energy and ketone body production
 Important during prolonged fasting
MCAD: Symptoms
 Usually presents at 3 to 24 months
 Triggered by fever, illness, or fasting
 Symptoms:
 Hypoglycemia, vomiting
 Lethargy → coma → death
 Encephalopathy, respiratory arrest, hepatomegaly,
seizures
 Long term outcomes after a clinical episode:
developmental & behavioural disabilities, chronic
muscle weakness, seizures, cerebral palsy, ADD
MCAD: a preventable cause of SIDS
 Sudden death is the first symptom in 25%
of MCAD cases
 Early diagnosis and treatment of MCAD
can prevent sudden death
 MCAD responsible for ~1% of SIDS
cases, all FAO disorders ~4%
 Opdal et al. Pediatrics 2004;114:506-512
MCAD: Management
 Infants require frequent feedings
 Formulas containing medium chain triglycerides as
the primary source of fat should be avoided
 Avoid prolonged fasting, hypoglycemia
 Aggressive treatment of illness often with
IV fluids especially when vomiting
Case 2
 Angela receives a call from the Ontario
Newborn Screening Program for a repeat
NBS sample for her newborn, Liam.
 Angela comes to your office for a routine
newborn visit.
 Liam’s newborn screening report:
 Positive, for cystic fibrosis
 Category B
 IRT>96%
 DeltaF508 (one mutation identified)
What are the next steps?
 ~1 in 40 chance of being affected with CF
 Sweat chloride test is next step
 3 possible results:
 Abnormal – affected with CF
 Borderline – inconclusive, follow up with specialist
 Normal – unaffected, but carrier of CF
 Blood work:
 Confirmatory genetic testing
 Genetic counselling is recommended
NBS for cystic fibrosis
 Some evidence that early identification leads to
better outcomes
 Lower incidence of malnutrition
 Improved growth (height, weight)
 Better lung function parameters at 10 years of age
 no evidence of difference in adulthood
 ?improved survival by 10 years of age
 ?reduced mortality
 Identification enables family planning
Liam’s results
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Sweat test results – Normal
Liam is a carrier of CF
He will not develop CF
Parents Angela and James have genetic
counselling…
 Angela – carrier of CF deltaF508 mutation + normal gene
 James – carrier of CF R553X mutation + normal gene
 Risk to have a child affected with CF
 25% with each pregnancy
NBS – Bottom Line

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Offer newborn screening
Discuss the benefits
Discuss how testing is done
Discuss timing
Repeat sample sometimes required
Discuss difference between screening and
diagnostic test
 Discuss possible results
 Answer questions/brochure
Provincial Educational Materials
 www.health.gov.on.ca/newbornscreening
 MOHLTC INFOline at 1-866-532-3161/TTY: 1800-387-5559
 Contact the Ontario Newborn Screening Program:
 Telephone: 613-738-3222
 www.newbornscreening.on.ca
 Educational materials are available free-of-charge
and can be ordered through www.health.gov.on.ca
or by calling 1-877-844-1944
Education:
http://www.health.gov.on.ca
Disorder Fact
Sheets
www.health.gov.on.ca/ne
wbornscreening
Parent Fact Sheets
www.newbornscreening.
on.ca
Resources
 ONSP Newborn Screening Website:
http://www.newbornscreening.on.ca/bins/index.asp
 March of Dimes:
www.marchofdimes.com
 Genetests:
www.genetests.org
 National Newborn Screening & Genetics
Resource Center:
genes-r-us.uthscsa.edu
 Pediatrix – US private lab offering NBS
www.pediatrix.com
Resources
 American College of Medical Genetics – fact
sheets
http://www.acmg.net/resources/policies/NBS/NBSsections.htm
 American Academy of Pediatrics – fact sheets
http://aappolicy.aappublications.org/cgi/content/abstra
ct/pediatrics;118/3/e934
 American Academy of Family Physicians –
Information & resources
http://www.aafp.org/afp/2008/0401/p987.html
 Ontario Medical Association – Important
changes to NBS in Ontario
http://www.oma.org/Health/newborn/06newborn.asp
The Genetics Education Project
Committee
 June C Carroll MD CCFP
 Judith Allanson MD
FRCP FRCP(C) FCCMG
FABMG
 Sean Blaine MD CCFP
 Mary Jane Esplen PhD
RN
 Sandra Farrell MD
FRCPC FCCMG
 Judy Fiddes
 Gail Graham MD FRCPC
FCCMG
 Jennifer MacKenzie MD
FRCPC FAAP FCCMG
 Wendy Meschino MD
FRCPC FCCMG
 Fiona Miller PhD
 Joanne Miyazaki
 Andrea L. Rideout MS
CGC CCGC
 Linda Spooner RN BScN
 Cheryl Shuman MS CGC
 Anne Summers MD
FCCMG FRCPC
 Sherry Taylor PhD
FCCMG
 Brenda Wilson BSc MB
ChB MSc MRCP(UK)
FFPH
References
1.
2.
3.
4.
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/archive
s/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/archive
s/nr_06/nov/nr_112306.html
Bellis 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/scree
ning/screen_sum.html
www.health.gov.on.ca/english/providers/program/child/screening/
screen_sum.html
References
5.
6.
7.
8.
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.”
“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.
References
9. Applegarth Da, Toone JR, Lowry RB. Incidence of inborn
errors of metabolism in British Columbia, 1969 – 1996.
Pediatrics 2000: 105:e10-e16.
10. 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.
11. Marsden D, Larson C, Levy Hl. Newborn screening for
metabolic disorders. J Pediatr 2006; 148:577-584.
12. Centers for Disease Control and Prevention. Impact of
expanded newborn screening – United States 2006
Morbidity and Mortality Weekly Report. 2008;57:10121015.
References
13.
14.
15.
16.
17.
18.
Seashore 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
References
19.
20.
21.
22.
23.
24.
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.
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.
References
25.
26.
27.
28.
29.
30.
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.
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 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.
References
31.
32.
33.
34.
35.
36.
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.
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
References
37.
38.
39.
40.
Roth 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.htm
Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet.
2005; 365: 2125-2136.
References
41.
42.
43.
44.
45.
46.
New 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.org
Wolf 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.
References
47.
48.
49.
50.
51.
Schweitzer-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.org
Moskowitz 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.
References
52.
53.
54.
55.
56.
57.
Cystic 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 AcylCoenzyme A Dehydrogenase Deficiency. Last update 3 February
2005. http://www.genetests.org
Opdal 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, Me´relle ME.Review of outcomes neonatal
screening for cystic fibrosis verses non-screening in Europe. J
Pediatr 2005; 147:s15-20.
Southern KW, Mérelle MME, Dankert-Roelse JE, Nagelkerke A.
Newborn screening for cystic fibrosis (Review). Cochrane
Database of Systematic Reviews, Issue 1, 2009.