mass screening using tandem mass spectrometry: friend or foe? dawn c. allain, ms, cgc childrens...
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Mass Screening Using Tandem Mass Spectrometry:
Friend or Foe?
Dawn C. Allain, MS, CGCChildren’s Hospital of Wisconsin
History of NBS
1957 - Dr. Centerwall
1961 - Dr. Guthrie
1963 - MA and OR implement legislation
History of NBS
1997 - NC begins piloting MS/MS
1999 - NC and MA begin newborn screening with MS/MS
2000 - WI begins MS/MS NBS
States Screening by MS/MS
Maine Massachusetts Minnesota North Carolina Ohio Wisconsin
** as of September 2001 – www.tylerforlife.com
Why Use MS/MS?
Small sample size requirement Fast Screens for many diseases Cost Public awareness and advocacy
Mass Spectrometry
Ion separation and quantification
Produces charged particles
Uses electrical and magnetic fields
Detection system
Sansom, Molecular Medicine Today, March 1999
MS/MS Analysis
Aminoacidopathies
Organic acidurias
Fatty acid oxidation disorders
Aminoacidopathies
Arginosuccinic Aciduria
Citrullinemia
Homocystinuria
Maple Syrup Urine Disease
Phenylketonuria
Tyrosinemia
Organic Acid Disorders
2,4-Dienoyl-CoA Reductase Deficiency
3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency
3-Ketothiolase Deficiency
Organic Acid Disorders
3-Methylcrotonyl-CoA Carboxylase Deficiency
3-Methylglutaconyl-CoA Hydratase Deficiency
Glutaric Acidemia Type I
Organic Acid Disorders
Isovaleric Acidemia
Methylmalonic Acidemia
Mulitple CoA Carboxylase Deficiency
Propionic Acidemia
Fatty Acid Oxidation Disorders
3-Hydroxy Long Chain Acyl-CoA Dehydrogenase Deficiency (LCHAD)
Carnitine Palmitoyl Transferase Deficiency Type II (CPT II)
Long Chain Acyl-CoA Dehydrogenase Deficiency (LCAD)
Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD)
Fatty Acid Oxidation Disorders
Multiple Acyl-CoA Dehydrogenase Deficiency (Glutaric Aciduria type II)
Short Chain Acyl-CoA Dehydrogenase Deficiency (SCAD)
Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD)
Newborn Screening Criteria
Criteria Incidence >1/100,000 Significant
morbidity/mortality Successful treatment Reasonable cost Technology
OA/FAOD/AA 1/5,000 to 1/10,000 Severe medical
complications/death Diet & avoid fasting < $10.00 MS/MS
False Positives
Cut-off levels of acylcarnitines may be too low
TPN feedings Prematurity Sampling Error
False Negatives
Cut-off levels of acylcarnitines may be too high
Mild clinical course
Sampling Error
Follow-up
Positive MS/MS NBS Result
PMD called and faxed resultsConsultant names providedMedical management recommendedF-up by PMD or Genetic Center
Organic Acidemia Follow-Up
Initial Follow-Up
Urine organic acidsAcylcarnitine profilePlasma carnitinePlasma amino acids
Additional OA Follow-Up
Enzyme analysis in lymphocytes
Enzyme analysis in fibroblasts
Molecular testing
Fatty Acid Oxidation Follow-Up
Initial work-up
Urine organic acidsUrine acylglycinesAcylcarnitine ProfilePlasma carnitineDNA mutations (MCAD and LCHAD)
Other FAOD Work-Up
Fibroblast studies Fatty acid oxidation studies Direct enzyme analysis Western blot
Test siblings
Aminoacidopathy Follow-Up
Initial work-upPlasma amino acids
Other Laboratory AnalysisOrotic acid AmmoniaUrine organic acidsDNA analysis
Wisconsin Experience
Pilot testing began May 1999 Analyzed all specimens received Established instrument reliability Developed reporting policies Developed follow-up protocols
Routine testing began April 2000 OA and FAO disorders only
Wisconsin ExperienceOrganic Acidemia
1 - PA
2 - 3-MBCDD
2 - C3/C212 - C3 2 - C5,C5/C3 1 - C5/C2,C5/C3 5 - C5 1 - C3, C5
23Possible
5 – 3-MCC2 - MMA
1 - MA
8 - C5OH 5 - C3,C3/C218 - C5,C5/C3,C5/C2 1 - C3DC 1 - C5DC
33Definite
3-MCC Case Study
Initial NBS result (6/7/01) C5OH = 6.45 (>0.6)
Referred to state consultant (6/9/01) Patient seen on 6/12/01 F-up laboratory analysis Results obtained (6/15/01) Sibling tested (6/22/01)
3-MCC NBS Issues
Prevalence
Diagnosis
Severity
Wisconsin ExperienceFAOD
1 - SCAD10 - C47 - C101 - C6,C8,C101 - C14,C14:1, C14:22 - C14,C14:11 - C10,C161 - C16,C18,C16:1,C18:1
24Possible
4 - SCAD2 - MCAD1 - GAII
5 - C4,C4/C2,C4/C32 - C6,C8,C10:1,C8/C101 - C4,C5,C14,C161 - C14,C14:1,C14:2,C16:1
9Definite
SCAD - NBS Issues
Prevalence Mild presentation 2 homozygous for G625A
polymorphism*
*Corydon et al, Ped Res 49 (1):28-23, 2001
Wisconsin ExperienceAminoacidopathies
3 Tyrosinemia – none confirmed
1 Citrullinemia - confirmed
Tyrosinemia Issues
Transient tyrosinemia
Prematurity
False negatives
Impact of NBS by MS/MS on Families
Anxiety
Unknown
Limited Resources
Impact of NBS by MS/MS on State Laboratories
Start-up cost/New technology
Programming
False negatives and false positives
Detection of undefined disorders
Impact of NBS by MS/MS on Genetic Clinics
Increased clinic load Long-term treatment Improved quality of life Natural history
Summary
Collaboration
Close Follow-up
Supportive Counseling
Acknowledgements
WI Newborn Screening Laboratory Gary Hoffman, PhD
Children’s Hospital of Wisconsin William J. Rhead, MD, PhD
Waisman Center, UW Jon Wolff, MD, PhD Kristine Hanson, MS, CGC