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The Newborn Screening System

The Newborn Screening System. Sheila Weiss, MS, LCGC sheila.weiss@doh.wa.gov. What is Newborn Screening?. A mandatory public health program designed “to detect, in newborns, congenital disorders leading to developmental impairments or physical disabilities”.

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The Newborn Screening System

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  1. The Newborn Screening System Sheila Weiss, MS, LCGC sheila.weiss@doh.wa.gov

  2. What is Newborn Screening? A mandatory public health program designed “to detect, in newborns, congenital disorders leading to developmental impairments or physical disabilities”

  3. Why is it Important? • It prevents death and disability to affected infants by providing early treatment • It benefits the public through savings in health care costs and institutional care Two 6 year old girls with congenital hypothyroidism

  4. WA’s Criteria for Screening • Early identification benefits the newborn • Treatment is available • Nature of the condition justifies population-based screening • A good screening test exists • The benefits justify the costs of screening

  5. A Complete System Includes Universal screening - all infants “Appropriate” follow-up response Diagnosis of affected infants Appropriate treatment & clinical care Evaluation of system effectiveness

  6. The Newborn Screening Process http://www.europaediatrics2008.org http://www2.aap.org http://www.cdc.gov/ncbddd/jaundice/families

  7. follow-up NBS lab testing transit time hospital – blood collection Time (days) 1 Birth 2 3 4 5 6 7 recommended window for 1st NBS specimen collection NBS Sequence of Events

  8. When to Screen Washington State law requires that every newborn be tested “prior to discharge from the hospital or within five days of age” 1st screen should be taken between 18 & 48 hours of life regardless of feeding status (earlier if therapies are administered) 2nd screen strongly recommended between 7 & 14 days of age Third screen recommended for sick and premature infants at 1 month

  9. Benefits of Repeat Screens • Maximizes detection of all disorders, particularly milder forms that may benefit from treatment • May be necessary for detection of some conditions, and is critical for assessment of cystic fibrosis • Verifies hemoglobin traits, eliminating need for diagnostic lab work

  10. Screening Compliance Some statistics … >99.95% of “eligible” infants receive screening (excludes refusals & neonatal deaths) ~94% of infants receive the recommended 2nd screen ~75% of sick & premature receive the recommended 3rd screen

  11. Newborn Screening in WA ~85,000 newborns are screened each year ~170,000 specimens processed ~5,500 results requiring follow-up ~2,100 false positives 170 - 200 true positives 2011 = 188 affected infants prevalence: 1 in 452!

  12. Father of Newborn Screening “Robert Guthrie, MD, Ph.D. was an American microbiologist, best known for developing the bacterial inhibition assay used to screen infants for phenylketonuria at birth, before the development of irreversible neurological damage.” Wikipedia

  13. Technology that Enables Expansion Tandem Mass Spectrometer - MS/MS

  14. MS/MS Plasma Amino Acids

  15. Biotinidase Screening

  16. Hemoglobin Screening FAE AE control FAC AFSC control FA normal

  17. Normal Affected 2.12 μM .78 μM 13.0 μM 101 μM Screening Results what we would like … 100% specificity 100% sensitivity

  18. NormalAffected 35 μM 200 μM 745 μM Screening Results what we usually get … Specificity vs. Sensitivity

  19. Abnormal Screening Results Response is dependent on disorder, magnitude of result, & demographics of infant (presumptive, borderline, inconclusive)

  20. . Stratifying Results Categorization of C3 Cutoffs * normal ranges for secondary markers: C3/C2 < 0.2 and C3/C16 < 2.2

  21. Follow-up Responses for abnormal C3 results … a - if first screen, wait for routine second; if second screen and previous normal, call health care provider and recommend third screen; if second screen and previous abnormal, call health care provider and recommend immediate diagnostic work-up b - call health care provider and recommend collecting subsequent screen ASAP c - call health care provider and recommend immediate diagnostic work-up d - call health care provider to request second screen ASAP

  22. High Urgency !! • CAH • Galactosemia • MSUD Diagnosis and treatment should be initiated ASAP!

  23. Moderate Urgency! • Congenital Hypothyroidism • MCAD deficiency • PKU Treatment recommended by 1 - 3 weeks of age

  24. No Medical Urgency .. can wait over a weekend to notify • Cystic Fibrosis • Sickle Cell Disease Treatment recommended by 2 to 4 weeks of age

  25. Special Issues for adrenal (CAH) results … • low birthweight & sick babies • steroids • different forms of the disorder - severe (salt-wasting) - non-life threatening (simple virilizing) - other forms

  26. Policy & Program Evaluation

  27. WAs Newborn Screening Timeline 1967 Phenylketonuria (PKU) 1977 Congenital Hypothyroidism 1984 Congenital Adrenal Hyperplasia (CAH) 1991 Hemoglobinopathies (includes SCD) 2004 Biotinidase deficiency Galactosemia Homocystinuria Maple Syrup Urine Disease (MSUD), Medium Chain Acyl co-A Dehydrogenase (MCAD) deficiency 2006 Cystic Fibrosis 20083 Amino acid disorders (ASA, CIT, TYR-1) 4 Fatty acid disorders (CUD, LCHAD, TFP, VLCAD) 8 Organic acid isorders (HMG, BKT, GA-I, IVA, CblA-B, MUT, MCD, PROP)

  28. # of conditions screened for by state, 2004

  29. Major 2008 Expansion 15 Additional Disorders: • 3-OH 3-CH3 glutaric aciduria (HMG) • Argininosuccinic acidemia (ASA) • Beta-Ketothiolase deficiency (BKT) • Carnitine uptake defect (CUD) • Citrullinemia (CIT) • Glutaric acidemia type I (GA 1) • Isovaleric acidemia (IVA) • Long-chain L-3-OH acyl-CoA dehydrogenase deficiency (LCHADD) • Methylmalonic acidemia (Cbl A, B) • Methylmalonic acidemia - mutase deficiency (MUT) • Multiple carboxylase deficiency (MCD) • Propionic acidemia (PROP) • Trifunctional protein deficiency (TFP) • Tyrosinemia type I (TYR I) • Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) 19 MS/MS disorders 49 markers

  30. What are we screening for? On seven 1/8 inch blood spots!

  31. 3-Methylcrotonyl-CoA carboxylase deficiency (3MCC) • Without treatment many people have no clinical symptoms. • Treatment prevents and corrects all problems in symptomatic patients. • Screening test is very good at detecting affected infants, but not totally specific. Also detects asymptomatic mothers. • Not evident at birth – a sudden metabolic crisis can bring on severe illness (but in a very small percentage of patients).

  32. Amino acids not used to make proteins are recycled by their specific metabolic pathways. Enzymatic deficiencies in these pathways lead to various clinical phenotypes. Diagnosed by plasma amino acids, urine amino acids, and/or urine organic acids PKU: severe, permanent ID MSUD: ID, hallucinations, ataxia HCY: connective tissue damage (joints, heart), ID, psychiatric disturbances CIT: risk of hyperammonemia  ID, coma, death ASA: brittle hair, liver disease ID TYR I: acute or chronic liver disease, liver cancer, neurologic pain crises Amino Acid Disorders

  33. Other: 1 ASA, 1 CIT, 1 HCY, 1 TYR

  34. Organic acids are breakdown products of protein and fatty acid metabolism. Defects in their breakdown lead to (generally): Vomiting, metabolic acidosis, elevated ammonia in crises ID, motor delay, ataxia, cardiac/renal/pancreatic problems Diagnosed by urine organic acids and/or plasma acylcarnitines IVA: Isovaleric acidemia GA I: Glutaric acidemia type I HMG: 3-OH 3-CH3 glutaric aciduria MCD: Multiple carboxylase deficiency MUT: Methylmalonic acidemia (mutase deficiency) 3MCC: 3-Methylcrotonyl-CoA carboxylase deficiency Cbl A,B: Methylmalonic acidemia PROP: Propionic acidemia BKT: Beta-ketothiolase deficiency Organic Acid Disorders

  35. Fatty acid disorders lead to impaired energy production Hypoglycemia, cardiomyopathy, muscle weakness can be seen Diagnosed by plasma acylcarnitines, and urine organic acids can be helpful MCAD: Medium-chain acyl-CoA dehydrogenase deficiency VLCAD: Very long-chain acyl-CoA dehydrogenase deficiency LCHAD: Long-chain L-3-OH acyl-CoA dehydrogenase deficiency TFP: Trifunctional protein deficiency CUD: Carnitine uptake defect Fatty Acid Disorders

  36. Objective for an Affected Child • PROMPT DIAGNOSIS & TREATMENT to prevent death and disability by: • modifying their feedings • supplementing carnitine • administering hormone replacement • other therapies

  37. Correct substrate imbalance Restrict phenylalanine intake to normalize plasma concentration Supply product Supplement tyrosine to maintain normal plasma tyrosine levels Clinical Management: PKU Phenylalanine ------------//---------------- Tyrosine (substrate) phenylalanine hydroxylase (product)

  38. Stabilizing Phe Levels Equilibrium achieved by 14 days of age Blood levels every 2 days because of rapid growth

  39. Management Tools • Specialized formula provides • 80-90% energy intake • 85-90% protein intake • tyrosine supplements • no phenylalanine • Phenylalanine to meet requirement from infant formula or foods

  40. Effective Phe Level Management Blood levels once per month, or more frequently if needed for good management

  41. Goals of PKU Management • Normal growth rate • Normal physical development • Normal cognitive development • Normal nutritional status

  42. Maternal PKU Concerns/Outcomes • Women with PKU are at high risk for delivering a damaged infant • Placenta concentrates phe 2-4x • Microcephaly • Cardiac problems • Infant IQ directly related to maternal blood phe level • Outcome improved with maternal blood phe <2 mg/dl prior to conception and during pregnancy

  43. Maternal PKU Syndrome … and moderate to severe intellectual disability

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