Newborn Screening in Texas

1. Newborn Screeningin Texas August 17, 2010 V. Reid Sutton vrsutton@texaschildrens.org

2. Goals Understand the process of NBS Develop skills to communicate with future parents about NBS Identify resources to provide expectant parents

3. Objectives Review history of NBS Discuss how we decide what to screen for List current diseases screened for Explain expanded NBS by tandem mass spectroscopy (MS/MS) Provide guidance for prenatal discussion of NBS Review samples of ACT/FACT sheets Share resources for parents

4. History 1963 – Robert Guthrie publishes “A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants.” [Pediatrics 1963 32:338-43] Method used blood spots on filter paper High phenylalanine levels inhibit bacterial growth on plate

5. Early Development of Other Tests Bacterial inhibition developed for galactosemia and other diseases Other conditions added New methods (fluorimetric) developed

6. Tenets for NBS The disorders screened for have been historically selected because: the disorder occurs with significant frequency an inexpensive and reliable method of testing exists an effective treatment/intervention exists if untreated, the baby may die or develop severe mental retardation the affected baby may appear normal at birth

7. How Disorders are Selected?

8. How Disorders are Selected!

9. How Disorders are Selected: State-by-state Legislatures pass law on “minimum required screening” Most funded by per-newborn charge back to hospital

10. Who Screens for Disorders? Single Central State Lab (e.g. Texas) Multiple state lab sites (e.g. CA) Collaborative lab (e.g. New England NBS Program) Referred to other states (e.g. AK done by WA) Contracted out to private lab (e.g. ND done by Neogen, Inc.)

11. ACMG/March of Dimes Recommendations 9 Organic acidemias (OA) 5 Fatty acid oxidation disorders (FAOD) 6 Amino acid disorders (AA) 3 Hemoglobinopathies Galactosemia Congenital hypothyroidism Congenital Adrenal hyperplasia Biotinidase deficiency CF Hearing

12. Incidence of Selected Metabolic Disorders MCAD (FAOD) PKU (AA) Hypothyroidism CAH Biotinidase MSUD (AA) Galactosemia Homocystinuria Cumulative incidence 1/20,000 1/14,000 1/3,000 1/19,000 1/60,000 1/230,000 1/50,000 1/340,000 1/4000

13. Goals - Texas NBS How many Newborn screens? Each baby born in Texas receives two newborn screening tests within the first 72 hours of life (preferably after 36 hours of age and 24 hours after the first feeding), or before hospital discharge second test at one to two weeks of age All infants testing outside of normal limits for a newborn screening disorder receive prompt and appropriate confirmatory testing All individuals diagnosed with newborn screening disorders are maintained on appropriate medical therapy

14. Inborn Errors of Metabolism Tandem Mass Spectroscopy & Enzyme Assay

15. History of Tandem Mass Spectroscopy (MS) Investigation of Reye syndrome & carnitine disorders in mid-1980s Multiple methods required Enzymology Radio-immunoassay Gas Chromotography/Mass Spectroscopy Single method needed Assays free/total & acylcarnitine levels

16. Tandem MS Methodology(Why is it called Tandem MS?)

17. Tandem MS & Newborn Screening 1990s – measurement of phenylalanine by tandem MS First methodology to permit huge expansion of NSB diseases with one test Mid-1990s – development of methods for NBS by Tandem MS

18. Amino Acid Disorders Detected by Expanded NBS Argininemia Argininosuccinate lyase deficiency Citrullinemia Maple syrup urine disease (MSUD) Phenylketonuria (PKU) Tyrosinemia Homocystinuria

19. Organic Acidopathies Detected by Tandem MS Methylmalonic acidemia Propionic acidemia Isovaleric acidemia Glutaric acidemia type I HMG-CoA lyase deficiency Malonic aciduria ß-Ketothiolase deficiency

20. Fatty Acid Oxidation Disorders Detected by Tandem MS Carnitine palmitoyltransferase II deficiency Medium chain acyl-CoA dehydrogenase deficiency (MCAD) LCHAD VLCHAD Multiple acyl-CoA dehydrogenase deficiency (MADD or GA type II) Trifunctional protein deficiency Carnitine uptake defect

21. Specifics of Tandem MS Newborn Screening All done on a single blood spot card Single prep for all tests done Highly automated 1 ½ minutes per sample for all analytes Cost ~ $10 per analysis Reported in 5-7 days

22. Uh-oh! Biochemical phenotypes without clinical phenotypes? Short chain acyl-CoA dehydrogenase (SCAD) deficiency 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency 2-methylbutyryl-CoA dehydrogenase deficiency (2-MBAD) [Hmong]

23. Change in Tenets for Newborn Screening Old Tenets – One test per disease Significant frequency Cheap & reliable test Effective treatment Severe if untreated Look normal at birth New Tenets - Single testing method +/- frequency Cheap & reliable test Effective treatment or Early diagnosis & recurrence risk counseling

24. Benefits – Medium Chain Acyl-CoA Dehydrogenase (MCAD) Pre-screening 25-33% die at presentation 25-33% of survivors have long-term neurologic disability

25. After NC Newborn Screening No missed diagnoses known No deaths in treated MCAD patients No neurological problems in those followed up to 3 years No episodes of hypoglycemia (<50 mg/dl) in treated individuals [McCandless SE, et al. ASHG 2000, abstract #3]

26. Cost-Effectiveness of NBS (Wisconsin Program) MCAD only Analysis of cost of death + neurological impairment vs. NBS Cost effective if under $13.05 per test Benefit of screening other disorders not counted [J Pediatr 2002. 141(4):524-531]

27. Enzyme Assays (Fluorimetric) Galactosemia (GALT enzyme assay) Heat inactivates enzyme – therefore in Texas cutoff values float Most abnormal are Duarte and do not need treatment TX – abnormal > reflex DNA testing Biotinidase deficiency < 10 % normal activity needs treatment

28. Follow-up testing Simply repeating the NBS is NOT appropriate. This is a screening test so there is a small false negative rate The sensitivity for many disorders drops beyond the newborn period

29. Endocrine Disorders

30. Congenital Hypothyroidism Detected using radioimmunoassay (RIA) of T4 – method published in 1975 High false-positive rate in low-birth weight and sick infants Follow-up with TSH & T4

31. 21-Hydroxylase Deficiency (CAH) Detected using radioimmunoassay (RIA) of 17-hydroxyprogesterone May be missed on 1st newborn screen; non-classic CAH may be missed Follow-up with electrolytes and 17-hydroxyprogesterone

32. Sickle Cell Disease

33. Hemoglobinopathies Detected by hemoglobin electrophoresis Will detect Hgb S, C, and thalassemias Affected by transfusion Reflex confirmatory testing for SS by targeted DNA mutation analysis in Texas

34. Cystic Fibrosis

35. Cystic Fibrosis Immunoreactive trypsinogen (IRT) Texas uses IRT/IRT/DNA Must have two abnormal IRTs to proceed to DNA. No mutation detected – no further testing One mutation – sweat test at CF center Two mutations – diagnosis confirmed

36. Hearing Loss

37. Deafness – Who screens Not all infants in Texas are screened – who is required to screen: (A) a hospital licensed under Health and Safety Code, Chapter 241 that offers obstetrical services and is located in a county with a population of more than 50,000; (B) a birthing center licensed under Health and Safety Code, Chapter 244 that is located in a county with a population of more than 50,000 and that has 100 or more births per year; or (C) a hospital that offers obstetrical services or a birthing center licensed under Health and Safety Code, Chapter 244:       (i) that participates in the State's medical assistance program; and       (ii) is not otherwise included in paragraphs (2)(A) or (2)(B) of this section but agrees with the department to provide hearing screening services for newborns in compliance with Health and Safety Code, Chapter 47, and accepts a one-time grant from the department for the purchase of newborn hearing screening equipment prior to August 31, 2002.

38. Deafness – Methodology No clear guidelines for how screening is done. Otoacoustic emissions (OAE) – done for low risk infants; measures response of hair cells to tone – does NOT detect retrocochlear deafness Auditory Brainstem Evoked Response (ABR) – measures brainstem response to tone – will detect all forms of hearing loss

39. Deafness – Follow-up Abnormal OAE should be followed up with an ABR

40. Communication Abnormal results can be alarming to new parents Relay that the test indicates that further testing is required and should be done quickly to prevent potential problems e.g. “Results of the newborn screen are back and they indicate that further blood and urine testing is required to ensure the health and safety of your baby.”

41. MOD A Parents Guide to NBS Video YouTube http://www.youtube.com/watch?v=yqQRio1-P6c

42. Expanded NBS Logistics in TX Multi-part card sold to hospital of birth Parents bring card with serial # with them to 1st pediatric visit Cutoffs are age-based, so important to do within required time frame Abnormal results called & faxed with ACT & FACT sheet Diagnostic testing/referral to metabolic center

43. NBS Collection FormParent Copy

44. NBS Collection FormDemographics Form

45. NBS Collection FormFilter Paper for Blood Collection

46. Resources ACT/FACT sheets Texas Department of State Health Services http://www.dshs.state.tx.us/newborn/default.shtm American College of Medical Genetics www.acmg.net

47. ACT Sheet

48. FACT Sheet

49. Contact Information for TX1-800-252-8023 Mon-Saturday CAH 2819 CH 3666 Galact 6827 Hbg/SSD 7715 PKU 6827 Biotinidase 2071 FAODs 3874 OA/AA 3871 General 7333 Supplies 7661 Billing 7317 Reporting 7578 Case Mgt 2193

50. Expanded NBS Advocacy Groups March of Dimes www.mod.com Save Babies through Screening Foundation, Inc www.savebabies.org Many parent support groups including: Fatty Oxidation Support Group www.fodsupport.org, National Urea Cycle Disorders Foundation www.nucdf.org, etc.

51. References Chace DH, Sherwin JE, Hillman SL, Lorey F, Cunningham GC. 1998. Use of phenylalanine-to-tyrosine ratio determined by tandem mass spectrometry to improve newborn screening for phenylketonuria of early discharge specimens collected during the first 24 hours. Clin Chem 44:2405-2409. Chace DH, DiPerna JC, Naylor EW. 1999. Laboratory integration and utilization of tandem mass spectrometry in neonatal screening: a model for clinical mass spectrometry in the next millennium. Acta Paediatr Suppl 88(432):45-47. Clayton PT, Doig M, Ghafari S, Meaney C, Taylor C, Leonard JV, Morris M, Johnson AW. 1998. Screening for medium chain acyl-CoA dehydrogenase deficiency using electrospray ionisation tandem mass spectrometry. Arch Dis Child 79:109-115. Pollitt RJ. 1999. Tandem mass spectrometry screening: proving effectiveness. Acta Paediatr Suppl 88(432):40-44. Wiley V, Carpenter K, Wilcken B. 1999. Newborn screening with tandem mass spectrometry: 12 months’ experience in NSW Australia. Acta Paediatr Suppl 88(432)48-51.