Expanded Newborn Screening: Public Health Policy and Clinical Impact

1. Expanded Newborn Screening: Public Health Policy and Clinical Impact Nutrition 526 October 26, 2011 Beth Ogata, MS, RD, CSP, bogata@uw.edu Cristine M Trahms, MS, RD, FADA

2. Newborn Screening A state-mandated public health program that begins with a “heel poke” for every baby before hospital discharge First screen must be taken 24-48 hours of life regardless of feeding status or weight Blood Sample on Guthrie Filter Paper Card

3. Who is screened? • Washington State law requires that every newborn be tested prior to discharge from the hospital or within five days of age • Second screen strongly recommended (between 7 and 14 days of age) • Third screen recommended for sick and premature infants

4. Why do newborn screening? • Screen a presumably healthy newborn population • Detect disease before symptoms present clinically • Goal: Prevent or reduce morbidity and mortality

5. Criteria for Newborn Screening • Important condition • Acceptable treatment available • Facilities for diagnosis and treatment • Difficult to recognize early • Suitable screening test • Natural history known • Cost-effective to diagnose and treat Wilson & Jungner, 1968

6. Tandem Mass Spectrometry (MS/MS) High Impact and High Throughput • One disease, one test is not cost-effective • Many diseases, one test is cost-effective • MS/MS allows for rapid, simultaneous analysis and detection of many disorders of amino acid, organic acid, and fatty acid metabolism

7. Tandem Mass Spectrometer (MS/MS)

8. MS/MS Methodology • Blood spots punched (3/16th inch disc) • Stable isotope internal standards added (deuterated) • Butyl esters derivatives made • Automatic injection into MS/MS via 96 well plates • Sample set up determines which masses and therefore which compounds are detected • 2 minute analysis time • Automated data processing for results

9. MS/MS Methodology – continued Compounds analyzed are amino acids and acylcarnitines • Amino acids – to identify PKU, MSUD, homocystinuria • Acylcarnitine – carnitine (vehicle) + fatty acid for identification of organic acidurias and fatty acid oxidation disorders

10. * 100% MCAD * C8 * * * C2 Intensity * C6 C10:1 C16 * * * * * * MS/MS Plasma Acylcarnitines 100% Control C2 Intensity * internal standards

11. MS/MS Plasma Amino Acids

12. What is the scope of newborn screening? Screen ~80,000 newborns Receive ~160,000 specimens Track ~3000 infants with abnormal results Prevent ~140 babies from death or disability For example: In WA State

13. Which disorders should be identified? • NBS mandates are under state control • Some states screened for 3 diseases, others 40+ • 2002 Maternal and Child Health Bureau commissioned ACMG • Analyze literature • Develop consensus on which disorders • Recommend a core panel to create uniform NBS across all states

18. Historical Harm (?) • Early PKU screening led to cases of over-restriction and/or implementation of diet prior to confirmation of diagnosis • Today, diagnosis is quite rapid • 40 years ago, it took much longer so more potential for harm • However, no published evidence of wide-spread physical/medical harm • BUT the cases do underscore need for expertise and resources for management

19. AA that are 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 (takes 2-5 days) 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

20. 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

21. 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

22. Who is identified? • Patients who need active management • Symptomatic at diagnosis • Strong evidence of pathology if untreated • Examples: PKU, classic galactosemia, MSUD, PROP, etc.

23. Who is identified? • Patients with disorders known to pose risk but reduced penetrance • i.e., probably not everyone needs to be treated • HPHE, MCAD • Both are/have mild ends of the spectrum that have only been identified through NBS • MCAD mutation c.199 C>T • Never seen in patients picked up clinically

24. Who is identified? • Patients who may not need any management • Disorders considered extremely rare but seen in large numbers via NBS programs • Reported cases have significant morbidity • NBS pickups are mostly mild • 3MCC, SCAD • Biochemical phenotype

25. Proceeding with Caution(Reasons to be Thoughtful) Proceeding with caution  Not screening • Core diseases vs. secondary targets / unintended targets • What is reported vs. withheld? • Will we pick up untreatable conditions? • What is the impact of false positives on families? • No long-term outcome data – consider research paradigm • Consider infrastructure needed for follow-up

26. What are we screening for?

27. How many infants does NBS identify?

28. Emma • 13 months old, healthy • Normal pregnancy and delivery • Normal eating pattern, no allergies or intolerances • Feb 2008: • Vomited 4-5 times throughout the weekend • No fever • Sleeping for extended periods – parents concerned, but previous fever had same pattern • Parents gave Pedialyte

29. Emma • 4½ yo brother, parents sick on Sunday/Monday; same symptoms • Monday night 9:30 checked on Emma • Raspy breathing – thought respiratory problem but not worried • Tuesday morning 11 am she was found motionless in her crib and pronounced dead at the scene

30. Emma • Autopsy revealed fatty changes to liver • Coroner requested newborn screening blood spot be sent for acylcarnitine profile • Diagnostic for very long chain acyl-co A dehydrogenase deficiency (VLCAD)

31. VLCAD • Disorder of long chain fatty acid breakdown • C14, C14:1 C16, C18 • Normal beta oxidation occurs in mitochondria

32. Fatty Acid Oxidation http://www.genomeknowledge.org/figures/saturatedbetao.jpg

33. VLCAD Presentations • Hypertrophic cardiomyopathy, with hypoglycemia and skeletal myopathy, lethargy, failure to thrive • Usually present birth to 5 months • Hypoglycemia, hepatomegaly, muscle weakness without cardiac manifestations • Late infancy – older childhood • Muscle weakness/pain, rhabdomyolysis with exercise or illness. No hypoglycemia or cardiac • Teens to adulthood

34. VLCAD Treatment • Diet low in long-chain fats (Portagen, Monogen = 87%, 90% of fats as MCT) • Additional medium chain fats (MCT oil, walnut oil) • Carnitine 100 mg/kg/day • Avoidance of fasting • Treating illness with IV glucose support

35. VLCAD Diagnosis • Newborn screening • Plasma acylcarnitine profile • Urine organic acids (should be normal) • DNA sequencing

36. Emma’s Family • Family referred to genetics by coroner • Parents requested testing for older brother (Zach) • Acylcarnitine ordered • DNA sequencing of ACADVL gene ordered

37. C14:1  C14  C16 - nl C16:1- nl Acylcarnitine – Zach (5 yo)

38. Zach Testing • Reported: mild elevation of C14 and C14:1 with low free carnitine. VLCAD cannot be ruled out • Recommend supplementing with carnitine and retest in 1 week • DNA testing results back before AC repeat: Zach’s DNA testing reveals he is affected • Family seen in clinic, started on treatment

39. Zach – Clinical Picture • 5 yo • Healthy • No symptoms of muscle weakness • CPK = 315U/L (35-230) • No hepatomegaly • AST= 49 (5-41) • ALT= 23 • Bilirubin conj, unconj = normal (0.0, 0.4) • No evidence of cardiac involvement • Has had several viral illnesses in his lifetime without difficulty • Once on carnitine, AC profile was classic for VLCAD

40. Components of Newborn Screening • Sampling • hospital partnerships • Screening • State Lab • Reporting • to health care provider • Referral • to specialty care provider • Short term follow-up • diagnosis • Long term follow-up • ongoing treatment & monitoring

41. Birth Day 1 First Screen NL + ++ Primary Doctor Primary Care Doctor/ Biochem Clinic ASAP 2nd Sample DX TX NL + Primary Care Doctor Biochem Clinic Long term Follow up DX • Timely/urgent • Systematic process TX Long term Follow up Washington State Newborn Screening

42. Informed Consent • Effective NBS requires a close working relationship between hospitals, newborn screening program, and follow-up program

43. Supporting understanding for families

44. Nutrition Involvement in NBS • Policy • Diagnostic/coordination • Clinical • Community

45. Example: infant with galactosemia • Symptoms in newborn, if untreated • Vomiting, diarrhea • Hyperbilirubinemia, hepatic dysfunction, hepatomegaly • Renal tubular dysfunction • Cataracts • Encephalopathy • E. coli septicemia result • Death within 6 weeks, if untreated • Also • Duarte variant • galactokinase deficiency • uridine diphosphate-galactose-4-epimerase deficiency Galactose-1-phosphate uridyl transferase (GALT) deficiency

46. Primary source is milk (lactose= galactose + glucose) Secondary sources are legumes Minor? sources are fruits and vegetables Food labels milk, casein, milk solids, lactose, whey, hydrolyzed protein, lactalbumin, lactostearin, caseinate Medications (lactose is often an inactive ingredient) Dietary supplements Artificial sweeteners Example: infant with galactosemia Treatment: eliminate all galactose from diet Monitoring: galactose-1-phosphate levels <3-4 mg/dl

47. Example: Infant with galactosemia POLICY RD participated on State Advisory Board to select disorders, including galactosemia • CLINICAL MANAGEMENT • RD provides nutrition care as member of the Biochemical Genetics Team: • Initiation of formula • Guidelines for monitoring intake • Plans for follow-up • RD as case manager DIAGNOSIS & COOORDINATION “Presumptive positive”  RD in contact with family and local providers to discuss appropriate feeding practices and arrange clinic appointment COMMUNITY RD at local health department provides ongoing education to family, local care providers

48. Nutrition and NBS: Policy • Screening process (disorders, procedures) RD participated in Advisory Board meetings, providing input about nutrition-related treatment • Services and reimbursement Nutrition consultant to state CSHCN Program RD provides input about relevant state Medicaid policies • Training and education RD provides information about management of metabolic disorders to local WIC agencies

49. Nutrition and NBS: Clinical Management – PKU • Phenylketonuria • Phenylalanine hydroxylase • Dihydropteridine reductase • Biopterin synthetase • Establish diagnosis • Presumptive positive NBS results • > 3 mg/dL, >24 hrs of age • Differential diagnosis •  serum phe, nl tyr • r/o DHPR, biopterin defects

50. Current Treatment Guidelines • With effective NBS, children are identified by 7 days of age • Initiate treatment immediately • Maintain phe levels 1-6 mg/dl (60-360 umol/L) • Lifelong treatment