1. Newborn Screening in Washington Cristine M Trahms, MS, RD, FADA Center on Human Development and Disability Division of Genetics and Development Department of Pediatrics

2. Objectives Discuss the Newborn Screening Program –Rationale –Plans Discuss nutrition intervention in disorders identified by newborn screening –Treatment paradigm –Medical nutrition therapy

3. What is newborn screening? A system that includes Universal screening of all infants Follow up to assure appropriate clinical response Diagnosis of affected infants Appropriate treatment and clinical care Evaluation of system effectiveness

4. Criteria to Screen for a Disease Symptoms usually absent in newborns Disease results in developmental impairment, serious illness, or death Sensitive, specific laboratory tests available on a mass population basis Disease occurs frequently enough to warrant screening Successful treatment procedures available Benefits of screening justify the cost

5. The Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children (ACHDGDNC) shall advise and guide the Secretary of HHS regarding the most appropriate application of universal newborn screening tests, technologies, policies, guidelines and programs for effectively reducing morbidity and mortality in newborns and children having or at risk for heritable disorders. NBS at the national level

6. The Scoring System

7. Core Conditions

8. Core Conditions: Metabolic

9. 2ndary Conditions

10. Washington State Newborn Screening

11. WA State system

12. Informed Consent

13. Supporting understanding for families

14. How is screening done?

15. Newborn Screening in Washington Newborns currently screened in Washington- –phenylketonuria (1963) –congenital hypothyroidism (1977) –congenital adrenal hyperplasia (1984) –hemoglobinopathies (1991) –galactosemia –medium-chain acyl- CoA dehydrogenase deficiency (MCAD) –biotinidase deficiency –maple syrup urine disease (MSUD) –homocystinuria –early hearing loss

16. By The Numbers Each year the Newborn Screening Program… Screens76,000 infants Receives 150,000 specimens Performs 1.5 million screening tests Follows up 3,000 abnormal findings Saves 80-100 babies from lifelong disability or death

17. What’s on the Horizon? Cystic fibrosis? Organic acid disorders? Other amino acid disorders? Other fatty acid oxidation disorders?

18. Resources Washington State Office of Newborn Screening –http://www.doh.wa.gov/EHSPHL/PHL/ Newborn/default.htm National Newborn Screening and Genetics Resource Center –http://genes-r-us.uthscsa.edu/ Genetics Home Reference –http://www.ghr.nlm.nih.gov/

19. Phenylketonuria

20. Newborn Screening Guidelines Phenylalanine (serum) –Normal: <180 mmol/L –Borderline: 189-239 mmol/L –Presumptive positive: >240 mmol/L

21. Phenylketonuria: Establish Diagnosis The enzymatic defect –Phenylalanine hydroxylase –Dihydropteridine reductase –Biopterin synthetase

22. Phenylketonuria: Establish Diagnosis Presumptive positive Newborn Screening results –>3 mg/dl >24 hours of age Differential diagnosis –  serum phenylalanine level, normal tyrosine level –R/O DHPR and Biopterin defects

23. Monitoring Adequacy of Treatment Measure plasma amino acids –maintain in treatment range Monitor nutrient intake –restrict phenylalanine, supplement tyrosine, adequate protein, energy, nutrients to support growth and ensure good health Monitor growth increments –typical growth expected Monitor cognitive development –typical achievement expected

24. Outcome Expectations With Newborn Screening and blood phenylalanine levels consistently in the treatment range –Normal IQ and physical growth are expected With delayed diagnosis or consistently elevated blood levels –IQ is diminished and physical growth is compromised

25. Galactosemia

26. Newborn Screening Guidelines Fluorometric assay of GALT activity (units/gHb) Normal: >3.0 units/gHb Borderline: 2.1-3.0 units/gHb Presumptive positive: <2.0 units/gHb

27. Galactosemia Elevated galactose-1- phosphate levels: –Poor suck –Failure to thrive –Jaundice –Vomiting –Diarrhea If untreated then, –E. coli sepsis –Shock, Death If neonatal survival but untreated: –Cataracts –Mental retardation –Cerebellar tract signs

28. Galactosemia Washington State NBS –Semi-quantitative assay of GALT –2 screens below cutoff (2.5) referred for diagnostic confirmation (if 0.9-1.0 referred after 1st screen) –Quantitative measurement of GALT requires venous blood draw, not blood spot

29. Galactosemia 1/30 000 - 1/50 000 classic galactosemia Galactose-1-phosphate uridyltransferase deficiency Also called GALT deficiency Catalyzes the production of glucose-1- phosphate & UDP-galactose from galactose- 1-phosphate and UDP-glucose Determine genotype Monitor galactose-1-phosphate levels

30. Galactosemia Types of Galactosemia –Classic galactosemia (denoted G/G) Two severe mutations GALT activity 0 or 1 (~0%) –Usually symptomatic at the time NBS results received –Duarte/Classic compound heterozygote (denoted D/G) One classic allele with Duarte allele (N314D) ~25% enzyme activity, rarely symptomatic –Duarte homozygote (denoted D/D) 50% enzyme activity, not symptomatic

31. Galactosemia - Treatment G/G Galactosemia Lactose/galactose restriction –Lactose = galactose + glucose –Use soy-based infant formula (Isomil, Prosobee) –All dairy products, tomatoes, legumes, some other vegetables –Supplemental calcium Even well treated can have some issues: –~80% of girls have ovarian failure (more likely if Q188R +/+) –Growth delay –Some learning disabilities (delayed vocab and articulation)

32. Galactosemia - Treatment D/G Galactosemia Controversy among BGC centers Treat for 6 months, treat for 1 year, don’t treat at all…… Recent outcome studies suggest no difference WA: if feeding difficulties (vomiting, diarrhea), switch to soy, otherwise, no need to treat D/D Galactosemia No treatment necessary (unlikely to see these)

33. Biotinidase Deficiency

34. Newborn Screening Guidelines Biotinidase enzyme (% activity) –Normal: >30% –Borderline: 10-30% –Presumptive positive: <10%

35. Biotinidase Deficiency Washington State NBS –Fluorescence assay (qualitative) –Two positive screens referred for follow-up Diagnostic confirmation done at CHRMC on new sample, measures biotinidase enzyme directly <10% activity = profound deficiency 10-30% activity = partial deficiency

36. Biotinidase Deficiency Inability to recycle biotin Symptoms- skin rash, alopecia, lactic acidosis, seizures, can lead to acute metabolic acidosis, death Also ataxia, hypotonia, developmental delay, hearing loss

37. Biotinidase Deficiency 1/40 000 - 1/60 000 Disorder of biotin recycling Cannot recycle endogenous biotin and cannot release dietary protein-bound biotin Free biotin (not protein bound) necessary co-factor for many enzyme reactions

38. Biotinidase Deficiency Profound - untreated –May have: seizures, hypotonia, rash, alopecia, ataxia, developmental delay, hearing loss, recurrent infections –Variable expression and symptoms generally develop between 1 week and 10 years, mean age 3.5 years Partial - untreated –May have: hypotonia, rash, hair loss –Particularly in times of stress –Some are only symptomatic during times of stress

39. Biotinidase Deficiency Treatment guidelines (UW BGC) Profound deficiency = 10mg free biotin daily Partial deficiency = 5-10 mg free biotin daily for 6 months, then discontinue. If symptomatic during times of stress can add biotin back All symptomatic children improve after biotin treatment (seizures, hair loss, rash). Hearing and vision loss may be resistant to therapy. Food sources of biotin: –Eggs, cauliflower, peanuts, almonds, tomato, carrots, fresh cheese (cottage, ricotta, fresh mozzarella)

40. Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD)

41. Medium-chain acyl-CoA dehydrogenase deficiency Disorder of ß- oxidation of fatty acids with fasting Vomiting, hypotonia, coma c fasting Elevated C6-C12 dicarboxylic acids in urine

42. Newborn Screening Guidelines Measure octanoyl carnitine: C8 Measure acyl carnitine: C2 Normal: C8 = <0.5 Borderline: C8= 0.5-0.79 Presumptive positive MCAD: C8= >0.8; C8 to C2 ratio = >0.02

43. MCAD 1/15 000 Disorder of medium chain fatty acid breakdown C6-C10 considered medium chain fats Fats are major source of energy once hepatic glycogen stores (source of glucose) are depleted Fats are converted to ketones can be used for energy Acylcarnitines are used to transport fats into the mitochondria

44. MCAD Washington State measuring C8 Elevated C8 not specific for MCAD, but MCAD is most common Elevations of C6, C8 and C10 acylcarnitines, with C8 elevations predominant is indicative of MCAD Diagnostic confirmation done with quantitative acylcarnitine profile. Urine for organic acids requested and blood sample for mutation analysis –Organic acids show excess medium chain dicarboxylic acids (C6>C8>C10), absence of ketones

45. MCAD genotypes Homozygous: –985A>G/985A>G = 70% of patients –985A>G/985A>G = increased C8/C10 ratios Heterozygous: –985A>G/ +/- 985A>G = includes 90% of patients

46. MCAD Symptoms all related to hypoglycemia –Lethargy, Pallor, Sweating –Decreased consciousness, Coma, –Death Treatment- general –Avoidance of fasting –+/- L-carnitine –+/- cornstarch –+/- low fat diet (<30% calories from fat)

47. Maple Syrup Urine Disease (MSUD)

48. Newborn Screening Guidelines Leucine (serum) –Normal: <300 mmol/L –Borderline: 300-349 mmol/L –Presumptive positive: >350 mmol/L

49. Maple syrup urine disease (Branched-chain ketoaciduria) Deficiency of enzyme that control pathway of metabolism or leucine, isoleucine, valine Death from profound ketoacidosis

50. Maple Syrup Urine Disease (MSUD) 1/200 000 (higher in Mennonite, Hutterite pop’ns) Disorder of branched chain amino acid breakdown Leucine, isoleucine, valine deficiency branched-chain alpha-keto- acid dehydrogenase (BCKDH)

51. Maple Syrup Urine Disease (MSUD) If unrecognized, elevation of leucine leads to encephalopathy: –Lethargy –Vomiting –Ataxia –Hallucinations –Coma and death. –When symptomatic, urine, skin and hair take on a characteristic sweet smell reminiscent of maple syrup.

52. Maple Syrup Urine Disease (MSUD) Washington State NBS Measures leucine and isoleucine (single peak) Diagnostic testing: –Full quantitative amino acid profile: Marked elevations of leucine, isoleucine, valine and presence of alloisoleucine Mild or moderate elevations without alloisoleucine can indicate non-specific liver disease, hyperalimentation or other organic acidemias

53. MSUD Treatment Precisely measured low protein diet –Medical food (low in branched chain amino acids) Supplemental valine and isoleucine for some chronically elevated leucine can lead to deficiency of val and ile –Aggressive management of routine illness –Risk of decompensation always exists –Hemodialysis sometimes necessary to rapidly lower blood leucine

54. Homocystinuria 1/200 000 - 1/335 000 Disorder of homocysteine breakdown

55. Newborn Screening Guidelines Methionine (serum) –Normal: <80 mmol/L –Borderline: 80-89 mmol/L –Presumptive positive >90 mmol/L

56. Homocystinuria Washington State NBS Measure methionine concentration Two positive screens referred for follow-up Diagnostic confirmation: –Quantitative plasma amino acids –Total homocysteine Elevated methionine can also indicate non- specific liver disease, excess protein intake, benign hypermethioninemia Other causes of homocystinuria- –Cobalamin disorders –MTHFR deficiency

57. Homocystinuria Deficiency in metabolism of homocystine- cystathionine β- synthetase Homocystine and methionine accumulate Slow development of symptoms downward dislocation of lenses thinning and lengthening of long bones seizures vascular thrombosis mental illness

58. Homocystinuria (Cystathionine Beta Synthase Deficiency) Elevations of hcys leads to: –developmental delay –ectopia lentis and/or severe myopia –skeletal abnormalities (tall stature and very long limbs, scoliosis, kyphosis) –increased risk of blood clots –Psychiatric and (some Treatment Low methionine diet Betaine Folate B12 Some are B6 responsive

59. Summary Newborn Screening is a critical part of identification of fragile infants Immediate diagnosis and treatment of inborn errors saves lives Treatment modalities have become more effective over time Outlook (and outcomes) are brighter for many infants and children

60. Eventual Goal