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Newborn Screening in Washington

Newborn Screening in Washington. Cristine M Trahms, MS, RD, FADA Center on Human Development and Disability Division of Genetics and Development Department of Pediatrics. Objectives . Discuss the Newborn Screening Program Rationale Plans

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Newborn Screening in Washington

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  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. 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 Criteria to Screen for a Disease

  5. NBS at the national level 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.

  6. The Scoring System

  7. Core Conditions

  8. Core Conditions: Metabolic

  9. 2ndary Conditions

  10. Washington StateNewborn Screening

  11. WA State system

  12. Informed Consent

  13. Supporting understanding for families

  14. How is screening done?

  15. 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 Newborn Screening in Washington

  16. By The NumbersEach 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. The enzymatic defect Phenylalanine hydroxylase Dihydropteridine reductase Biopterin synthetase Phenylketonuria:Establish Diagnosis

  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. 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 Galactosemia

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

  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)

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