newborn screening in washington cristine m trahms, ms, rd, fada center on human development and...
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![Page 1: Newborn Screening in Washington Cristine M Trahms, MS, RD, FADA Center on Human Development and Disability Division of Genetics and Development Department](https://reader030.vdocuments.us/reader030/viewer/2022032521/56649d5f5503460f94a3ed62/html5/thumbnails/1.jpg)
Newborn Screening in Washington
Cristine M Trahms, MS, RD, FADA
Center on Human Development and Disability
Division of Genetics and Development
Department of Pediatrics
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Objectives
• Discuss the Newborn Screening Program– Rationale– Plans
• Discuss nutrition intervention in disorders identified by newborn screening– Treatment paradigm– Medical nutrition therapy
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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
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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
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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
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The Scoring System
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Core Conditions
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Core Conditions:Metabolic
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2ndaryConditions
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Washington StateNewborn Screening
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WA State system
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Informed Consent
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Supporting understanding for families
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How is screening done?
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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
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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
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What’s on the Horizon?
• Cystic fibrosis?
• Organic acid disorders?
• Other amino acid disorders?
• Other fatty acid oxidation disorders?
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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/
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Phenylketonuria
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Newborn Screening Guidelines
• Phenylalanine (serum)– Normal: <180 mmol/L– Borderline: 189-239 mmol/L– Presumptive positive: >240 mmol/L
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Phenylketonuria:Establish Diagnosis
• The enzymatic defect– Phenylalanine
hydroxylase– Dihydropteridine
reductase
– Biopterin synthetase
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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
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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
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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
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Galactosemia
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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
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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
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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
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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
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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
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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)
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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 treatD/D Galactosemia• No treatment necessary (unlikely to see these)
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Biotinidase Deficiency
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Newborn Screening Guidelines
• Biotinidase enzyme (% activity)– Normal: >30%– Borderline: 10-30%– Presumptive positive: <10%
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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
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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
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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
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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
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Biotinidase Deficiency
Treatment guidelines (UW BGC)Profound deficiency = 10mg free biotin dailyPartial 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)
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Medium Chain Acyl-CoA Dehydrogenase Deficiency(MCAD)
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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
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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
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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
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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
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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
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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)
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Maple Syrup Urine Disease (MSUD)
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Newborn Screening Guidelines
• Leucine (serum)– Normal: <300 mmol/L– Borderline: 300-349 mmol/L– Presumptive positive: >350 mmol/L
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Maple syrup urine disease(Branched-chain ketoaciduria)
• Deficiency of enzyme that control pathway of metabolism or leucine, isoleucine, valine
• Death from profound ketoacidosis
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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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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.
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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
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MSUDTreatment• 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
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Homocystinuria
1/200 000 - 1/335 000Disorder of homocysteine breakdown
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Newborn Screening Guidelines
• Methionine (serum)– Normal: <80 mmol/L– Borderline: 80-89 mmol/L– Presumptive positive >90 mmol/L
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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
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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
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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
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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
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Eventual Goal