newborn screening in washington cristine m trahms, ms, rd, fada center on human development and...

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

• Discuss nutrition intervention in disorders identified by newborn screening– Treatment paradigm– Medical nutrition therapy

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

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

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

The Scoring System

Core Conditions

Core Conditions:Metabolic

2ndaryConditions

Washington StateNewborn Screening

WA State system

Informed Consent

Supporting understanding for families

How is screening done?

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

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

What’s on the Horizon?

• Cystic fibrosis?

• Organic acid disorders?

• Other amino acid disorders?

• Other fatty acid oxidation disorders?

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/

Phenylketonuria

Newborn Screening Guidelines

• Phenylalanine (serum)– Normal: <180 mmol/L– Borderline: 189-239 mmol/L– Presumptive positive: >240 mmol/L

Phenylketonuria:Establish Diagnosis

• The enzymatic defect– Phenylalanine

hydroxylase– Dihydropteridine

reductase

– Biopterin synthetase

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

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

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

Galactosemia

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

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

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

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

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

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)

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)

Biotinidase Deficiency

Newborn Screening Guidelines

• Biotinidase enzyme (% activity)– Normal: >30%– Borderline: 10-30%– Presumptive positive: <10%

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

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

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

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

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)

Medium Chain Acyl-CoA Dehydrogenase Deficiency(MCAD)

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

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

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

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

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

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)

Maple Syrup Urine Disease (MSUD)

Newborn Screening Guidelines

• Leucine (serum)– Normal: <300 mmol/L– Borderline: 300-349 mmol/L– Presumptive positive: >350 mmol/L

Maple syrup urine disease(Branched-chain ketoaciduria)

• Deficiency of enzyme that control pathway of metabolism or leucine, isoleucine, valine

• Death from profound ketoacidosis

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)

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.

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

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

Homocystinuria

1/200 000 - 1/335 000Disorder of homocysteine breakdown

Newborn Screening Guidelines

• Methionine (serum)– Normal: <80 mmol/L– Borderline: 80-89 mmol/L– Presumptive positive >90 mmol/L

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

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

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

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

Eventual Goal