the newborn screening system

The Newborn Screening System

Sheila Weiss, MS, LCGC sheila.weiss@doh.wa.gov

What is Newborn Screening?

A mandatory public health program designed

“to detect, in newborns, congenital disorders leading to

developmental impairments or physical

disabilities”

Why is it Important?

It prevents death and disability to affected infants by providing early treatment

It benefits the public through savings in health care costs and institutional care

Two 6 year old girls with congenital hypothyroidism

WA’s Criteria for Screening

Early identification benefits the newborn

Treatment is available

Nature of the condition justifies population-based screening

A good screening test exists

The benefits justify the costs of screening

A Complete System Includes

Universal screening - all infants

“Appropriate” follow-up response

Diagnosis of affected infants

Appropriate treatment & clinical care

Evaluation of system effectiveness

The Newborn Screening Process

http://www.europaediatrics2008.org http://www2.aap.org

http://www.cdc.gov/ncbddd/jaundice/families

NBS Sequence of Events

recommended window for 1st NBS specimen collection

hospital – blood collection

transit time

NBS lab testing

follow-up

Birth 1Time (days)

2 3 4 5 6 7

When to Screen

Washington State law requires that every newborn be tested “prior to discharge from the hospital or within five days of age”

1st screen should be taken between 18 & 48 hours of life regardless of feeding status (earlier if therapies are administered)

2nd screen strongly recommended between 7 & 14 days of age

Third screen recommended for sick and premature infants at 1 month

Benefits of Repeat Screens

• Maximizes detection of all disorders, particularly milder forms that may benefit from treatment

• May be necessary for detection of some conditions, and is critical for assessment of cystic fibrosis

• Verifies hemoglobin traits, eliminating need for diagnostic lab work

Screening Compliance

Some statistics …

>99.95% of “eligible” infants receive screening (excludes refusals & neonatal deaths)

~94% of infants receive the recommended 2nd screen

~75% of sick & premature receive the recommended 3rd screen

Newborn Screening in WA

~85,000 newborns are screened each year

~170,000 specimens processed

~5,500 results requiring follow-up

170 - 200 true positives

2011 = 188 affected infants prevalence: 1 in 452!

~2,100 false positives

Father of Newborn Screening

“Robert Guthrie, MD, Ph.D. was an American microbiologist,

best known for developing the bacterial inhibition assay used

to screen infants for phenylketonuria at birth, before the development of irreversible

neurological damage.”

Wikipedia

Technology that Enables Expansion

Tandem Mass Spectrometer - MS/MS

MS/MS Plasma Amino Acids

Biotinidase Screening

Hemoglobin Screening

FAE

AE control

FAC

AFSC control

FA normal

Normal Affected

13.0 μM2.12 μM.78 μM 101 μM

100% specificity 100% sensitivity

Screening Results

what we would like …

Screening Results

Normal Affected

200 μM 35 μM 745 μM

Specificity vs. Sensitivity

what we usually get …

Abnormal Screening Results

Response is dependent on disorder, magnitude of result, & demographics of infant

(presumptive, borderline, inconclusive)

Stratifying ResultsCategorization of C3 Cutoffs

Age ≤ 6 days Age > 6 daysC3

mmol/L serum

not all 2° markers* elevated

all 2° markers* elevated

not all 2° markers* elevated

all 2° markers* elevated

< 4.1 normal normal normal normal

4.1 – 4.89 normal normal borderlinea Presumptivec

4.9 – 6.09 normal borderlineb borderlinea Presumptivec

6.1 – 8.39 borderlinea Presumptive c borderlinea Presumptive c

8.4 – 11.99 borderlined Presumptive c borderlined Presumptive c

≥ 12.00 Presumptivec Presumptive c Presumptive Presumptive c

.

* normal ranges for secondary markers: C3/C2 < 0.2 and C3/C16 < 2.2

Follow-up Responses

a - if first screen, wait for routine second; if second screen and previous normal, call health care provider and recommend third screen; if second screen and previous abnormal, call health care provider and recommend immediate diagnostic work-up

b - call health care provider and recommend collecting subsequent screen ASAP

c - call health care provider and recommend immediate diagnostic work-up

d - call health care provider to request second screen ASAP

for abnormal C3 results …

High Urgency !!

• CAH

• Galactosemia

• MSUD

Diagnosis and treatment should be initiated ASAP!

Moderate Urgency!

• Congenital Hypothyroidism

• MCAD deficiency

• PKU

Treatment recommended by 1 - 3 weeks of age

No Medical Urgency

.. can wait over a weekend to notify

• Cystic Fibrosis

• Sickle Cell Disease

Treatment recommended by 2 to 4 weeks of age

Special Issues

for adrenal (CAH) results …

• low birthweight & sick babies

• steroids

• different forms of the disorder - severe (salt-wasting) - non-life threatening (simple virilizing) - other forms

Policy & Program Evaluation

WAs Newborn Screening Timeline1967 Phenylketonuria (PKU)1977 Congenital Hypothyroidism1984 Congenital Adrenal Hyperplasia (CAH)1991 Hemoglobinopathies (includes SCD)2004 Biotinidase deficiency

GalactosemiaHomocystinuriaMaple Syrup Urine Disease (MSUD), Medium Chain Acyl co-A Dehydrogenase (MCAD) deficiency

2006 Cystic Fibrosis2008 3 Amino acid disorders

(ASA, CIT, TYR-1)4 Fatty acid disorders (CUD, LCHAD, TFP, VLCAD)8 Organic acid isorders (HMG, BKT, GA-I, IVA, CblA-B, MUT, MCD, PROP)

# of conditions screened for by state, 2004

Major 2008 Expansion15 Additional Disorders:• 3-OH 3-CH3 glutaric aciduria (HMG) • Argininosuccinic acidemia (ASA) • Beta-Ketothiolase deficiency (BKT) • Carnitine uptake defect (CUD) • Citrullinemia (CIT) • Glutaric acidemia type I (GA 1) • Isovaleric acidemia (IVA) • Long-chain L-3-OH acyl-CoA dehydrogenase deficiency (LCHADD) • Methylmalonic acidemia (Cbl A, B) • Methylmalonic acidemia - mutase deficiency (MUT) • Multiple carboxylase deficiency (MCD) • Propionic acidemia (PROP) • Trifunctional protein deficiency (TFP) • Tyrosinemia type I (TYR I)• Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD)

19 MS/MS disorders 49 markers

What are we screening for?

9 OA 5 FAO 6 AA 3 Hb Pathies 6 Others

CORE PANEL

IVAGA IHMGMCDMMAMUTPROPBKT

3MCC

MCADVLCADLCHADTFPCUD

PKUMSUDHCYCITASATYR I

Hb SSHb S/ßThHb S/C

CHBIOTCAHGALTHEARCF

On seven 1/8 inch blood spots!

3-Methylcrotonyl-CoA carboxylase deficiency (3MCC)

• Without treatment many people have no clinical symptoms.

• Treatment prevents and corrects all problems in symptomatic patients.

• Screening test is very good at detecting affected infants, but not totally specific. Also detects asymptomatic mothers.

• Not evident at birth – a sudden metabolic crisis can bring on severe illness (but in a very small percentage of patients).

Amino Acid Disorders

• Amino acids 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

• 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

Other: 1 ASA, 1 CIT, 1 HCY, 1 TYR

Organic Acid Disorders

• 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

• 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

Objective for an Affected Child

PROMPT DIAGNOSIS & TREATMENT to prevent death and

disability by:

• modifying their feedings• supplementing carnitine• administering hormone

replacement• other therapies

NeoLynx PQ (3.5kV, 25V, 15eV) NL102.1 30-Oct-2004Quattro Micro S/N QAA 709

140 145 150 155 160 165 170 175 180 185 190 195 200 205 210 215 220 225 230 235 240 245 250m/z0

100

%

NL102_MCA_OCT3004_NEWBORN 1 (0.518) Neutral Loss 102ES+ 1.46e7191.08

172.05

145.95149.01

161.97

186.01

182.07

174.05

176.06

227.14

222.07

209.11192.08

212.18

238.15

228.20

240.22

246.04

Ala *Ala

Val

Pro

Ser

Thr

*Val

Tyr

*Met

*Leu

Leu

His

*Phe

Phe

Met

*Tyr

Clinical Management: PKU

• Correct substrate imbalance– Restrict phenylalanine

intake to normalize plasma concentration

• Supply product

– Supplement tyrosine to maintain normal plasma tyrosine levels

Phenylalanine ------------//---------------- Tyrosine

(substrate) phenylalanine hydroxylase (product)

Stabilizing Phe Levels

Blood levels every 2 daysbecause of rapid growth

Equilibrium achieved by 14 days of age

Management Tools

• Specialized formula provides– 80-90% energy intake– 85-90% protein intake– tyrosine supplements– no phenylalanine

• Phenylalanine to meet requirement from infant formula or foods

Effective Phe Level Management

Blood levels once per month, or more frequently if needed for good management

Goals of PKU Management

• Normal growth rate• Normal physical

development• Normal cognitive

development• Normal nutritional status

Maternal PKU Concerns/Outcomes

• Women with PKU are at high risk for delivering a damaged infant– Placenta concentrates phe 2-4x

• Microcephaly• Cardiac problems

• Infant IQ directly related to maternal blood phe level

• Outcome improved with maternal blood phe <2 mg/dl prior to conception and during pregnancy

Maternal PKU Syndrome

… and moderate to severe intellectual disability

Other Program Services

Provide metabolic treatment products

Subsidize low-protein foods for low-income families

Contract consultant & clinical services

Evaluate long-term outcomes

On the Horizon

Current National Recommendations

• Severe combined immunodeficiency (SCID)

• (Congenital Heart Defects)

Potential Additions to National List

• Lysosomal storage disorders

• Fragile X

• Spinal Muscular Atrophy

• Muscular dystrophy

Washington State Newborn Screening

www.doh.wa.gov/nbs

(206) 418-5410

or

1-866-660-9050