newborn screeening

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NewbornScreeningLaboratoryBulletin

October

2008

U.S.DepartmentofHealthandHumanServices

Centers

for

Disease

Control

and

Prevention

NationalCenterforEnvironmentalHealth


4/32

CentersforDiseaseControlandPrevention

NationalCenterforEnvironmentalHealth

DivisionofLaboratorySciences

Atlanta,

Georgia

30341-3724

NCEHPub.No.08-ae043

TheCentersforDiseaseControlandPrevention(CDC)protectspeopleshealthandsafetybypreventingandcontrollingdiseases

andinjuries;enhanceshealthdecisionsbyprovidingcredibleinformationoncriticalhealthissues;andpromoteshealthyliving

throughstrongpartnershipswithlocal,national,andinternationalorganizations.


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TableofContents

I. NewbornScreening.......................3

OverviewofNewbornScreening

II.

CDCs

Laboratory

Role

in

Newborn

Screening

.................................5

Overview

of

the

Newborn

Screening

Quality

Assurance

Program

(NSQAP)

NSQAPsPartnershipwithLaboratories

ASnapshotofNSQAP

III.

CDCs

Role

in

Translation

Research

................................15

CollaboratingwithStatePublicHealthLaboratories

IV.

Future

Directions.............................19

NewbornScreeningNationalContingencyPlan

Environmental

Uses

of

Dried

Blood

Spots

V. NextGenerationNewbornScreening............................................................................21

Genomics

EmergingTechnologies

VI. References........................................................................................................................23

VII.

Selected

Publications

......................................................................................................25


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I.

Newborn

Screening

Overview

of

Newborn

Screening

Newborn

screening

is

one

of

the

nations

most

successful

public

health

programs

(1).

Newborn

screening

programs

testbabiesfordisordersthatareoftennotapparentat

birth.Suchdisordersmaybeinherited,infectious,or

caused

by

a

medical

problem

of

the

mother.

If

these

disorders

are

not

detected

and

treated

soon

after

birth,

they

may

cause

mental

retardation,

severe

illness,

or

premature

death.

More

than

4

million

newborns

are

screenedannuallyintheUnitedStates,andthousandsofinfantsare

rescuedfromdisabilityanddeath.

Newborn

screening

begins

within

24

to

48

hours

of

a

childs

birth

when

a

few

drops

of

blood

are

obtained

from

aheelstick.Thebloodspotsaresenttoalaboratorythatis

apartofthestateorterritorialpublichealthdepartment.

The

spots

are

analyzed

by

several

different

laboratory

methods

to

test

for

biochemical

and

genetic

markers

that

reveal

hidden

congenital

(present

at

birth)

disorders.

If

such

markers

are

found,

the

newborn

screening

follow-up

programnotifiestheparentsandphysicianssothatthe

baby

can

receive

immediate

attention.

Follow-up

programs

arrange

for

diagnostic

tests

to

confirm

the

newborn

screening

results.

Follow-up

programs

also

refer

thechildtoatreatmentcentertoprovideaccesstothe

essentialmedicalservicesneededtominimizetheeffectsof

theunderlyingdisorder.

Newbornscreeningofferslife

without

physical

disability

PhotocourtesyofDr.HolmesMorton

Thethreechildreninthephotographallhavean

inheritedmetabolicdisordercalledglutaric

aciduria

type

I,

which

occurs

when

the

body

is

unabletodegradecertainaminoacids(the

buildingblocksofproteins)completely.

Excessivelevelsoforganicacidsaccumulatein

thebrainandcausedegenerationinaregionof

thebrainthatcontrolsmovement(2). Inthe

past,

children

with

brain

damage,

like

the

boy

in

thepicture,wereoftensaidtohavecerebral

palsy.Hewasborninahospitalwherenewborn

screeningforglutaricaciduriawasnotbeing

done. Thesisters(nothissiblings)oneachside

ofhimweretestedforglutaricaciduriaaspartof

a

regional

newborn

screening

program

to

developnewmethodstodiagnoseandtreatthe

disorder. Earlydetectionandintervention,

whichincludedaspecialdietandintravenous

glucosetreatments,preventedthesistersfrom

becoming

disabled.

The

different

health

outcomes

for

these

children

and

reports

about

successinidentifyingandtreatingglutaric

aciduriathroughouttheUnitedStatesand

Europehaveledtowidespreadscreeningof

newbornsforthistreatabledisorder.


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II CDC s Laboratory Role in

Newborn

Screening

Overview o the Newborn Screening Qual ity Assurance Program NSQAP)

n 1978, CDC established the

Newborn

Screening QualityAssurance Program (NSQAP)

to

enhance

and

mainta in the quality

of

newborn

screening tests performed in the United States.

NSQAP housed

in CDC s Environmental Health Laboratory-

has grown

to

become the only comprehensive

program

in

the

world devoted

to

quality assurance of

newborn

screening tests.

Since its inception, NSQAP has steadily

added

disorders

and

analytes* (Figs. 1

and

2)

to

the

program and

continues

to

expand

the

program.

t

NSQAP provides training, consultation, proficiency testing, guidelines, and reference materials

to

state

public health laboratories

and

othe r laboratories responsible for

newborn

screening in the Uni ted States

and

in several other

countries. Because of NSQAP, parents and doctors in

the

United States can trust the results of

newborn

screening tests.

Figure 1

Sample listing of disorders

added

to NSQAP

1978

Congenital Hypothyroidism

1980

Phenylketonuria

1988

Galactosemia & HIV Seroprevalence

1990

Congenital Adrenal Hyperplasia

1991

Sickle Cell Disorders

1992

Maple Syrup Urine Disease

1995

Homocystinuria

1997

Biotinidase

2000

Fatty Acid Oxidation & Organic

Acid Disorders

2002

Cystic Fibrosis/IRT & Diabetes

(type 1)

2005

Toxoplasmosis

2006

2nd Tier Congenital Adrenal

Hyperplasia

2007

Cystic Fibrosis DNA Mutation Panel

2008

Succinylacetone

(Tyrosinemia type 1)

Future Years: Lysosomal Storage Disorders,

Severe Combined Immune Deficiency, Wilson's

Disease, Cytomegalovirus, and others,

Figure 2

rowth of

NSQAP: Disorders and analytes) in NSQAP

1978

1

disorder, 2 analytes)

1988 8 disorders, 5 analytes)

1998 't tt, (17 disorders, 13 analytes)

2008 tt

t t

t t t

t

t

(48 disorders, 44 analytes)

*An

analyte is

a

substance

that

can

be

measured

in the laboratory, and its presence or

absence

can show

abnormal

processes resulting in

disease,

The number ofanalytes

and the

number of

disorders in newborn screening tests are not

identical

numbers. The

newborn

screening tests

conducted

in

laboratories

look for analytes that are associated with disorders. Some analytes

identify

more

than

one disorder, and

some disorders

are

related

t

more

than one analyte.

tThe American College

o Medical

Genetics (ACMG)

recommends

that

states

conduct

newborn

screening tests

for

a core

panel

of29

disorders

(including

hearing screening, which

does

not

routinely

involve

blood spot

analysis). ACMG

has noted

that screeningfor the core

panel

will provide data

that

enable states

to

include

a secondary

set

of25 disorders.

CDC s

goal s to

include primary

analytes

for the

5 disorders that can be screened

using dried blood spots in

NSQAP

so

that it

can

help

the

state newborn

screening

programs meet the ACMG

recommendations with

confidence

and accuracy

NSQAP is currently at 48

disorders

plus

toxoplasmosis

and

HIV.


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NSQAPs

Partnership

with

Laboratories

AsNSQAPhasdeveloped,sohaveitsrelationshipswithpublic

healthpartners.OneofNSQAPsmostimportantpartnersis

theAssociationofPublicHealthLaboratories(APHL),which

serves

as

a

dynamic

interface

between

CDC

and

local,

state,

and

territorial

public

health

laboratories.

For

the

past

30

years,

APHL

has

worked

closely

with

NSQAP

to

assure

the

highest

standardsofperformancefornewbornscreeningnationwide

forpublicandprivatelaboratories.

Through

its

Newborn

Screening

and

Genetics

in

Public

Health

Committee,

APHL

is

involved

in

a

broad

range

of

issues

includingtraininginlaboratorymethodsusingadvanced

technology,developmentofpolicystatementsonnewborn

screeningissues,andcontingencyplanningforcontinued

newborn

screening

in

the

event

of

a

disaster

or

other

public

health

emergency.

APHL

promotes

the

scientific

and

technologicexpertiseofNSQAPtopublichealthofficialsatthe

stateandfederallevels.APHLalsoprovidesvaluablestrategic

guidanceandexpertisetoNSQAP.WithAPHLsassistance,

NSQAP

is

recognized

worldwide

and

serves

as

a

model

program

of

quality

assurance

for

newborn

screening

for

many

other

countries.

6


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PreventingLife-LongDisability

Tayla

Cunzenheim

ThebirthofTaylaCunzenheimin

Wisconsin

on

December

23,

2002,

wasanearlyChristmaspresentfor

herhappyparents,SherylandJim.

ShortlyaftertheybroughtTayla

homeonChristmasDay,they

received

a

call

from

the

hospital

telling

them

that

Taylas

newborn

screeningtestshowedthatshehad

acongenitaldisorder.Taylahad

phenylketonuria(PKU),aninheritedandtreatablemetabolic

disorder. WithPKU,thebodycannotprocesstheaminoacid

called

phenylalanine

(Phe),

which

is

in

almost

all

foods

that

contain

protein.

If

left

untreated,

the

Phe

level

can

get

too

high

in

the

blood,

resultinginmentalretardation(3).

WhenparentsaretoldthattheirbabyhasadisorderlikePKU,they

need

to

know

for

certain

that

the

tests

are

accurate.

NSQAP

works

with

all

state

public

health

laboratories,

including

the

Wisconsin

State

Laboratory

of

Hygiene

that

analyzed

Taylas

test,

to

assure

thatalltestresultsareaccurateandthatnodisordersaremissed.

Inmanycases,newbornscreeningmakesthedifferencebetween

lifeanddeathfornewborns;inotherinstances,identifyingbabies

withadisordermeansthattheycanbetreatedandthusnotface

life-long

disability

or

cognitive

impairment.

ThegoodnewsfortheCunzenheimsisthattodayTaylaisthriving.

ThetreatmentforTaylainvolveskeepingheronaspecialdietand

specialformula.TheCunzenheimsworkedwithadieticianfromthe

WaismanCenterattheUniversityofWisconsintodevelopthisdiet

plan.

Her

parents

describe

Tayla

as

smart

as

a

whip.

She

attends

schoolandlovestodrawandcolor.Whatagift!

Inmanycases,newborn

screeningmakesthe

differencebetweenlifeand

deathfornewborns;inother

instances,

identifying

babies

withadisordermeansthat

theycanbetreatedandthus

notfacelife-longdisabilityor

cognitiveimpairment.


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A

Snapshot

of

NSQAP

Newbornscreeningbeginswithaheelstickthatisdone

within24-48hoursofababysbirth.Ahealth-care

professionalcollectsbloodfromthebabysheelontoa

filter-paper

card,

which

is

the

blood-collection

device

(card).

This

card

is

sent

to

a

newborn

screening

laboratory

for

testing.

Photo

courtesy

of

Dr.

Brad

Therrell

Workingwithmanufacturers,NSQAPtestsallofthefilter

paperusedintheblood-collectiondevicesbeforetheyare

releasedforsale.Filter-papermanufacturersprovideCDC

with

sample

sets

of

paper

from

the

beginning,

middle,

and

end

of

their

production

lots.

The

amount

of

paper

sent

to

CDCvarieswiththesizeoftheproductionlots;however,

thousandsofstripsofrandomlyselectedpaperaretested

eachyear.Thefilterpaperneedstoadheretostrict

specifications

so

that

the

blood

can

be

collected

and

analyzed

correctly.

NSQAP

provides

quality

assurance

products,

including

training,

consultation,

proficiency

testing,

guidelines,

and

reference

materials,

to

state

public

health

laboratories

and

other

laboratories

responsible

for

newborn

screening.

Currently,

NSQAP

workswithlaboratoriesineverystateandU.S.territoryaswellaswithlaboratoriesworldwide.


13/32

One

of

NSQAPs

primary

efforts

is

to

prepare

dried

blood

spot

reference

materials

for

distribution

to

laboratories

participating

in

the

programs

quality

assurance

tests.

Each

year,

NSQAP

createsandsendsoutnearlyamilliondriedbloodspot

referencespecimens.CDCscientistsstartwithprescreened

blood

from

blood

banks.

They

enrich

the

blood

with

selected

biomarkers

(i.e.,

chemical

substances

associated

with

the

specific

disorders

in

newborn

screening

tests).

Thebloodisthenspottedeitherbyhandorthroughuseofarobotontofilterpaper.


14/32

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Volume 25 January 2008

EVALUATION:Nomisclassificationswerereported- 100%Satisfactory

The

quality

assurance

efforts

at

CDC

involve

a

continual

interaction

between

NSQAP

and

the

participating

laboratories.

NSQAP

prepares

panelsofdriedblood-spotspecimensand

sendsthemouttoparticipatinglabs.

The

laboratories

analyze

the

specimens

and

return

their

assessments

to

NSQAP

for

review.

NSQAP

then

compiles

and

reports

the

results

tohelplaboratoriesmaintainaccurateand

reliabletestingpractices.TheDataVerification

and

Evaluation

reports,

along

with

NSQAPs

dedicated

efforts

to

work

with

laboratories,

help

newborn

screening

laboratories

get

the

rightanswereverytime.

2007 ANNUAL SUMMARY REPORT

The

spots

are

carefully

dried

and

packed

to

avoid

any

degradation

and

then

stored

in

a

freezer

until

neededforqualitycontrolandproficiencytests.

0


15/32

NSQAPmonitorsnewbornscreeningworldwidesothatitcanstayontopofnewtechnologyandtests.Thegraphic

belowlistscountrieswithoneormorelabsparticipatinginNSQAP.

NSQAP

Worldwide

Participants

ArgentinaArmeniaAustraliaAustria

BelgiumBrazil

CanadaChileChina

Colombia

Costa

RicaCuba

CzechRepublicDenmark

Egypt

EstoniaFinlandFrance

GermanyGreece

GreenlandHungaryIcelandIndia

IrelandIsrael

ItalyJapan

LatviaLebanonLithuania

LuxembourgMalaysiaMexico

NetherlandsNewZealand

NorwayPakistanPanama

PeruPhilippines

Poland

PortugalQatar

RussiaSaudiArabia

Singapore

SouthAfricaSouthKorea

SpainSweden

SwitzerlandTaiwan

ThailandTurkey

UkraineUnitedArabEmirates

United

KingdomUnitedStates

VenezuelaVietnam

Since1978,NSQAPhassteadilyaddedlaboratoriestotheprogram.Whereasonly31laboratoriesparticipatedin1978,

nearly

500

labs

were

enrolled

in

NSQAP

by

2007

(Fig.

3).

Figure3

Numberofactivelabs inNSQAP(byyear)

1978:

1988:

1998:

2002:

2004:

2006:

2007:

2018:

(31)

(75)

(198)

(313)

(406)

(439)

(458)

(700)


16/32

NSQAPmakessurethatthereis

sustainedqualityinnewborn

screeningsothatadiagnosis

suchasGabrielsisnotmissed.

Obtainingaccurateresults

GabrielGeorge

GabrielGeorge

wasdiagnosed

with

sickle

cell

diseasewhenhe

wasjustthree

weeksold. Sickle

celldiseaseisa

groupofinherited

red

blood

cell

disorders.Healthy

redbloodcellsareround,andtheymove

throughsmallbloodvesselstocarryoxygento

allpartsofthebody.Insicklecelldisease,the

redbloodcellsbecomehardandsticky,and

consequently

clog

the

blood

flow

in

small

bloodvessels. Thisconditioncancausepain

andotherseriousproblems,suchasanemia

andinfections(4). NSQAPmakessurethat

thereissustainedqualityinnewbornscreening

so

that

a

diagnosis

such

as

Gabriels

is

not

missed.

Sincehisdiagnosis,Gabrielsparents,Charles

andCherylGeorge,havebeenactively

involvedintheMarcThomasSickleCell

Foundation

in

Austin,

Texas.

Gabriel

enjoys

reading,

riding

his

bike,

and

spending

time

with

hisbrotherNathaniel. Gabrielwasnamedthe

2007-2009posterchildfortheSickleCell

DiseaseAssociationofAmerica,Inc.

2


17/32

Improvinghealthoutcomes

Matthew

Fisch

WhenJillLevy-Fischsthirdchild,

Matthew,wasborn,sheknew

somethingwasnotquiteright. Hewas

developmentally

delayed,

and

he

never

smiled.Atageone,Matthewweighed

22pounds. Bythetimehereachedhis

secondbirthday,Matthewstillweighed

22pounds. Duringthefirsttwoanda

half

years

of

Matthews

life,

Jill

went

from

doctor

to

doctor

searching

for

an

answer

inwhatissometimescalledamedicaldiagnosticodyssey.Matthew

enduredtestaftertest,andtheexperiencewasanemotionalstrain

oneveryoneinthefamily.Atagethree-and-a-half,Matthewwas

finallydiagnosedwithshortchainacyl-CoAdehydrogenase

deficiency

(SCADD).

SCADD

is

a

rare

condition

that

prevents

the

body

from

converting

certain

fats

into

energy.

Some

of

the

symptomsofSCADDincludevomiting,lowbloodsugar,alackof

energy,poorfeeding,andfailuretogainweightandgrowat

expectedrates.Otherfeaturesofthisdisordermayincludepoor

muscle

tone,

seizures,

and

developmental

delays

(5).

While

there

is

no

standard

treatment

for

SCADD,

Matthew

has

a

feeding

tube,

takesdietarysupplementstorestorehismetabolism,andrequires

physicaltherapy.Inaddition,becauseofhisdevelopmentaldelay,he

visitsareadingtutorfourdaysaweek.

NewbornscreeningforSCADDwasnotavailableinMatthewsstate

at

the

time

of

his

birth

in

2001.

Spurred

to

action,

Jill

began

working

fortheSaveBabiesThroughScreeningFoundation,avolunteer

organizationthatsupportsnewbornscreening.Shewantstomake

surethatnofamilyhastoendureamedicaldiagnosticodysseylike

her

family

did.

Had

Matthew

been

diagnosed

through

newborn

screening,therapiescouldhavebeenintroducedearlier,andhis

health

outcomes

would

have

been

better.

While

Matthew

did

not

receivethebenefitofanaccurate,earlydiagnosis,Jillisthrilledthat

todayherstatescreensforSCADDandthatNSQAPworkswithher

statelaboratorytoensureaccuratenewbornscreeningtestsfor

SCADD.

HadMatthewbeendiagnosed

throughnewbornscreening,

therapiescouldhavebeen

introducedearlier,andhishealth

outcomeswouldhavebeenbetter.


18/32

4


19/32

III.CDCsRoleinTranslationResearch

CollaboratingwithStatePublicHealthLaboratories

Cutting-edgetechnologyisavailablenowthatcantestnewbornsformorediseasesthanhaseverbeenpossible.CDCis

working

to

harness

the

latest

advances

in

science

and

technology

so

that

more

disorders

can

be

detected

accurately

and

treated

quickly.

In

2005,

CDC

established

the

Newborn

Screening

Translation

Research

Initiative

(NSTRI)

with

the

CDC

Foundation.

Working

with

corporate,

academic,

and

Foundation

partners,

NSTRI

assures

the

quality

of

research

methods

duringbothpilotstudiesandroutinescreening.GoalsforNSTRIinclude

developing

new

screening

tests

for

specific

disorders.

adapting

innovative

methods

such

as

DNA

testing

and

nanotechnology

for

screening

and

quality

assurance.

transferringnewscreeningtechnologiestostatepublichealthlaboratories.

assisting

states

with

pilot

studies

related

to

new

screening

tests

for

newborns.

supporting

state

laboratory

functions

when

states

add

disorders

to

their

current

panel

of

tests.

NSTRI

has

developed

laboratory

projects

focusing

on

a

variety

of

disorders,

including

lysosomal

storage

disorders

(LSD)

andseverecombinedimmunedeficiency(SCID). In2008,CDCsupportedthreepilotstudiesforSCID,includingone

involvingtheIndianHealthServiceandtheWesternNavajoReservationinArizona.By2018,CDCanticipatesthatitwill

collaborate

on,

support,

or

fund

15

pilot

projects

for

conditions

such

as

Pompe

disease,

Krabbe

disease,

Fabry

disease,

Niemann-Pick,

metachromatic

leukodystrophy

(MLD),

DiGeorges

disease,

and

X-linked

adrenoleukodystrophy

(X-ALD).

Lysosomal

Storage

Disorders

(LSDs):

Assuring

the

quality

of

new

tests

LeAGartzke

In1996,MickiGartzkegavebirthtoadaughternamedLeA.Asanewborn,LeA

ateandsleptlikeallothernewbornsandbegantonoticetheworldaroundher.

Within

a

few

months,

LeAs

physical

condition

changed

dramatically.

Her

body

became

rigid.

She

cried

constantly,

and

she

would

not

eat.

At

10

months,

LeA

was

diagnosedwithKrabbedisease,whichispartofagroupofapproximately40rare

diseasesknownaslysosomalstoragedisorders(LSDs).

LSDsarecausedbydeficientenzymesthatnormallyeliminateunwantedsubstancesinthecellsofthebody(6).

Becausethediagnosistookmonths,LeAwaspasttheperiodwhenshecouldreceivetreatment.Herphysical

condition

worsened

to

where

she

needed

feeding

tubes,

specialty

formulas,

36

doses

of

medicine

a

day,

oxygen,

suctioning,

and

in-house

nursing.

After

a

quarter

of

a

million

dollars

worth

of

medical

bills,

LeA

died

at

theageoftwo. HermothersaysthatearlydiagnosisandinterventioncouldhavemadethedifferenceinLeAs

life,andforthisreason,MickiGartzkebecameastrongadvocatefornewbornscreening.Today,sheworkswith

foundations,researchers,corporations,andlegislatorstoraiseawarenessabouttheimportanceofscreening.

OnestateNewYorknowscreensforKrabbedisease,andCDCplanstoprovidethereagentsthatcanbe

usedtoperformtheKrabbetests. Inaddition,CDChasestablishedaprogramtoensurethattheKrabbetest

resultsareaccurate. IllinoishaspassedlegislationmandatingnewbornscreeningforKrabbeandfourother

LSDs

(Pompe,

Fabry,

Niemann-Pick,

and

Gaucher

diseases).

CDC

will

provide

the

reagents

and

will

assure

the

qualityofallfivetests.


20/32

SevereCombinedImmuneDeficiency(SCID):

Guidingthetransitiontoroutinetests

Jeffrey

Modell

JeffreyModellwasasweet,cheerful,outgoingkid. Hewaslikeeveryother

boy

his

age,

except

he

got

sick

very

often.

His

life

was

filled

with

normal,

happytimes,butwasfrequentlydisruptedwithsuddenhighfevers,bronchitis,

sinusitisandotherinfectionsthatledtoextendedperiodsonmedicationand

lengthy

hospital

stays.

Plans

for

fun

activities

were

made

in

spite

of

the

strong

possibilitythatJeffreymightbetoosicktoattend.Evenperiodsofgood

healthwerestrainedwiththeever-presentthreatofsuddenillnesscausedby

Jeffreys

immune

deficiency.

Three

decades

ago,

no

one

knew

very

much

aboutprimaryimmunedeficiencies.Theywereconsideredsorare,thatmany

doctorsknewtoolittleaboutthemandhadevenfewertreatmentoptions.Lay

peoplehadneverheardofthesedisorders,andprimaryimmunedeficiencieswerenotatthetopofmany

researchagendas.

At

15,

Jeffreys

condition

overwhelmed

him

and

took

his

life.

Inspired

by

Jeffrey's

courage

and

optimism,hisparents,FredandVickiModell,startedaFoundationtoraiseawarenessaboutprimary

immune

deficiencies,

including

severe

combined

immune

deficiency

(SCID).

Sometimes

known

asBubbleBoyDisease,SCIDischaracterizedbyaninabilitytoresistinfections.Withoutearlydiagnosis

andtreatment,babieswithSCIDusuallydiewithinayearofbirth.NewbornswithSCIDdonotgenerally

exhibit

signs

of

infection

or

illness

because

during

the

first

few

weeks

after

birth,

they

are

protected

by

the

antibodies

passed

on

to

them

from

their

mothers

and

because

they

have

not

yet

been

exposed

to

infection.

Newbornscreeningenablesdiagnosisandtreatmentbeforetheonsetofinfectionandrelatedmedical

complications;earlydetectionalsoimproveshealthoutcomesandhelpsreducehospitalizations(7).

TheModellsrecognizethathavinganaccuratetestleadstoanearlydiagnosisandthebestopportunity

for

effective

treatment.

Before

newborn

screening

for

SCID

can

be

implemented

at

the

state

level,

an

effectiveandefficientscreeningmethod(thatcouldprocesshundredsofsamplesdaily)isneeded(7).

With

Congressional

funding,

CDC

is

addressing

this

need

through

cooperative

agreements

that

encouragestatestoresearch,develop,andevaluatenewbornbloodspotscreeningtestsforSCID.

6


21/32

LysosomalStorageDisorders(LSDs):

Encouragingresearchanddevelopment

John,

Jack,

and

Christopher

Evanosky

Bob

and

Sonya

Evanosky

know

the

benefits

of

early

diagnosis

and

intervention.

Both

of

their

twin

boys,

John

and

Christopher,

wereprematurebabieswhentheywerebornin2001,andsoit

wasnotsurprisingtotheirparentsthattheymetgrowthand

developmentmilestonesmoreslowlythantheirpeers.At15

months

of

age,

the

twins

were

struggling

to

walk.

This

is

when

the

Evanoskys

difficult

search

for

answers

began.

After

a

batteryoftests,JohnandChristopherwerediagnosedwith

cerebralpalsy. Thetwinsbegantherapyforcerebralpalsy;

however,theysoonbegantolosetheabilitytowalk,theirspeech

worsened,andtheywerestrugglingtoeat. Thetwinswere

eventuallydiagnosedwithmetachromaticleukodystrophy(MLD),

an

LSD.

AlthoughthereisnocureforMLD,experimentaltreatmentinvolvingbonemarrowtransplantorcordblood

stemcelltransplantcandelaytheprogressionofthediseaseininfantswithoutsignificantsymptoms(8).

John

and

Christopher

were

not

candidates

for

treatment

because

they

showed

significant

symptoms.

TheEvanoskysyoungestchildJacktestedpositiveforMLDonemonthafterthetwins,andbecausehe

showed

no

symptoms,

he

underwent

a

stem

cell

transplant.

Post-transplant,

Jack

is

doing

well,

but

unfortunatelythefutureforJohnandChristopherisbleak.

TheEvanoskys,throughtheirFoundation,areworkingwithCDCtodevelopnewbornscreeningforMLD.

Thiscollaborationwillalsoestablishadriedbloodspotcardrepositoryforconditionsthatarepartofpublic

healthnewbornscreeningprogramsaswellasconditionsthatmaybeaddedinthefuture.Thisrepository

will

help

CDC

enhance

quality

assurance

by

providing

biologic

reference

materials

for

current

and

newly-

implementedscreeningtests.AlthoughtheirchildrencannotbenefitfromnewbornscreeningforLSDs,

theEvanoskysthinkthatnewbornscreeningisthebestwaytomakesurethatotherchildrenhavea

chance

at

a

normal

life.

They

recognize

that

ensuring

the

accuracy

of

the

tests

is

critical

and

believe

that

familiesmusthavethehealthinformationtheyneedtomakeinformeddecisions.

John,

Jack

and

Christopher

Evanosky

have

metachromatic

leukodystrophy

(MLD),

which

is

a

genetic

disease.


22/32

8


23/32

IV.FutureDirections

NewbornScreeningNationalContingencyPlan

WhenHurricaneKatrinahitNewOrleansandtheleveeswerebreached,thestatesnewbornscreeninglaboratorywas

decimated,andthenormaloperationsofnewbornscreening,diagnosis,andfollow-upwereinterruptedforseveralweeks.

Oneofthelessonslearnedfromthatexperienceisthataback-upsystemorcontingencyplanisessentialtokeepthis

critical

service

functioning

without

interruption.

The

Newborn

Screening

Saves

Lives

Act,

which

was

signed

into

law

in

2008,

requires

the

development

of

a

national

contingencyplanfornewbornscreeningforusebyastate,region,orconsortiaofstatesintheeventofapublichealth

emergency.CDCisworkingwiththeHealthResourcesandServicesAdministration,statepublichealthdepartments,and

otherstodevelopaplanthataddresses

the

collection

and

transport

of

specimens;

the

shipment

of

specimens

to

state

newborn

screening

laboratories;

theprocessingofspecimens;

thereportingofscreeningresultstophysiciansandfamilies;

the

diagnostic

confirmation

of

positive

screening

results;

ensuringtheavailabilityoftreatmentandmanagementresources;

educating

families

about

newborn

screening;

and

carryingoutotheractivitiesdeterminedappropriatebytheSecretaryofHealthandHumanServices.

The

establishment

and

continued

refinement

of

a

national

contingency

plan

will

help

ensure

that

all

babies

receive

the

benefits

of

newborn

screening,

even

under

emergency

circumstances.


24/32

Environmental

Uses

of

Dried

Blood

Spots

Foratleastthreedecades,scientistsatCDChavebeendeterminingwhichenvironmentalchemicalspeoplehavebeen

exposedtoandhowmuchofthosechemicalsactuallygetsintotheirbodies.Thistechniqueisknownasbiomonitoring.

CDCiscombiningitsbiomonitoringexpertisewithitsnewbornscreeningexpertisetoexaminethepossibilityofusing

newborn

screening

dried

blood

spots

to

measure

exposure

to

environmental

chemicals,

such

as

pesticides

and

metals.

The

benefit

of

using

dried

blood

spots

is

that

researchers

will

be

able

to

determine

which

environmental

chemicals

are

actually

in

newborns.

Such

research

will

improve

pediatric

studies,

for

example,

that

currently

depend

on

interviews

and

memory

totryandreconstructexposurehistory(9).

Althoughthisisapromisingareaofstudy,anumberofsignificantissuesneedtobeaddressedbeforeanykindof

widespread

use

can

begin.

For

example,

overcoming

sample

volume

limitations,

determining

the

priority

chemicals

to

measure,

and

facing

analytical/methodological

challenges

are

all

valid

concerns

that

can

be

addressed

through

further

researchandcollaboration.

CDCcanuseitslaboratoryandnewbornscreeningexpertisetocollaboratewithstatesandotherresearchpartnersto

develop

laboratory

methods

that

can

take

the

microliter

volume

of

whole

blood

available

in

dried

blood

spots

and

still

produce

precise,

accurate

measurements

of

selected

environmental

chemicals.

0


25/32

V.NextGenerationNewbornScreening

Genomics

CDCstrivestostayintheforefrontoftechnologicalandscientificadvancementinordertocontinuallyimproveits

newbornscreening-relatedactivities.RecentlyCDCexpandedlaboratorycapabilitiesforitsNewbornScreeningQuality

AssuranceProgram(NSQAP)byincludingagroupofitsscientists(molecularbiologists)whohaveextensiveexpertisein

understanding

how

genetics

and

changes

in

DNA

are

associated

with

important

public

health

issues

such

as

diabetes,

kidney

disease,

birth

defects,

and

asthma.

The

expertise

of

these

scientists

helps

newborn

screening

research

because

DNA-based

testing

can

be

used

to

confirm

the

results

when

a

newborn

tests

positive

for

a

disorder.

canbedone,toconfirmapositiveresult,onthesamebloodspotusedfortheinitialtest(allowingallscreeningresultstobereportedatthesametimewithoutworryingfamiliesabouttestingandretesting).

can

be

used

to

add

new

disorders

to

panels

for

newborn

screening.

Thenewlyexpandedlaboratoryhasfocusedoncysticfibrosis,aparticularlycomplexdiseasewithmorethan1500known

mutations.

The

collaboration

of

CDC

scientists

and

the

Cystic

Fibrosis

Foundation

(which

was

instrumental

in

providing

donor

case

samples)

resulted

in

the

development

of

proficiency

testing

materials

that

are

now

being

used

by

state

laboratories

to

assure

high-quality

DNA-based

confirmatory

testing

of

positive

screening

results.

Asgenetictestsbecomemoreavailable,manynewbornscreeninglaboratoriesareconsideringtheuseofDNA-based

testingtoconfirmpositiveresultsfordisorderssuchasgalactosemia,congenitaladrenalhyperplasia,severecombined

immune

deficiency

and

lysosomal

storage

disorders.

As

states

move

testing

in

this

direction,

it

will

be

critical

for

them

to

have

access

to

technical

expertise

as

well

as

the

kind

of

blood

spot

materials

necessary

for

quality

assurance

and

proficiency

testing.

As

newborn

screening

laboratory

testing

evolves,

CDC

will

continue

to

provide

the

technical

expertise

and

the

materialsrequiredasmoredisordersareaddedtothestatesscreeningpanels.NSQAPtheonlycomprehensivequality

assuranceprogramfornewbornscreeninghastheexperience,theinfrastructure,andthesolidreputationinthe

newborn

screening

community

to

respond

to

the

changing

technology

and

rapid

expansion

of

this

field.


26/32

Emerging

Technologies

AlthoughDNA-basedtestingisadevelopingpartofnewbornscreening,biochemicaltestingiswidelyusedinstate

newbornscreeningprograms.CDCcanuseitsexpertiseinbothgeneticsandbiochemistrytocollaboratewithstates,

researchpartners,andstakeholderstoprovidecomprehensivedatafornewmethods,newapplications,andnewblood

spot

materials

for

use

in

newborn

screening.

In

particular,

CDC

is

interested

in

collaborative

research

that

helps

states

maintain

high

standards

of

proficiency

as

they

expand

their

newborn

screening

tests

and

programs.

seeks

to

understand

how

genetic

and

biochemical

differences

that

occur

within

the

diverse

population

of

the

United

States

will

help

improve

newborn

screening.*

explores

innovative

testing

technologies

(e.g.,

nanotechnology

and

a

lab

on

a

chip).

Ultimately,

the

knowledge

gained

from

future

research

and

collaborationswillleadtoimprovementsandexpansionofnewborn

screeningactivitiesthatsavelivesandimprovethehealthandwell-

beingofallbabies.

*Understandingthegeneticandbiochemicaldifferenceswillnotonlyhelpimprovenewbornscreeningbutalsoallowforresearchthat

provides

a

better

understanding

of

the

disease

process.

CDC

scientists

will

collaborate

on

population

studies

with

research

partnersatthefederalandstatelevel.

DNAmicroarrayordigitalmicrofluidics(e.g.,chiptechnologyorlabonachip)canbeusedfordetectingdiseasemarkers.Thistechnologyisappealingtothefieldofnewbornscreeningbecause,withadditionalresearchanddevelopment,itholdsthepotential

toscreensimultaneouslyforhundredsofdisorders,improvetestingspecificity,improvepredictionofdiseaseseverity(whichcanguidetreatmentdecisions),enabletheinclusionofinfectiousagents,reducetheamountofbloodneededfortesting,andproducefaster

results

(10).

ImagecourtesyofDr.DavidMillingtonof

Duke

University

Medical

Center

2


27/32

VI.References

1

American

Academy

of

Pediatrics,

Newborn

Screening

Task

Force.

Newborn

Screening:

A

Blueprint

for

the

Future.

Pediatrics.2000;106(2)S:383-427.

2

Genetics

Home

Reference:

Your

Guide

to

Understanding

Genetic

Conditions

[Internet].

Bethesda:

U.S.

National

Library of Medicine; c2007-2008 [cited 2008 March 20].

Glutaric acidemia type I. Available from:

http://ghr.nlm.nih.gov/condition=glutaricacidemiatypei.

3 NationalInstituteofChildHealthandHumanDevelopment[Internet].Bethesda:NationalInstituteofChildHealth

andHumanDevelopment;c2006[cited2008Mar20].PKU(Phenylketonuria).Availablefrom

http://www.nichd.nih.gov/health/topics/phenylketonuria.cfm.

4

Centers

for

Disease

Control

and

Prevention.

[Internet].

Atlanta:

CDC;

c2008

[cited

2008

Mar

20].

Sickle

Cell

Disease.

Availablefrom:http://www.cdc.gov/ncbddd/sicklecell/.

5 GeneticsHomeReference:YourGuidetoUnderstandingGeneticConditions[Internet].Bethesda: NationalLibrary

of

Medicine;

c2006-2008

[cited

2008

Mar

20].

Short

chain

acyl-coenzyme

A

dehydrogenase

deficiency

disorder.

Available

from

http://ghr.nlm.nih.gov/condition=shortchainacylcoenzymeadehydrogenasedeficiency.

6 MehtaAB,LewisS,LaveryC.Treatmentoflysosomalstoragedisorders: increasedawarenessanddiagnosisare

importantastreatmentisnowfeasible.BMJ.2003;327:462-463.

7

National

Human

Genome

Research

Institute

[Internet].

Bethesda:

National

Human

Genome

Research

Institute;

c2007-2008

[cited

2008

Mar

26].

Learning

About

Severe

Combined

Immunodeficiency

(SCID).

Available

from

http://www.genome.gov/13014325.

8 NationalInstituteofNeurologicalDisordersandStroke[Internet].Bethesda: NationalInstituteofNeurological

Disorders

and

Stroke;

c2007-2008

[cited

2008

Mar

26].

NINDS

Metachromatic

Leukodystrophy

Information

Page.

Available

from

http://www.ninds.nih.gov/disorders/metachromatic_leukodystrophy/metachromatic_leukodystrophy.htm.

9 AFOlshan.2007.TheUseofNewbornBloodSpotsinEnvironmentalResearch:OpportunitiesandChallenges.

EnvironmentalHealthPerspectives.115(12):1767-1769.

10

Green

NS,

Pass

KA.

Neonatal

screening

by

DNA

microarray:

spots

and

chips.

Genetics.

2005

Feb;6:147-151.


28/32

4


29/32

VII. SelectedPublications

Chace DH,Adam BW, Smith SJ, Alexander JR,Hillman SL,Hannon WH. Validation of

accuracy-based amino acid

referencematerialsindried-bloodspotsbytandemmassspectrometryfornewbornscreeningassays.ClinChem.

1999;45:1269-77.

Wang

SS,

Fernhoff

PM,

Hannon

WH,

Khoury

MJ.

Medium

chain

acyl-CoA

dehydrogenase

deficiency:

human

genome

epidemiologyreview.GenetMed.1999;1(7):332-9.

HannonWH,HendersonLO,BellCJ.Newbornscreeningqualityassurance.In:KhouryMJ,BurkeW,ThomsonEJ,

editors.

Genetics

and

public

health

in

the

21st

century:

using

genetic

information

to

improve

health

and

prevent

disease.

New

York:

Oxford

University

Press,

2000:243-58.

Mei JV, Alexander JR,Adam BW, Hannon WH.Use of

filter paper for the collection and analysis of

human whole bloodspecimens.JNutr.2001;131:1631S-6S.

Centers

for

Disease

Control

and

Prevention.

Using

tandem

mass

spectrometry

for

metabolic

disease

screening

among

newborns:

a

report

of

a

work

group.

MMWR

Morb

Mortal

Wkly

Rep.

2001;50(No.

RR-3):1-34.

DottM,ChaceD,FierroM,KalasTA,HannonH,WilliamsJ,RasmussenSA.Metabolicdisordersdetectablebytandem

massspectrometryandunexpectedearlychildhoodmortality:apopulation-basedstudy.AmJMedGenet.

2006;140A:837-42.

Li

L,

Zhou

Y,

Bell

CJ,

Earley

MC,

Hannon

H.

Development

and

characterization

of

dried

blood

spot

materials

for

the

measurement

of

immunoreactive

trypsinogen

(IRT).

J

Med

Screen.

2006:13;79-84.

OlneyRS,MooreCA,OjoduJ,LindegrenML,HannonH.Storageanduseofresidualdriedbloodspotsfromstate

newbornscreeningprograms. JPediatr.2006:148;618-22.

Sweetman

L,

Millington

DS,

Therrell

BL,

Hannon

H,

Popovich

B,

Watson

MS,

Mann

MY,

Lloyd-Puryear

MA,Van

Dyck

PC.

Naming

and

counting

disorders

(conditions)

included

in

newborn

screening

panels.

Pediatrics.

2006:117;308-14.

TherrellBL,HannonH.Evaluationofnewbornscreeningatthenationallevel.MentRetardDevDisabilResRev.2006;

12:236-45.

Hannon

WH,

Whitley

RJ,

Davin

B,

Fernhoff

P,

Halonen

T,

Lavochkin

M,

Miller

J,

Ojodu

J,

Therrell

BL

Jr.

Blood

collection

onfilterpaperfornewbornscreeningprograms:approvedstandard-fifthedition. Wayne(PA):CLSI;CLSIDocument

LA4-A5,2007.

Centers

for

Disease

Control

Prevention.

Impact

of

Expanded

Newborn

ScreeningUnited

States,

2006.

MMWR.

2008;57(37):1012-15.


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Centers for Disease Control and Prevention

National Center for Environmental Health

Division of Laboratory Sciences

Mail Stop F-20

4770 Buford Highway, NE

Atlanta, Georgia 30341-3724

Telephone (toll-free): 1-800-CDC-Info (1-800-232-4636)

Email: [email protected]

Web site: www.cdc.gov/nceh/dls/newborn.htm

newborn screeening

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