Dietrich Matern, M.D. - Newborn Screening

Newborn Screening

Dietrich Matern, M.D., FACMGBiochemical Genetics LaboratoryMayo Clinic College of Medicine

Rochester, MN

History & Increasing Impacton Medical Practice

Disclosure

Relevant Financial

Relationship(s)

None

Off Label Usage

None

Objectives

• Demonstrate a deeper understanding

of newborn screening (NBS);

• Be aware of available tools to react

appropriately to abnormal results.

• What is Newborn Screening?

• Impact on Medical Practice

– The ACMG* uniform panel

– Short-term follow up and confirmation

– Newborn Screening Performance

• What’s next in newborn screening?

Outline• What is Biochemical Genetics?

*American College of Medical Genetics

What is Biochemical Genetics?

• the evaluation and diagnosis of patients and families with inherited metabolic disease;

• monitoring of treatment;

• distinguishing heterozygous carriers from non-carriers by metabolite and enzymatic analysis of physiological fluids and tissues.

ACMG: Standards and guidelines for Clinical Genetics Laboratories. 2nd ed, 1999

A discipline concerned with:

A discipline traditionally practicing and supporting individualized medicine!

Biochemical GeneticsTo achieve early detection and prevention of

disease, Biochemical Genetics has a strong

emphasis on screening based upon the

analysis and interpretation of metabolic

profiles in body fluids and tissues:

• Prenatal diagnosis (at risk patients)

• Newborn screening (pre-symptomatic patients)

• High risk screening (symptomatic patients)

• Postmortem screening (metabolic autopsy)

Rinaldo P, Hahn S, Matern D. Clinical Biochemical Genetics in the 21st century. Acta Paed 2004; 445(Suppl): 1-6








Newborn ScreeningA public health program:

• aimed at identification of conditions for which early intervention can prevent

- mortality

- morbidity

- disabilities

• performed by analysis of diagnostic markers in blood spots collected on filter paper on the second day of life

Phenylalanine

Tyrosine

Phenylpyruvate

2-Hydroxy-Phenylpyruvate

2-Hydroxy-Phenylacetate

Phenyllactate PAH

Phenylketonuria (PKU)

Phenylketonuria (PKU)

Incidence: 1 : 15,000 live births in MN

Inheritance: autosomal recessive

Symptoms: • mental retardation (IQ usually <50)

• ~30% of patients:spasticity or muscle

hypertonia

• ~25% of patients: seizures

Treatment: Phe-restricted diet

Prognosis: excellent with initiation of treatment shortly after birth

The Traditional NBS Model(Testing as SIMPLE as Possible)

• One disease PKU

• One test BIA

• One marker Phe

• One cut-off (N/Abn) 4 mg/dL

Drivers of Expansion

• “New” disorders

MCAD DeficiencyFirst description of Medium-Chain Acyl-Coenzyme A

Dehydrogenase (MCAD) deficiency by Kolvraa et al in 1982.

Incidence: 1: 15,000 live births

Gene: ACADM (1p31) (common mutation 985A G)

Symptoms: - hypoketotic hypoglycemia

- Reye-like syndrome (hypoglycemia, hyperammonemia,

elevated transaminases, brain edema, fatty liver)

- sudden unexpected death

Treatment: avoidance of fasting, IV glucose during stress

Prognosis: - excellent when treated before onset of symptoms

- 30-50% of mortality during first acute episode

Diagnosis: Acylcarnitine profile by tandem mass spectrometry


• New powerful technology (MS/MS)


MS/MS

+Prec (85.10): 0.401 to 1.202 min from Sample 8 (PATE) of AC 101003 DATA.wiff (Turbo Spray) Max. 3.8e4 cps.

260 280 300 320 340 360 380 400 420 440 460 480 500m/z, amu

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

55%

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65%

70%

75%

80%

85%

90%

95%

100%

Re

l. In

t. (%

)

Inte

nsi

ty100%

*

* * *

*

*

MCADDeficiency

+Prec (85.10): 0.401 to 1.202 min from Sample 9 (BADER) of AC 101003 DATA.wiff (Turbo Spray... Max. 3.5e4 cps.

260 280 300 320 340 360 380 400 420 440 460 480 500m/z, amu

5%

10%

15%

20%

25%

30%

35%

40%

45%

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55%

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100%

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l. In

t. (%

)

*

* * * *

*

C2

100%

Inte

nsi

ty

*: internal standards

Control

C2

C16

C8

C10:1C6

Acylcarnitine Analysis

NBS by MS/MS(Multiplex Testing)

• Many conditions (IEM)n

• One test

MS/MS• Many markers (AA,AC)n

• Many cut-offs 0.1-1,000 µM

Science 2001;254:2272

The ability to scan one sample for some two dozen inherited disorders is about to cause an

explosion in neonatal screening: few health systems are prepared for the consequences


• Subjective factors– Public pressure– Political action– Scrutiny of mass media (WSJ, 10/30/07, D1)

• New powerful technology (MS/MS)

• Objective evidence and guidelines– Reports of state experiences– ACMG uniform panel report







Outline• History of Newborn Screening


Primary Evaluation Criteriaof Conditions Consideredfor Newborn Screening

1. Clinical characteristics (e.g., incidence, burden of disease if not treated, phenotype in the newborn);

2. Analytical characteristics of the screening test (e.g., availability, features of the platform);

3. Diagnosis, treatment and management of the condition in both acute and chronic forms (includes the availability of health professionals experienced in diagnosis, treatment, and management).

29Primary Targets

25Secondary

TargetsNot Yet

Appropriate

ACMG Panel: Final Score

Uniform Screening Panel

• 29 Core Conditions

– 20 detected by MS/MS (AA, FAO, OA)

– 3 hemoglobinopathies

– 6 others (BIOT, CAH, CF, CH, GAL, HEAR)

• 25 secondary targets

– 22 detected by MS/MS

S

E

C

O

N

D

A

R

Y

T

A

R

G

E

T

S

22 “Secondary” targets

Phenylketonuria

MSUD

Homocystinuria

Tyrosinemia type I

Argininosuccinic acidemia

Citrullinemia type I

Hyperphenylalaninemia

Tyrosinemia type II

Biopterin defects (Bios)

Tyrosinemia type III

Biopterin (Reg)

Argininemia

Hypermethioninemia

Citrullinemia type II

MCAD deficiency

VLCAD deficiency

LCHAD deficiency

TFP deficiency

Carnitine uptake defect

M/SCHAD deficiency

SCAD deficiency

MCKAT deficiency

CPT-I deficiency

Glutaric acidemia type II

CACT deficiency

Dienoyl red. deficiency

CPT-II deficiency

Isovaleric acidemia

Glutaric acidemia type I

HMG deficiency

3MCC deficiency

BKT deficiency

Multiple carboxylase deficiency

Methylmalonic acidemia (MUT)

Methylmalonic acidemia (Cbl A,B)

Propionic acidemia

Methylmalonic acidemia (Cbl A,B)

2M3HBA deficiency

IBG deficiency

2MBCAD deficiency

Methylglutaconic acidemia

Malonic acidemia

U

N

I

F

O

R

M

P

A

N

E

L

HRSA/ACMG Uniform Panel (MS/MS)

20 Primary targets

http://genes-r-us.uthscsa.edu/updated 3/4/08

Newborn Screening 2008Number of disorders screened for in the USA

35

35

DC

20-29

40-49 50-52

53

10-19

<10

30-39

Impact on Medical Practice

Pediatrics/Family Medicine only?









Case Report• Male born at term (3,320g)

• Normal pregnancy and delivery

• 1st child of non-consanguineous parents

• Newborn screening result:

– Propionylcarnitine (C3):6.6 µmol/L (normal <5.25)

– C3/C2 Ratio: 0.23 (normal <0.31)

– C3/C16 Ratio: 2.55 (normal <2.0)

What now?

http://www.acmg.net/resources/policies/ACT/condition-analyte-links.htm

Case Report• Baby is clinically healthy, feeding well

• Laboratory:

– Glucose, E’lytes, BGA, NH3, CBC all normal

– Urine organic acids, plasma C3-acylcarnitine,

plasma homocysteine all normal

End of Story?False Positive Newborn Screen?

Case Report• Mother tells you that she is known to have

anemia.

• Mother tells you that she had gastric bypass

surgery 2 years ago.

• Mother is not aware of ever having been told

to take vitamin B12!

• You (recommend) treat(-ing) the mother’s

iatrogenic vitamin deficiency

Maternal Disease Identified by Newborn Screening

• Pediatrics

• Family Medicine

• Internal Medicine

• Obstetrics/Gynecology

• Genetics

Impact on Medical Practice

Family History!









What Does Performance Mean to YOU?

Actual PPV: 5%Actual PPV: 5%

CONCLUSIONS

Expanded newborn screening may

lead to improved health outcomes for

affected children and lower stress for

their parents. However, false-positive

screening results may place families

at risk for increased stress and

parent-child dysfunction.

The Minnesota Model

A public-private partnership between

The Minnesota Department of Health (MDH)

The University of Minnesota

Mayo Clinic College of Medicine(established June 2004)

BirthingPlace

ResultInterpretation

NewbornScreening

MDHLaboratory

ResultInterpretation

MS/MSScreeningMetabolic

Clinics

++-

MayoBGL

AA, OA, FAO (MS/MS) FU S,2T

21-Hydroxylase deficiency S,FU 2T

Congenital hypothyroidism S,FU

Galactosemia S,FU

Hemoglobinopathies S,FU

Biotinidase deficiency S,FU

Cystic fibrosis (CF) S,FU

AA=Amino Acidopathies; OA=Organoacidopathies; FAO=Fatty Acid Oxidation disorders2T=2nd-tier testing; FU=follow-up; S=screening

Conditions

MN Newborn Screening Program

2nd Tier Tests• A cost effective means to implement clinically

defined cutoffs when normal population and disease range overlap (poor specificity)

• Same specimen, no additional patient contact

• Normal result overrules primary screening

• Steroids (CAH)

• HCY/MMA/MCA/EMA (Met, C3, C4)

• Allo-ILE (BCAA)

2nd Tier Tests

Changing CAH Screening in MN(2007)

• False positives 710 41

• False (+) rate 0.97% 0.06%

Cost clinical F/U $847 per case

Cost 2nd tier test $35 per test

w/o 2nd Tier w/ 2nd Tier

• Cost clinical F/U $601,370

$38,115

• Cost 2nd tier test $0 $24,850

• Total F/U cost $601,370

$62,965

MayoBGL

MDHLaboratory

BirthingPlace

NewbornScreening

CHGALTCAHSCA

2nd TierTest

2nd tier re

quested

NormalResult (~90%)

CAH

NORMAL

Changing CAH Screening in MN(2007)

• False positives 710 41

• False (+) rate 0.97% 0.06%

Cost clinical F/U $847 per case

Cost 2nd tier test $35 per test

w/o 2nd Tier w/ 2nd Tier

• Cost clinical F/U $601,370 $38,115

• Cost 2nd tier test $0 $24,850

• Total F/U cost $601,370 $62,965

• Cost difference (savings) (89.5%)

Minnesota NBS Performance73,013 babies screened in 2007

Presumptive + TP FP FPR PPV

Amino Acidemias 16 9 7 0.01% 56.3%

Biotinidase def. 82 14 68 0.09% 17.1%

CAH 45 6 39 0.05% 13.3%

CH 188 48 140 0.19% 25.5%

CF 272 13 259 0.35% 4.8%

FAO disorder 30 8 22 0.03% 26.7%

Galactosemia 49 15 34 0.05% 30.6%

Hgb 39 18 21 0.03% 46.2%

Organic Acidemias 45 14 31 0.04% 31.1%

TOTAL 766 145 621 0.85% 18.9%

NBS Performance in the USA• False positive rate (MS/MS): 0.07% to 3.0%

• True positive rate (MS/MS):1:2,000-1:15,000

581.4Unnecessary evaluations WEEKLY (/100,000 births)

0.2%39%Positive predictive value

120,0002,800False positives / Year

2671,780True positives / Year

3.00%0.07%False positive rate

1:15,0001:2,249Detection rate

WORST caseBEST case

US scenarios (4 Millions births/year)

PE

RF

OR

MA

NC

E








Partial List of Candidate Conditionsfor Expansion of Uniform Panel

(in alphabetical order)

• ALD (X-linked)• CDG Ib• CMV• Creatine defects• Duchenne• G6PD• Gaucher (LSD)• HIV• MPS I/II/IIIa/VI (LSD)• Fabry (LSD)

• Fam. Hypercholesterol.• Fragile X• Friedreich ataxia• Krabbe (LSD) NY

• Niemann-Pick (LSD)• Pompe (LSD) Taiwan

• SCID WI

• SLO• SMA• Wilson disease

Late-Onset Dilemma is NOT Uniqueto LSD Screening

• Heterozygous FH:• Incidence: 1:500• Symptoms: xanthomata and corneal arcus may

occur already in childhood; premature ischemic heart disease

• Homozygous FH:• Incidence: 1:1,000,000• Symptoms:

• tendon and skin xanthomata and corneal arcus in early childhood; intermittent arthralgia;

premature arteriosclerosis with evidence of cardiac dysfunction (e.g. angina) before 10 y/o• fatal myocardial infarction by 2nd or 3rd decade

Familial Hypercholesterolemia

NBS for Hypercholesterolemia- Impact on Medical Practice -

Confirmation of diagnosis

Treatment

Counseling (family, patient)

Affected family members:

– (older) siblings?

– parents!

– aunts, uncles, cousins, etc.

– future children of patient

?

+NBS

?

• In the last 8 years, significant changes have taken

place in newborn screening.

• A Uniform Screening Panel was recommended and

endorsed by all stakeholders

• Follow up guidelines have been/are being

developed

• NBS Performance is highly variable.

• The expansion of NBS will continue.

• The impact of NBS on Medical Practice beyond

Pediatrics will increase.

Conclusions

Dietrich Matern, M.D. - Newborn Screening

Documents

clinical biochemical

clinical genetics laboratories

medical practice

diagnosis of patients

hydroxy phenylpyruvate

analysis of diagnostic

phenylketonuria pku

heterozygous carriers