newborn screening rutledge · • expected clinical presentation based on mutations • cannot get...

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2017 Alabama Newborn Screening Conference2017 Alabama Newborn Screening Conference

Marriott Hotel and Conference CenterPrattville, Alabama

Friday, August 18, 2017

Marriott Hotel and Conference CenterPrattville, Alabama

Friday, August 18, 2017

Inherited Disorders of Metabolism

Inherited Disorders of Metabolism

S Lane Rutledge, MDS Lane Rutledge, MD

Professor of Genetics and Pediatrics

Director of Clinical Services

Department of Genetics

University of Alabama at Birmingham

Professor of Genetics and Pediatrics

Director of Clinical Services

Department of Genetics

University of Alabama at Birmingham

Inherited Disorders of Metabolism DefinitionInherited Disorders of Metabolism Definition

• Clinical or biochemical condition

caused by an enzyme deficiency

• Enzyme may have completely or

• Clinical or biochemical condition

caused by an enzyme deficiency

• Enzyme may have completely or y y p y

partially absent activity: so patient

can present early or later

• Enzyme is deficient as a result of

genetic mutation

y y p y

partially absent activity: so patient

can present early or later

• Enzyme is deficient as a result of

genetic mutation

Inherited Disorders of Metabolism Biochemistry


• Biochemical abnormality precedes

signs and symptoms: a latent period

where the biochemistry is abnormal

b t th i f t i ll

• Biochemical abnormality precedes

signs and symptoms: a latent period

where the biochemistry is abnormal

b t th i f t i llbut the infant is well

• This latent period is basis of

newborn screening

• Want to diagnose baby before illness

is apparent!

but the infant is well

• This latent period is basis of

newborn screening

• Want to diagnose baby before illness

is apparent!



• The abnormality is not always an

enzyme

• However, the abnormality does always

• The abnormality is not always an

enzyme

• However, the abnormality does always

involve a biochemical pathway

• So there should be some biochemical

test available for the disorder

• We do screen for the full recommended

panel

involve a biochemical pathway

• So there should be some biochemical

test available for the disorder

• We do screen for the full recommended

panel

NORMAL IEM

A→B A→B↓ ↓

C

X

C Cso: ↑A (substrate)

↓ B (product)

↑ C (minor product)

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Alabama Newborn Screening for Inherited

Disorders of Metabolism


Disorders of Metabolism• Most common abnormalities

– Premature infants

• Most common abnormalities

– Premature infants

• Many false positives due to TPN

• “expected abnormalities in light

of clinical setting”

• Many false positives due to TPN

• “expected abnormalities in light

of clinical setting”





– High tyrosine level due to enzyme

immaturity or liver disease

– High tyrosine level due to enzyme

immaturity or liver disease

• 4 most common diagnoses of

confirmed metabolic disorders

• 4 most common diagnoses of

confirmed metabolic disorders





– hyperphenylalaninemia

– MCAD

– hyperphenylalaninemia

– MCAD

– VLCAD

– galactosemia

– VLCAD

– galactosemia

2011 Diagnoses2011 Diagnoses 2016 Diagnoses2016 Diagnoses

HyperpheHyperphe=4=4 HyperpheHyperphe=4=4

PKU=5PKU=5 PKU=2PKU=2

Galactosemia=0Galactosemia=0 GalactosemiaGalactosemia=4=4

Duarte Duarte GalactosemiaGalactosemia=10=10 Duarte Duarte GalactosemiaGalactosemia=4=4

VLCADD=1VLCADD=1 VLCADD=3VLCADD=3

VLCADD Carriers=4VLCADD Carriers=4 VLCADD Carriers=3VLCADD Carriers=3

MCADD=5MCADD=5 MCADD=3MCADD=3C 5C 5 C 3C 3

MCADD Carriers=12MCADD Carriers=12 MCADD Carriers=0MCADD Carriers=0

CUD=2CUD=2 CUD=1CUD=1

CUDCUD Carriers=0Carriers=0 CUD Carriers=2CUD Carriers=2

Maternal 3MCC=1Maternal 3MCC=1 Maternal 3MCC=0Maternal 3MCC=0

CitrullinemiaCitrullinemia Carrier=0Carrier=0 CitrullinemiaCitrullinemia Carrier=2Carrier=2

GA1=1GA1=1 GA1=0GA1=0

PKUPKU

PKU HistoryPKU History• 1934: Fölling first described unusual

compound in urine of 2 intellectually

disabled siblings

– Really the story of a determined

• 1934: Fölling first described unusual

compound in urine of 2 intellectually

disabled siblings

– Really the story of a determinedReally the story of a determined

mom and a doctor who listened!

• 1951: successful treatment with diet

• 1960: Guthrie test developed and

newborn screening started

Really the story of a determined

mom and a doctor who listened!

• 1951: successful treatment with diet

• 1960: Guthrie test developed and

newborn screening started

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The discovery of The discovery of phenylketonuriaphenylketonuria: the : the story of a young couple, two retarded story of a young couple, two retarded children, and a children, and a scientist.scientist.CenterwallCenterwall SA, SA, CenterwallCenterwall WR.WR.Pediatrics. 2000 Jan;105(1 Pt 1):89Pediatrics. 2000 Jan;105(1 Pt 1):89--103103..

NORMAL IEM

A→B A→B ↓ ↓

C

X

C C

PKU: Clinical UntreatedPKU: Clinical Untreated

• Gradual onset (first year of life) of

significant intellectual disability

– 50-70% IQ < 35

• Gradual onset (first year of life) of

significant intellectual disability

– 50-70% IQ < 35

– 90% IQ < 65

– 2-5% IQ normal

– 90% IQ < 65

– 2-5% IQ normal

PKU: Clinical UntreatedPKU: Clinical Untreated

• Fair pigmentation for ethnic group

• Eczema

• Musty odor

• Fair pigmentation for ethnic group

• Eczema

• Musty odor

PHENYLKETONUIAPHENYLKETONUIA

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PKU TreatedPKU Treated• Normal IQ!!

• Best outcome with strict, lifelong

adherence to diet

• Discontinuation of diet will result in

• Normal IQ!!

• Best outcome with strict, lifelong

adherence to diet

• Discontinuation of diet will result in• Discontinuation of diet will result in

loss of IQ points and psychological

abnormalities for most patients

• Diet treatment in first few weeks of

life leads to normal outcome

• Discontinuation of diet will result in

loss of IQ points and psychological

abnormalities for most patients

• Diet treatment in first few weeks of

life leads to normal outcome

INITIAL WORK UP FOR PKUINITIAL WORK UP FOR PKU• Differential diagnosis of elevated

phenylalanine levels

– PKU

Biopterin defects

• Differential diagnosis of elevated

phenylalanine levels

– PKU

Biopterin defects– Biopterin defects

– Infant on TPN

– Biopterin defects

– Infant on TPN

INITIAL WORK UP FOR PKUINITIAL WORK UP FOR PKU• Obtain plasma amino acids and urine

and blood for biopterin studies

before come to clinic

• In general, we do not obtain any

• Obtain plasma amino acids and urine

and blood for biopterin studies

before come to clinic

• In general, we do not obtain any g , y

genetic testing

g , y

genetic testing

Initial clinic visit: PKUInitial clinic visit: PKU• Confirm diagnosis

– Initiate treatment as soon as family

notified

Clinic visit ASAP

• Confirm diagnosis

– Initiate treatment as soon as family

notified

Clinic visit ASAP– Clinic visit ASAP

• Confirm diagnosis same day as

clinic visit

– In most patients, treatment initiated

within 7-14 DOL

– Clinic visit ASAP

• Confirm diagnosis same day as

clinic visit

– In most patients, treatment initiated

within 7-14 DOL

Initial clinic visit: PKUInitial clinic visit: PKU• Education about

– Newborn screening

– Condition

• Education about


– Condition

– Genetics– Genetics

Initial clinic visit: PKUInitial clinic visit: PKU• Diet explanation

– Washout

– Daily diet: changes weekly

b d l l

• Diet explanation

– Washout

– Daily diet: changes weekly

b d l lbased on levels

• Lots of phone numbers and contact

info and f/u visit within 7-10 days

based on levels



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INBORN ERRORS OF FATTY ACID METABOLISM

INBORN ERRORS OF FATTY ACID METABOLISM

We screen for several, but just discuss our more common todayWe screen for several, but just discuss our more common today

COMMON FEATURES OF FATTY ACID OXIDATION DEFECTS


• Metabolic decompensation during fasting

a) In children: fasting, especially with illness decreased oral intake, increased energy needs

• Metabolic decompensation during fasting

a) In children: fasting, especially with illness decreased oral intake, increased energy needs

b) Altered mental status progressing to coma

c) SIDS (1-3%)

d) Positive family history, recurrent episodes

b) Altered mental status progressing to coma

c) SIDS (1-3%)

d) Positive family history, recurrent episodes

• Metabolic decompensation: other precipitants:

a) Exposure to cold

b) Excessive alcohol ingestion

• Metabolic decompensation: other precipitants:

a) Exposure to cold





c) Exercise

d) Fat rich diet

e) Prolonged fasting


c) Exercise

d) Fat rich diet

e) Prolonged fasting

MCAD UntreatedMCAD Untreated• Patients are clinically well

• They develop a “routine” childhood illness

with loss of appetite and usually with

vomiting

• Patients are clinically well

• They develop a “routine” childhood illness

with loss of appetite and usually with

vomiting

• They may have an episode with longer

recovery than other family members OR

• They may be found dead 1-3 days into

course of illness

• They may have an episode with longer

recovery than other family members OR

• They may be found dead 1-3 days into

course of illness

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Disorders of FAO β 0xidation CLINICAL PRESENTATIONS

Medium Chain Fats


Medium Chain Fats• For unscreened (undiagnosed)

patients:

D th i 25 30% f ti t ith

• For unscreened (undiagnosed)

patients:

D th i 25 30% f ti t ith– Death in 25-30% of patients with

first episode

– Neurocognitive residual in 32%

survivors of an episode of

metabolic decompensation

– Death in 25-30% of patients with

first episode

– Neurocognitive residual in 32%

survivors of an episode of

metabolic decompensation

• NBS changes all of this

– 5 fold higher risk of death in

d ti t

• NBS changes all of this

– 5 fold higher risk of death in

d ti t


Medium Chain Fats


Medium Chain Fats

unscreened patientsunscreened patients

Initial Clinic Visit: MCADInitial Clinic Visit: MCAD• Send testing to confirm diagnosis

– Initiate treatment with first phone

call, prior to confirmation

– Clinic visit ASAP

• Send testing to confirm diagnosis

– Initiate treatment with first phone

call, prior to confirmation

– Clinic visit ASAPClinic visit ASAPClinic visit ASAP

Initial Clinic Visit: MCADInitial Clinic Visit: MCAD• Education about


– Condition

G ti

• Education about


– Condition

G ti– Genetics– Genetics

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Initial Clinic Visit: MCADInitial Clinic Visit: MCAD• Plan for intercurrent illnesses

– mild illnesses with normal appetite

– Illnesses which meet our admit

criteria

• Plan for intercurrent illnesses

– mild illnesses with normal appetite

– Illnesses which meet our admit

criteriacriteria



criteria



Disorders of FAO βOxidation TREATMENT


• GOAL:

– Avoid fasting, especially fasting

with increased metabolic rate

• GOAL:

– Avoid fasting, especially fasting

with increased metabolic rate

– Provide appropriate types of fat in

diet

– Provide appropriate types of fat in

diet



• METHODS:

– Normal meal/snack pattern

– cornstarch

• METHODS:

– Normal meal/snack pattern

– cornstarch

– Increase calories from sugar when

needed

– Carnitine in some

– Treat illness aggressively

– Increase calories from sugar when

needed

– Carnitine in some

– Treat illness aggressively


Medium Chain Fats


Medium Chain Fats• Known diagnosis:

• Admit for illness criteria

• Known diagnosis:

• Admit for illness criteria

– vomiting >2 times in < 8hours

– Fever of 101º for > 4 hours

– Diarrheal illness

– vomiting >2 times in < 8hours

– Fever of 101º for > 4 hours

– Diarrheal illness


Medium Chain Fats


Medium Chain Fats– Anything we think needs

admitting!

– Anything we think needs

admitting!

• If they look very ill, or glucose is low

– we have waited too long!

• If they look very ill, or glucose is low

– we have waited too long!

MCAD: Metabolic DecompensationMCAD: Metabolic Decompensation

What exactly are we doing?

IV glucose: shutting down ongoing fat metabolism, decreasing substrate into

What exactly are we doing?

IV glucose: shutting down ongoing fat metabolism, decreasing substrate into g

system

Carnitine: promoting metabolic flux

AVOIDING FURTHER DEAD CHILDREN

gsystem

Carnitine: promoting metabolic flux

AVOIDING FURTHER DEAD CHILDREN

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Current problems with evaluation for MCAD

Current problems with evaluation for MCAD

• Alert values only

– This means we work up any newborn

who meets our criteria

• Alert values only

– This means we work up any newborn

who meets our criteria

• Often: quite clear have MCAD

• Sometimes: values are not as clear cut

– Ancillary testing helps with this

• UNABLE TO GET MOLECULAR ANALYSIS

ON MEDICAID PATIENTS

• Often: quite clear have MCAD

• Sometimes: values are not as clear cut

– Ancillary testing helps with this

• UNABLE TO GET MOLECULAR ANALYSIS

ON MEDICAID PATIENTS


Long chain fats: 3 Clinical Presentations



• Early onset and severe (occasionally

in utero)

Heart liver hypoketotic

• Early onset and severe (occasionally

in utero)

Heart liver hypoketotic– Heart, liver, hypoketotic

hypoglycemia

– Significant fatality rate

– Heart, liver, hypoketotic

hypoglycemia

– Significant fatality rate

• Infancy onset, milder

– Onset with infections

• Infancy onset, milder

– Onset with infections





– Heart, liver hypoketotic

hypoglycemia

– Heart, liver hypoketotic

hypoglycemia

• Later onset and myopathic

– Often induced by exercise or i f ti

• Later onset and myopathic

– Often induced by exercise or i f ti





infection

– Muscle: may include rhabdomyolysis

– Early onset presentations who survive may evolve to this

infection

– Muscle: may include rhabdomyolysis

– Early onset presentations who survive may evolve to this

VLCADVLCAD• If 3 different presentations, how do

we decide what the baby is at risk

for?

– Ancillary biochemical testing not

• If 3 different presentations, how do

we decide what the baby is at risk

for?

– Ancillary biochemical testing not

helpful (may normalize)

– Can do skin fibroblasts

• Mildly invasive procedure

• Takes weeks for results

helpful (may normalize)

– Can do skin fibroblasts

• Mildly invasive procedure

• Takes weeks for results

VLCADVLCAD– Molecular

• Expected clinical presentation

based on mutations

• Cannot get molecular testing on

– Molecular

• Expected clinical presentation

based on mutations

• Cannot get molecular testing onCannot get molecular testing on

Medicaid patients

– We can order but Medicaid won’t

pay and family will get large bill

Cannot get molecular testing on

Medicaid patients



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VLCADVLCAD• Insurance maybe 80/20

– Family may get large bill

• This really hurts our ability to care

for these patients

• Insurance maybe 80/20



for these patientsfor these patientsfor these patients

VLCAD: echo pre and post RXVLCAD: echo pre and post RX

RV

RVIVS

IVS

LV

POST LV WALLPE

LV

POST LV WALL

NO EFFUSION

GALACTOSEMIAGALACTOSEMIAInborn Error of Carbohydrate Inborn Error of Carbohydrate y

Metabolismy

Metabolism

Inherited Disorders of Carbohydrate Metabolism

Inherited Disorders of Carbohydrate Metabolism

1. Deficiencies in stored glucose (glycogen)

metabolism

2. Deficiencies in ability to metabolize

i t d ( l t f t )

1. Deficiencies in stored glucose (glycogen)

metabolism

2. Deficiencies in ability to metabolize

i t d ( l t f t )ingested sugars (galactose, fructose)

3. Deficiencies in muscle carbohydrate

metabolism: metabolic myopathies

4. Many things (hormones) affect

carbohydrate metabolism

ingested sugars (galactose, fructose)

3. Deficiencies in muscle carbohydrate

metabolism: metabolic myopathies

4. Many things (hormones) affect

carbohydrate metabolism

GALACTOSEMIAGALACTOSEMIA• EARLY CLINICAL

– FTT

– vomiting and diarrhea

LIVER h t th di t bili

• EARLY CLINICAL

– FTT

– vomiting and diarrhea

LIVER h t th di t bili– LIVER: hepatopathy: direct bili,

coags, transaminases

– LIVER: hepatopathy: direct bili,

coags, transaminases

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GALACTOSEMIAGALACTOSEMIA• LABORATORY

– elevated LFT’s/coagulopathy

– E Coli infection

iti i d i

• LABORATORY

– elevated LFT’s/coagulopathy

– E Coli infection

iti i d i– positive urine reducing

substances: not glucose

– positive urine reducing

substances: not glucose

GALACTOSEMIAGALACTOSEMIA• LATE CLINICAL

– ovarian failure

– speech delay

• LATE CLINICAL

– ovarian failure

– speech delay

GALACTOSEMIA NOWGALACTOSEMIA NOW• Most patients detected by newborn

screening before becoming ill

• Carriers are detected by newborn

screening

• Most patients detected by newborn

screening before becoming ill

• Carriers are detected by newborn

screening

• Approximately 1 new case of classic

galactosemia/year

• Many carriers diagnosed/year

• Must be on galactose to be symptomatic

• Approximately 1 new case of classic

galactosemia/year

• Many carriers diagnosed/year

• Must be on galactose to be symptomatic

How do we diagnose?How do we diagnose?• State lab measures enzymes but

– This is just a screen

– Get result of < 2.5 u/dl, presumed

positive

• State lab measures enzymes but

– This is just a screen

– Get result of < 2.5 u/dl, presumed

positivepositive

– Often picks up carrier

positive

– Often picks up carrier

How do we diagnose?How do we diagnose?• So how do we figure out who has

disease?

• Galactosemia genes can come in

1 of 3 ways

• So how do we figure out who has

disease?

• Galactosemia genes can come in

1 of 3 ways

– Normal “N”: normal enzyme activity

– Classic galactosemia “G”: no enzyme

activity

– Duarte “D”: some residual enzyme

activity

– Normal “N”: normal enzyme activity

– Classic galactosemia “G”: no enzyme

activity

– Duarte “D”: some residual enzyme

activity

How do we diagnose?How do we diagnose?• We often pick up, as positive, babies

who have

– NG: no treatment required

– DG: treatment probably not

• We often pick up, as positive, babies

who have

– NG: no treatment required

– DG: treatment probably notDG: treatment probably not

required but we do change formula

And ongoing studies about

treatment requirements

DG: treatment probably not

required but we do change formula

And ongoing studies about

treatment requirements

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How do we diagnose?How do we diagnose?• We would like to do genetic

confirmation

– that will tell us exactly what infant has

• Currently we base our specific

• We would like to do genetic

confirmation

– that will tell us exactly what infant has

• Currently we base our specific• Currently, we base our specific

diagnosis on enzyme activity

• Usually effective, can be a little iffy

• Currently, we base our specific

diagnosis on enzyme activity

• Usually effective, can be a little iffy

How do we diagnose?How do we diagnose?• Cannot get molecular testing on

Medicaid patients



• Cannot get molecular testing on

Medicaid patients


pay and family will get large billpay and family will get large bill




for these patients





for these patients

The world of lab testing coverage must keep pace

with what is necessary, and least expensive, in 2017

The world of lab testing coverage must keep pace

with what is necessary, and least expensive, in 2017least expensive, in 2017

Practicing 20th century medicine in 21st century

least expensive, in 2017

Practicing 20th century medicine in 21st century

PKU & MCAD Examples of Why NBS Works


• PKU:

– Patients develop severe brain

damage over time

• PKU:

– Patients develop severe brain

damage over time

– Early treatment prevents the brain

damage

– We can detect it early enough to

prevent any brain injury from

occurring

– Early treatment prevents the brain

damage

– We can detect it early enough to

prevent any brain injury from

occurring



• MCAD:

– Patients are well and normal until their

first significant illness

⅓ to ½ of patients with undiagnosed

• MCAD:

– Patients are well and normal until their

first significant illness

⅓ to ½ of patients with undiagnosed– ⅓ to ½ of patients with undiagnosed

MCAD will die with their first significant

illness

– These deaths are prevented by knowing

that the child has MCAD and treating

with IV glucose for illnesses

– ⅓ to ½ of patients with undiagnosed

MCAD will die with their first significant

illness

– These deaths are prevented by knowing

that the child has MCAD and treating

with IV glucose for illnesses

PKU & MCAD Why difference in Initiating Treatment?


• PKU:

– Treatment is restriction of

phenylalanine by restricting

i d ddi i l

• PKU:

– Treatment is restriction of

phenylalanine by restricting

i d ddi i lprotein and adding special

metabolic formula

– This can be quite dangerous to do

if you do NOT have PKU or

hyperphenylalaninemia

protein and adding special

metabolic formula

– This can be quite dangerous to do

if you do NOT have PKU or

hyperphenylalaninemia

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• MCAD:

– Treatment is primarily IV glucose with significant intercurrent illness

• MCAD:

– Treatment is primarily IV glucose with significant intercurrent illness

– So not dangerous to treat with IV glucose if you do NOT have MCAD

– very dangerous to NOT treat with IV glucose if you do have MCAD and develop an illness

– So not dangerous to treat with IV glucose if you do NOT have MCAD

– very dangerous to NOT treat with IV glucose if you do have MCAD and develop an illness

Current Problems in Metabolic Newborn Screening


• Too many repeats!!

– Do enough and something will

show up as abnormal

• Too many repeats!!

– Do enough and something will

show up as abnormalp

– Just do the gold standard test

– Especially true in NICU patients

– Follow protocol but beyond that…

p

– Just do the gold standard test

– Especially true in NICU patients

– Follow protocol but beyond that…



• Sending incorrect confirmatory

testing

– ASK ALICIA 205-996-6983

• Sending incorrect confirmatory

testing

– ASK ALICIA 205-996-6983

Current problems in Metabolic Newborn Screening

Current problems in Metabolic Newborn Screening

• Inability to get genetic analysis

– Not just for the ones I discussed

but true for many of these

• Inability to get genetic analysis

– Not just for the ones I discussed

but true for many of thesey

• Still often called “the PKU test”

• DO NOT CALL IT THE PKU TEST!!

y

• Still often called “the PKU test”

• DO NOT CALL IT THE PKU TEST!!

Produced Produced by theby the

Distance Learning &Distance Learning &

Telehealth Telehealth DivisionDivision

Alabama Department of Public HealthAlabama Department of Public Health

Produced Produced by theby the

Distance Learning &Distance Learning &

Telehealth Telehealth DivisionDivision

Alabama Department of Public HealthAlabama Department of Public HealthAlabama Department of Public HealthAlabama Department of Public Health

(334) 206(334) 206--56185618

[email protected]@adph.state.al.us

August 2017August 2017

Alabama Department of Public HealthAlabama Department of Public Health

(334) 206(334) 206--56185618

[email protected]@adph.state.al.us

August 2017August 2017

newborn screening rutledge · • expected clinical presentation based on mutations • cannot get...

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