20-0845 galactosemia research from the fridovich-keil lab - … national conference/20... ·...

20-0845 Galactosemia Research from the Fridovich-Keil Lab - Fridovich-Keil 1

A research update from the

Fridovich-Keil lab

Judith L. Fridovich-Keil, PhDDept of Human GeneticsEmory University School of [email protected]

*no conflicts of interest to disclose

In the next 45 minutes…

• BIG picture of where we have been and where we are going in galactosemia research

• Brief updates on three projects:

• Ovarian function in galactosemia

• Scholastic outcomes in galactosemia

• What have we learned from the flies and what does it mean for people?

Want to hear more about galactosemia research from “team Emory”?

Friday 2:15-3:15pm: • Ovarian function in galactosemia (Fridovich-Keil)• Movement Disorders 101 (Testa)

Saturday 10-11am: • Galactosemia Research: finally flying forward (Fridovich-Keil)• How to help your child learn (Taddeo)

Saturday 11:15am-12:15pm: • POI and fertility in galactosemia (Spencer and Badik)• Scholastic and behavioral issues (Fridovich-Keil and E. Ryan)

Saturday 3-4pm: • How to help your child learn (Taddeo)

Galactosemia research in the Fridovich-Keil lab: BIG picture

“We want to understand what causes the acute and long-term complications

experienced by people with galactosemia so we can do

something positive about it.”

Our approaches then and now…

• a yeast model system to distinguish mild from severe mutations in human GALT

• search for modifiers of outcome in patients (ovarian, scholastic, neurological, growth…)

• a whole animal genetic model (fruit fly) to• test candidate genetic and environmental modifiers• screen for new and unexpected modifiers of outcome• test potential interventions

• connecting the dots from mutation to biochemical and metabolic defect, to acute and long-term outcome, to effective intervention

Why galactosemia research is like hashing*…

* a group running activity originated in 1938 by British colonial officials and expatriates living in Kuala Lumpur, Malaysia

START

FINISH

“on-on”

“checking” false trail

false trail

false trail

true trail


update on:

ovarian function in galactosemia

Old news:>80% of girls and women with classic galactosemia experience POI

Questions: • when/where does the problem occur?• biomarkers of ovarian function?• mechanism?

Goals:•accurate prognosis•safe and effective intervention

ovarian function in galactosemia:When does the problem occur? How do we know?

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0 10 20 30Age (yrs)

controls

GG

AM

H (

ng

/mL

)

n=110

n=291

Spe

ncer

, Bad

ik, e

t al.

in p

repa

ratio

n

ovarian function in galactosemia:

What can we learn from FSH?

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200

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Age (Yrs)

FS

H (

mIU

/mL

)

controlsn=72

GGn=213

Spe

ncer

, Bad

ik, e

t al.

in p

repa

ratio

n

ovarian function in galactosemia:Is predicted residual GALT activity a prognostic indicator of outcome?

Some GALT alleles with residual activity detected in yeast

Some GALT alleles with no residual activity detected in yeast

S135L L195P D136H P183T D98N A78TD197G Y209C

Q188R R204X F171S Q206R D98H R148PM142K 5kb del

Gle

ason

et a

l. in

pre

para

tion


GALT activity influences biomarkers

Age (yrs)

AM

H (

ng

/mL

)

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null GALT

alleles

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residual GALT

activity

Spencer, Badik, et al. in preparation


Predictors of spontaneous menses

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InducedN= 14

SpontaneousN=23

Menses

AM

H (

ng

/mL

)

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InducedN=11

SpontaneousN=28Menses

Pre

dic

ted

GA

LT (

% W

ild

Typ

e)

Spencer, Badik, et al. in preparation


What does this tell us about mechanism, and what does it mean for girls and women with classic galactosemia?

update on: scholastic outcomes in galactosemia

Intelligence

CommunicationAppropriate

Behavior

Social skills with peers and adults

Rya

n et

al.

in p

repa

ratio

n

Scholastic performance

scholastic outcomes in galactosemia:

from previous reports we know…

• range of IQ but average is below normal• higher than normal incidence of depression• speech difficulties common• anecdotal evidence of difficulty in school

– does this reflect a cognitive problem?– is this secondary to a speech problem?– other options….


our study volunteers (ages 4 to 18 yrs)

Enrolled: 54

25 boys

29 girls

12

4-6yr olds

14

7-10 yr olds

19

11-14 yr olds

9

14-18 yr olds

Ryan et al. in preparation


what data did we collect?

Study Volunteer

School records

1-2 Teacher Surveys

GALT genotype

Parental Surveys

Standardized test scores, IEP assessments, evaluations, etc.

Questions regarding how the study volunteer interacts with peers, siblings, and adults.

Questions regarding how the study volunteer interacts with peers, and adults. What tasks or behaviors in the classroom are difficult?

Either previously reported or via blood or saliva sample

What tasks or behaviors in the home are difficult for the child?



results…

• about half of the children in each age group were achieving below grade level

• about half were receiving some kind of special educational services

• most common behavioral problems reflected “internalizing” behaviors and difficulty with social skills



scholastic outcomes in galactosemia: Is residual GALT activity a prognostic indicator?

Predicted GALT activity(as a % of wild-type level)

0-1% >1%

Overall (n=53) 47 6

Enrolled in special education (n=17) 15 2

Not enrolled in special education (n=15) 12 3

Achieving in Math (n=16) 11 5

Not Achieving in Math (n=19) 18 1

Achieving in Language Arts (n=18) 13 5

Not Achieving in Language Arts (n=17) 16 1


scholastic outcomes in galactosemia: Is residual GALT activity a prognostic indicator?

Teacher responsesSocial Skills

<1% WT >1% WT

Sta

nda

rdiz

ed S

core

Parent responses Internalizing Problems

<1% WT >1% WT

Sta

ndar

dize

d S

core


What does this tell us about mechanism, and what does it mean for children with classic

galactosemia?

What have we learned from the fliesand what does it mean for people?

Deleting fly GALT

Kus

hner

et a

l (20

10)

DM

M

GALT-deficient Drosophilaare galactose-sensitive

Kus

hner

et a

l (20

10)

DM

M


GALT-deficient Drosophilaare rescued

by expression of human

GALT

Kus

hner

et a

l (20

10)

DM

M

GALT-deficient Drosophila die as larvae when exposed to

galactose

Kushner et al (2010) DMM

glc glc + gal

+/+ +/+

−/− −/−

1mm 1mm

1mm1mm

Impact of

dietary galactose exposure

Kus

hner

et a

l (20

10)

DM

M

long-term neuromuscular complication

Kushner et al (2010) DMM

So, now we have an animal model of GALT-deficiency that demonstrates both acute and long-term

complications; how can we use it to learn about

galactosemia?

a little bit of GALT activity goes a long way

Rya

n et

al (

201

2) D

MM


Oxidative stress contributes to acute outcome in GALT-deficient Drosophila

Jumbo-Lucioni et al (2012) DMM

Galactose exposure

contributes to oxidative stress in GALT-null

larvae


impact of oxidative stress on survival of GALT-null Drosophila

acts downstream

or independent of gal-1P


Does loss of GALK rescue acute outcome in GALT-null Drosophila? No

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fra

cti

on

an

ima

ls s

urv

ivin

g t

o a

du

lth

oo

d****

****

*******

GALT-

GALK+

GALT-

GALK-

Jum

bo-L

ucio

niet

al i

n pr

epar

atio

n

What’s next?

What can YOU do to help?

• Please participate in research!• Several teams doing research

here at the conference

• Please encourage your representatives in government to support funding for biomedical research (NIH budget).


START

FINISH

“on-on”

“checking” false trail

false trail

false trail

true trail

Fridovich-Keil labDept. of Human Genetics, Emory Univ. School of Medicine

Thank you…

20-0845 galactosemia research from the fridovich-keil lab - … national conference/20... ·...

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