Intervention and Outcomes in Duarte galactosemia

Angela Wittenauer*, MSN, FNP-C, RNNewborn Screening Follow Up Director

Emory University, Department of Human Genetics

* No conflicts of interest to report.

Published as:Carlock G, Fischer ST, Lynch ME, Potter NL, Coles CD, Epstein MP, Mulle JG, Kable JA, Barrett CE, Edwards SM, Wilson E, and Fridovich-Keil JL. Developmental Outcomes in Duarte Galactosemia. Pediatrics. 2019;143(1):e20182516.

In the next 15 minutes....

• What is Duarte galactosemia (DG)?

• What were the goals of our study?

• What did we do?

• What did we find?

• What does it mean for NBS?

Duarte galactosemia (DG) results from PARTIAL deficiency of GALT.

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DG versus classic galactosemia

• November 2015-November 2017 (2 years)• 17 testing blocks in 13 states• 3-5 days per testing block, up to 6 children tested per day• Testing team: Study coordinator, 2 Psych testers, 2

Speech/Motor testers• Some states had low enrollment and so we did not test there,

but eligible families were invited for testing in adjacent states

States Tested:CaliforniaTexasAlabama,Georgia,South CarolinaTennesseeIowaMissouriIndianaIllinoisMichiganOhioVirginia

States recruited but not tested:North CarolinaNew JerseyPennsylvaniaMaryland/DC*

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AK AL AR AZ CA GAFL IL IN KS ME MI MO MS NE NJ NY SC UT WI

CG

DG

FalsePositives*(Years of data included)

*

*

Should babies with DG drink milk or low-galactose formula?• Infants with DG

generally thrive while drinking milk

• No strong direct evidence of long-term complications

• Breastfeeding has many known benefits… do we really want to interfere with that?

• Newborns with DG accumulate elevated galactose metabolites while drinking milk

• We know from CG that long-term complications can occur even in children who experienced no acute symptoms

Aim 1: Test whether children with Duarte galactosemia, ages 6-12 years old, demonstrate increased prevalence of developmental difficulties relative to controls, and

Aim 2: Test whether dietary exposure to galactose (milk) in infancy associates with developmental outcomes of children with Duarte galactosemia.

What were the goals of our study?

An observational case-control studyAim 1 Aim 2

Study design:Initial recruitment (17 states + DC)

Part 1 (online parent/guardian survey)

Informed consent

Part 2 (direct child assessment +

more parent/guardian surveys)

Data analysis

What information did we gather from enrolled volunteers?

• demographics, SES• other covariates• child’s diet in infancy and beyond

by parent/guardian response surveys

• Thinking and Problem Solving Skills

• Socioemotional Development

• Physical measures (height, weight, head circumference)

• Auditory Processing

• Speech and Language Development

• Physical Development (Movement/ Coordination)

by direct assessments

What did our data look like?• 350 subjects (206 cases, 144 controls)

• Case/control status confirmed by GALTgenotyping of DNA from saliva samples

• 73 outcome variables quantified per child (representing 5 developmental domains)

• Covariates collected (age, sex, race/ethnicity, annual household income, breast milk exposure, highest parent education, US region, WASI II IQ)

How did we analyze our data?

• All statistical analyses performed using R (version 3.4.0)

• Descriptive statistics to compare demographics between groups and identify covariates relevant to different outcomes

• Test for “missingness” between cases and controls

• Split data set (25:75) into independent discovery (n=87) and validation (n=263) sets

• Tested all 73 outcomes for association with DG status in the discovery set; identified top 10 (smallest p values)

• Tested these top 10 for association with DG status in the validation set

• Tested same top 10 for association with diet among cases in the validation set

Top 10 outcomes from the discovery set also tested for possible association with DG in the validation set.

** By chance alone we would have expected to find 1 outcome with p<0.05; we found 2. Bonferroni-adjusted cut-off for significance= 0.0025.

Discovery set

Validation set

Diet (dairy exposed)

A closer look at the NEPSY II Route Finding Score %

Children with DG scored BETTER than controls!

A closer look at head circumference

Discovery set

Validation set

Diet (dairy exposed)

Tiny difference; not significant after multiple test correction

Top 10 outcomes from the discovery set also tested for possible association with milk exposure of DGs in the validation set.

** None reached even nominal significance.

So what did we find?

1. Did children with Duarte galactosemia, ages 6-12 years old, demonstrate increased prevalence of developmental difficulties relative to controls?

2. Did dietary exposure to galactose (milk) in infancy associate with developmental outcomes of children with Duarte galactosemia?

NO

NO

Example outcome tested: WASI IQ

Controls(n=144)

Children with DG(n=206)

Children with DG:

Soy(n=123)

Children with DG:

Milk(n=83)

WAS

I IQ

WAS

I IQ

Example outcome tested: Height Z Score Differential

Controls(n=144)

Children with DG(n=206)

Hei

ght Z

Sco

re

Diff

eren

tial

Hei

ght Z

Sco

re

Diff

eren

tial

Children with DG:

Soy(n=123)

Children with DG:

Milk(n=83)

Example outcome tested: Auditory Processing

ABER

Wav

e 3

Late

ncy

ABER

Wav

e 3

Late

ncy

Controls(n=132)

Children with DG(n=191)

Children with DG:

Soy(n=113)

Children with DG:

Milk(n=78)

Example outcome tested: Speech/ MotorTE

TRAS

Sco

re

Controls(n=144)

Children with DG(n=206)

Children with DG:

Soy(n=123)

Children with DG:

Milk(n=83)

TETR

AS S

core

Recognizing our limitations:

• This is only one study.• 350 is a big number for DG, but it is not huge.• Age range 6-12 years; we did not test younger or

older volunteers.• Diet information gathered from family by

retrospective survey.• All volunteers from US; almost all white.• We tested 73 outcomes; there are outcomes we did

not test.• Other

Our results suggest that children with DG are not at significantly increased risk of developmental disorders regardless of milk exposure. IF THIS IS TRUE…

• DG families: can breastfeed with confidence

• Clinicians: can give evidence-based prognostic and diet recommendations to DG families

• Public health: evidence for removing DG from the NBS panel, adjusting NBS GALT cut-off level to lower the false-positive rate

Mindful of the limitations, what do our results mean?

Breast milk consumption in infancy by 324 cases and 243 controls

Children with DG

Controls

0-1 month 2-6 months 7-12 months

CG and DG detection rates in Utah before and after changing the GALT NBS cutoff

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*may include carriers and other variants.

Thank you!• Amazing families and wonderful colleagues who made this study

possible• Funding from the Patient-Centered Outcomes Research Institute

(http://www.pcori.org/research-results/2015/intervention-and-outcomes-duarte-galactosemia)

• The late Dr. Paul Fernhoff who encouraged us to start this project

Questions?

References and web sites:• Carney AE, Sanders RD, Garza KR, McGaha LA, Bean LJ, Coffee BW, Thomas JW, Cutler DJ,

Kurtkaya NL, Fridovich-Keil JL. Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase. Human molecular genetics. 2009;18(9):1624-32.

• Fernhoff PM. Duarte galactosemia: how sweet is it? Clinical chemistry. 2010;56(7):1045-6. • Ficicioglu C, Thomas N, Yager C, Gallagher PR, Hussa C, Mattie A, Day-Salvatore DL, Forbes BJ.

Duarte (DG) galactosemia: a pilot study of biochemical and neurodevelopmental assessment in children detected by newborn screening. Mol Genet Metab. 2008;95(4):206-12.

• Ficicioglu C, Yager C, Segal S. Galactitol and galactonate in red blood cells of children with the Duarte/galactosemia genotype. Mol Genet Metab. 2005;84(2):152-9.

• Fridovich-Keil J, Gambello M, Singh R, Sharer J. Duarte Variant Galactosemia. In: Pagon R, Adam M, Ardinger H, Bird T, Dolan C, Fong C, Smith R, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 2014.

• Lynch M, Potter N, Coles C, Fridovich-Keil J. Developmental outcomes of school-age children with Duarte galactosemia: A pilot study. JIMD Reports. 2015; 19:75-84.

• Powell KK, Van Naarden Braun K, Singh RH, Shapira SK, Olney RS, Yeargin-Allsopp M. Long-term speech and language developmental issues among children with Duarte galactosemia. Genetics in medicine : official journal of the American College of Medical Genetics. 2009;11(12):874-9.

• Pyhtila BM, Shaw KA, Neumann SE, Fridovich-Keil JL. Newborn screening for galactosemia in the United States: looking back, looking around, and looking ahead. JIMD Rep. 2015;15:79-93.

• Duartegalactosemia.org• https://clinicaltrials.gov/ct2/show/NCT02519504?term=duarte+galactosemia&rank=1

Inclusion and Exclusion CriteriaInclusion Criteria• Child is 6-12 years old at the time of direct assessment• Child has DG (case) or child does not have any form of galactosemia but is the sibling of a

child with DG (control)• Both child and at least one parent/guardian are conversant in English• Both child and at least one parent/guardian are available to participate in one of the Direct

Testing Blocks offered

Exclusion Criteria• Any severe developmental disorder, severe intellectual disability, or severe medical condition

that could affect the same developmental outcomes being tested for possible associationwith DG (10 children, including 6 cases and 4 controls, were excluded for this reason)

• Unable to complete Part 2 testing due to a severe hearing, visual, or motor disability (0children were excluded for this reason)

• Child participated in our previous pilot study (7 children were excluded for this reason)• Child DNA sample unavailable or GALT genotype inconclusive (6 children were excluded for

this reason)

Milk vs. low-galactose formula consumption in infancy by 206 cases and 144 controls

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Cases ControlsChildren with DG Controls

milk

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