Newborn Screening for Galactosemia

Newborn Screening for Galactosemia

News on the GalNet NBS project

Matthias Gautschi, MD PhD

Dept of Paediatrics, University Hospital Bern, Switzerland

Galactosemias Network (GalNet)

(www.galactosemianetwork.org)

Newborn Screening for Galactosaemia / M Gautschi

Universitätsklinik für Kinderheilkunde

NBS programmes in the World and in Europe

Martinez-Morillo E et al, 2016; Loeber JG et al, 2012

In Europe (11/40): Austria, Belgium (part), (Estonia: pilot), Germany, Greece, Hungary, Ireland, Italy, Netherlands, (Spain: only Galicia), Sweden, Switzerland

Countries



• «Already the great variability of approaches to NBS for Galactosemia, including set-up, cut-offs etc. clearly shows…

• … the remaining uncertainties and

• … the lack of evidence.»

• Can we improve? And how? => Galactosemia NBS Working Group

Jumbo-Lucioni PP et al, 2012; Varela-Lema L et al, 2016

NBS for Galactosemia: „some countries do, others do not“



Starting point:

1. What should be done theoretically?

2. How is it done today practically/technically

3. What is the outcome now?

Jumbo-Lucioni PP et al, 2012; Varela-Lema L et al, 2016



POLL QUESTION 1

• Is there a Newborn Screening (NBS) for Galactosemia in your country?

–Yes

–No

• Do you think Galactosemia should be part of NBS in everycountry?

–Yes

–No



US & EU Recommendations for NBS programmes

Martinez-Morillo E et al, 2016

ND = not discussed

Group 1B = high prevalence and feasible screening test«they consider that the health gain for … GALT is proven.»

Objective: Harmonization of NBS programmes

But: Galactosemia is outside the box



Long-standing Debate on Newborn Screening

“All screening programs do harm. Some do good as well and, of these, some do more good than harm at reasonable cost.”

Sir Muir Gray

Cornel M et al, 2011



1. Condition is an important health problem yes

2. Natural history of the disease well understood yes/no

3. Detectable at early stage (presymptomatic) yes?

4. Benefit of pre-symptomatic treatment no?

5. Suitable screening test yes, but false positives

6. Reliable confirmatory test yes

7. Sufficient medical expertise (screening) yes

8. Sufficient medical expertise (clinical workload) yes, but

9. Physical and psychosocial risks less than benefits yes

10. Costs balanced against benefits yes?

Wilson–Jungner Criteria, 1968 Principles of Practice of screening for Disease (Public Health Paper Nr 34, WHO Geneva)

1. Condition is an important health problem

2. Natural history of the disease well understood

3. Detectable at early stage (presymptomatic)

4. Benefit of pre-symptomatic treatment

5. Suitable screening test

6. Reliable confirmatory test

7. Sufficient medical expertise (screening)

8. Sufficient medical expertise (clinical workload)

9. Physical and psychosocial risks less than benefits

10. Costs balanced against benefits

one test - one disease - one therapy

=> Gal

Courtesy Dr. Jean-Marc Nuoffer



POLL QUESTION 2

• How have you / has your family member been diagnosedto have Galactosemia?

–By Newborn screening?

–By Family screening? (another member of the family hadbeen diagnosed before)

–By Selective screening? (because of disease manifestations)

–By other means

–Don’t know



3 major arguments why galactosemia isexcluded from the NBS programs

• disease can be diagnosed clinically,

• high rate of false positives (Duarte type galactosaemia!)

• long-term complications common in spite of early treatment

• Diagnostic delay: early manifestation vs late NBS result

• Low incidence rate

• High costs (confirmatory diagnosis)

• Selective screening more efficient than universal NBS

Ohlsson A et al, JIMD Rep, 2011; Gal-NBS Survey 2020

Further arguments



Findings of EU Tender Report on NBS practices 2012

Burgard P et al, 2012

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 days

Symptomes of Galactosemia

birth

heel prickstart of treatment

diagnosticconfirmation

arrival at lab& analysis



POLL QUESTION 3

• At what age have you / has your family member beendiagnosed to have Galactosemia & treatment started*?

–Before 1 week of age

–Between 1 and 2 weeks

–After 2 weeks of age, but before 1 month

–Later than 1 month, but before 2 months

–Later than 2 months

–Don’t know

* age at treatment initiation if known



POLL QUESTION 4

• When did you / your family member first develop symptomsof Galactosemia (such as poor feeding, vomiting, hypotonia, strong jaundice…)?

–Before 2 days of age

–At 3-4 days of age

–Before 1 week of age

–Before 2 weeks of age

–Later than 2 weeks of age

–None at all (with NBS)

–None at all (without NBS)

–Don’t know



Survey for Professionals conc NBS for Galactosemias

• Aims:–To get solid data for the methods and procedure for Gal NBS

–To get solid data on the outcome of Gal NBS

–To know the reasons for not screening for Galactosemia

–To find out criteria for a possibly «ideal» Gal NBS

=> Recommendations / Position Paper

• Questions:–Screening Y/N? (dates?)

–What is screened? GALT/GALK/GALE

–How is it screened? methods, algorithm

–Timeline?

–Outcome? (number of total/true/false positives; false negatives)

–What happens after a positive result?



«Survey for Professionals concerning Gal NBS»

27th June 2020

18th August 2020

23rd October2020

Evaluation

(1st Results)

Survey

1st Mailing

1st Deadline

Aim: assess the (technical) details of NBS & outcome



Received (20):Australia (Y)Austria (Y)Belgium (Y/N)Bulgaria (N)Croatia (N)Czech Republic (N)Estonia (Y pilot)France (N)Germany (Y)Greece (Y)Ireland (Y)Italy (Y)Lithuania (N)Netherlands (Y)Poland (N)Portugal (N)Spain (N, (Y))Sweden (Y)Switzerland (Y)UK (N)

Y:N=11:9

Thank you, all of you!

Missing:Hungary, Israel, USA, BrazilRegions in Germany (14?), Italy (18?), Australia

Denmark, Luxembourg, Norway, Finland, …



Countries in Europe & North America outside GalNet

=> Contacts?



- Have a NBS for CG (*only part of the country)

- Have no NBS for CG (*only part of the country)

- Had one in the past, not now- Pilot study

**



Principle of Screening (measured in red blood cells)

GALT

GalGK

Gal-1-P

UDP-GalGlu-1-P

UDP-GluEpimerase

Lactose

GalactitolScreening: 2 tests

1.- Total Galactose

2.- GALT Activity

Cut-offs:tot Gal: ? mmol/LGALT activity: ? %



tGaltGal and GALTGALT

Almost universal testing:both total galactose +

residual GALT activity

But: differences in- Algorithm (1>2 / 2>1 / 1+2)

- Cut-off values

Next steps:- Clarify data- Analyse outcomes

Method / Tests used for Gal NBS



Example Sweden: A model to copy?

Ohlsson A et al, 2011

Objective: Optimization of sequence / cut-offs

Screens exclusivelyfor GALT!



Conclusions: requirements for a good NBS => Gal?

• Specific – few false positives => how many? How to improve?

• Sensitive – few false negatives => really none or any???

• Predictive – diagnosed newborns will have the disease

• Acceptable – low risk of procedure

Consider: (what do we know about that?)

• Avoid/minimise any harm => IEM reference centers, GL…

• Privacy / autonomy aspects

• Ethical, legal, societal aspects

• Consequences of genetic condition for the whole family

• reduce diagnostic delay, improve access to therapy & research

www.eurordis.org

≤ 14d!? = incentive for NBS



AcknowledgementsDavid Coman (Queensland, Australia)

Dorothea Moeslinger (Austria)

François Boemer (Wallonia, Belgium)

François Eyskens (Flanders, Belgium)

Daniela Avdjieva-Tzavella (Bulgaria)

Danijela Petkovic Ramadza (Croatia)

Dagmar Prochazkova (Czech Republic)

Katrin Õunap (Estonia)

Philippe Labrune (France)

Nils Janzen (Germany)

Anastasia Skouma (Greece)

Ina Knerr (Ireland)

Alberto Burlina (Italy)

Birute Burnyte (Lithuania)

Estela Rubio (Netherlands)

Jolanta Sykut-Cegielska (Poland)

Laura Vilarinho (Portugal)

María L. Couce (Spain, Galicia)

Mª Josep Coll (Spain, remaining)

Ulrika von Döbeln (Sweden)

Matthias Baumgartner (Switzerland)

Stephanie Grunewald (UK)

The GalNet NBS working group

Estela Rubio,

Annet Bosch and

Jose Alonso Fernandez

Lena Manten (MD Student)

Thank you!

Questions?

À suivre!



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Newborn Screening for Galactosemia

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