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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
• «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“
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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?
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
«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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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, …
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
Countries in Europe & North America outside GalNet
=> Contacts?
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
- 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
**
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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: ? %
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
Example Sweden: A model to copy?
Ohlsson A et al, 2011
Objective: Optimization of sequence / cut-offs
Screens exclusivelyfor GALT!
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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!
Newborn Screening for Galactosaemia / M Gautschi
Universitätsklinik für Kinderheilkunde
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