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Optimising newborn screening for galactosaemia: reclassifying GALE and GALM deficiencies as non-target conditions to
Doris Wong1, Kai Mun Hong1, Joy Lee1
1Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
Insights
Newborn screening for galactosaemia in Australia now includes more types, improving early intervention access. However, screening for epimerase and mutarotase deficiencies results in too many false positives, suggesting they should not be targeted.
Area of Science:
- Biochemistry and Metabolic Disorders
- Neonatal Screening and Public Health
- Genetics and Genetic Testing
Background:
- Historically, inconsistent newborn screening for galactosaemia across Australian jurisdictions led to inequitable access to early intervention.
- Victoria implemented expanded screening for galactosaemia types 1-4, including galactose-1-phosphate uridyl transferase (GALT-D), galactokinase (GALK-D), epimerase (GALE-D), and mutarotase (GALM-D) deficiencies.
Purpose of the Study:
- To evaluate the suitability and performance of expanded galactosaemia screening assays in a neonatal population.
- To establish clinical decision limits for total galactose (TGAL) and GALT enzyme activity in dried blood spots.
- To assess the impact of including all four galactosaemia types on screening outcomes and clinical referrals.
Main Methods:
- A suitability study analyzed 4,421 dried blood spot (DBS) samples using Revvity test kits for TGAL quantification and GALT semi-quantitative analysis.
- Decision limits were developed based on TGAL concentrations (16-1,323 μmol/L) and GALT activity (<20-250 U/L).
- An 18-month review study monitored performance, including referrals to the clinical team for 115,091 screened neonates.
Main Results:
- Clinical decision limits were set at TGAL >600 μmol/L and GALT <20 U/L.
- During the 18-month review, 13 neonates were referred (screen positive), with one confirmed case of classical galactosaemia.
- The automated TGAL and GALT assays demonstrated robust performance for the neonatal population.
Conclusions:
- Expanded galactosaemia screening assays are reliable for neonatal screening.
- Including GALE-D and GALM-D deficiencies increases false positives due to a lower TGAL cut-off.
- Recommends designating GALE-D and GALM-D as non-target conditions within the Australian Newborn Bloodspot Screening (NBS) framework to balance benefits and harms.
Objectives:
Traditionally, neonates were screened for classical galactosaemia in 4 of the 5 jurisdictions in Australia creating inequitable access to early intervention. A push to nationally harmonise newborn bloodspot screening enabled the state of Victoria to proceed with implementation of screening for galactosaemia types 1 to 4 enzyme deficiency i.e. galactose 1-phosphate uridyl transferase (GALT-D), galactokinase (GALK-D), epimerase (GALE-D) and mutarotase (GALM-D) deficiencies. This also provided the opportunity to take a modern look at an old screening condition.
Methods:
As part of the implementation of galactosaemia screening two studies were conducted. 1) Suitability study, where dried bloodspot (DBS) samples were analysed using Revvity test kits over a three-week period: first-tier total galactose (TGAL) quantification and second-tier GALT semi-quantitative analysis was performed using 3.2 mm DBS punches and a Genetic Screening Processor. 2) 18-month review study of performance based on the referrals made to the clinical team.
Results:
The suitability study analysed 4,421 DBS samples, comprising 48.7 % female and 51.3 % male, with gestational ages 22-43 weeks to develop decision limits. TGAL concentrations ranged from 16 to 1,323 μmol/L, while GALT enzyme activity varied between <20 and 250 U/L. Clinical decision limits were established at >600 μmol/L for TGAL and <20 U/L for GALT. A total of 115,091 babies were screened during the 18-month review period and 13 were referred for clinical follow-up (i.e. screen positive); with one baby confirmed to have classical galactosaemia.
Conclusions:
The studies demonstrated that performance of the automated TGAL and GALT assays is robust for our neonatal population. However, attempting to formally include all four forms of galactosaemia as target conditions results in a lower TGAL cut-off and more false positives. With the need to consider balancing benefits vs. harms, we recommend that screening for galactosaemia due to GALE-D or GALM-D be changed to non-target conditions in the Australian NBS framework.
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