Japan newborn screening program flags 77 potential Fabry cases
2006-2022 data show that early diagnosis is key, researchers say
Written by |
A large newborn screening (NBS) program in Japan identified 77 potential cases of Fabry disease from 2006 to 2022, according to a study.
The number includes infants with genetic mutations known to cause Fabry disease, as well as infants with mutations that might be linked to the condition (variants of unknown significance, or VUS). They represented 0.013% of all screened infants. During follow-up, five children, including two with VUS, required treatment for Fabry.
“These findings highlight the importance of early diagnosis using NBS and regular monitoring,” the researchers wrote.
The study, “Newborn screening for Fabry disease in Japan: an additional 3-year report,” was published in Molecular Genetics and Metabolism Reports.
Mutations in the GLA gene cause Fabry disease by disrupting an enzyme, alpha-galactosidase A (alpha-Gal A), which breaks down certain fatty molecules. These molecules can accumulate over time, leading to progressive organ damage and Fabry symptoms if untreated.
Different mutations, different effects
Not all GLA mutations result in the same disease manifestations. Some cause classic Fabry disease, a severe form of the condition, while others don’t. Other mutations cause late-onset Fabry or other milder disease types, or have unknown effects on alpha-Gal A.
Enzyme replacement therapy (ERT) is the standard Fabry treatment, helping to reduce the buildup of harmful fatty molecules by replacing the missing or deficient enzyme. Treatment is generally most effective when Fabry is diagnosed early, allowing for proactive monitoring and timely initiation of ERT before irreversible organ damage develops.
“Newborn screening programs may provide an important opportunity for early diagnosis, longitudinal follow-up, and timely therapeutic intervention in affected individuals,” the researchers wrote.
One such NBS program, in western Japan, identified 57 potential cases from 2006 to 2018, according to previously published results. In the new study, the team extended the analysis through 2022.
During this entire period — 2006 to 2022 — the program screened 782,591 infants using blood tests. Of these, 1,327 showed abnormal alpha-Gal A enzyme activity on the first test. Per NBS protocols, these newborns received another alpha-Gal A test to confirm the results. On the second test, 182 babies had abnormal results.
For children with low alpha-Gal A activity on the second test, the program recommended a closer clinical examination, and, typically, genetic testing. In combination with enzyme tests, genetic tests can confirm a Fabry diagnosis or identify a VUS.
In total, 77 children, or 0.013% of the screened population, had genetic test results that were potentially consistent with Fabry. Forty-nine had a known disease-causing mutation, and 28 had a VUS. Across all children, the team identified 20 disease-causing GLA variants and nine VUS.
Because the GLA gene is on the X chromosome, a sex chromosome, the condition can vary between males and females. In the Japanese screening program, boys made up about three-quarters of the Fabry cases.
Six participants in the study carried the GLA variant c.436C > T, which is associated with severe classic Fabry disease. “However, individuals with this variant in our study, as well as some family members, have shown no symptoms related to [Fabry disease],” the team wrote.
The same was true for certain other classic mutations.
This could be due to limited follow-up time, and participants may later develop symptoms, the researchers noted. However, it also underscores the unpredictability of the condition, even after genetic testing.
Three children with classic Fabry-causing genetic variants, on the other hand, did show symptoms. These children began ERT, which helped ease their symptoms.
The researchers also identified two siblings sharing a VUS. Neither sibling developed symptoms, but monitoring revealed abnormal lab test results indicative of Fabry in both. Because of these signs, they also started ERT.
These results support the use of newborn screening and follow-up monitoring to help identify and address Fabry-related problems early, according to the team.
“An evaluation system for clinical follow-up should be established, and the timing of ERT initiation for each individual with a pathogenic variant should be considered based on prior reports and variant information,” the researchers wrote.
Leave a comment
Fill in the required fields to post. Your email address will not be published.