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Sex-Based Disparities in Fabry Disease Cause Challenges in Newborn Screening
Yutaka Furuta1, Neena S Agrawal2, Natalie N Owen2
1Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA, yutakafuruta8@gmail.com.
Public Health Genomics
|May 21, 2026
Summary
Newborn screening for Fabry disease (FD) misses most females due to higher residual enzyme activity. This leads to delayed diagnosis and treatment for affected females compared to males.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Fabry disease (FD) is an X-linked lysosomal storage disorder impacting multiple systems.
- Decreased alpha-galactosidase activity is the primary cause of FD.
- Current newborn screening (NBS) methods may not effectively detect affected females.
Purpose of the Study:
- To investigate sex-based diagnostic disparities in Fabry disease.
- To understand how limitations in enzyme-based newborn screening affect female diagnosis.
- To identify potential improvements for early detection in females.
Main Methods:
- Retrospective analysis of Fabry Registry and Tennessee NBS data (2001-2024).
- Comparison of sex differences in diagnosis, biochemical phenotype, symptom onset, and treatment initiation.
- Statistical analysis using Wilcoxon and Chi-square tests.
Main Results:
- Enzyme-based NBS identified 73 individuals (67 males, 6 females) from the Fabry Registry.
- Affected females exhibited significantly higher residual alpha-galactosidase activity than males.
- Females experienced delayed symptom onset, diagnosis, and lower treatment rates compared to males.
Conclusions:
- Females with Fabry disease face delays in symptom onset, diagnosis, and treatment.
- Current enzyme-based NBS misses most affected females due to higher residual enzyme activity.
- Implementing sex-specific cutoffs or molecular sequencing in NBS can enhance early detection and reduce disparities.
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