Fabry newborn screening test misses girls, study shows
Tennessee program effectively identifies boys with condition
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Since its implementation in 2017, newborn screening (NBS) for Fabry disease in Tennessee has sharply increased early diagnosis for baby boys, but continues to miss affected girls, a study found.
From 2017 to 2024, statewide screening identified 25 boys with Fabry but no girls. Yet clinical data from roughly the same period showed the condition affected boys and girls in nearly equal numbers. While screening directly boosted diagnoses in boys, it only led to Fabry diagnosis in girls through cascade testing of mothers after a son was found to have the disease, the study found.
“NBS effectively identifies affected males but fails to detect females with [Fabry disease], though it can indirectly facilitate diagnosis of older female relatives,” wrote the researchers, who called for “improved NBS strategies” to enable earlier and more equitable detection in females.
The study, “Sex-Specific Diagnostic Inequality in Fabry Disease: Lessons Learned from Analysis of Newborn Screening and Cascade Testing in Tennessee from 2017 to 2024,” was published in Public Health Genomics.
Fabry disease is caused by mutations in the GLA gene that provide instructions for making the alpha-galactosidase A (alpha-Gal A) enzyme, which normally breaks down certain fatty molecules. When this enzyme doesn’t function properly, these fatty substances accumulate to toxic levels within cells, damaging organs and causing Fabry symptoms.
Boys and girls affected in different ways
Because the GLA gene is located on the X chromosome, one of the two sex chromosomes, the disease can affect boys and girls differently. Males, who have only one X chromosome, typically have very low enzyme levels and more severe symptoms. Females have two X chromosomes, and one is randomly switched off in each cell, a process known as X-chromosome inactivation. As a result, enzyme levels and symptom severity in girls vary depending on how many cells keep the healthy copy of the gene active.
Early diagnosis is essential to allow timely initiation of Fabry treatments, particularly in boys. For this reason, several countries and some U.S. states have had NBS programs for Fabry in place since 2014. Although Fabry is not included in the federal list of conditions recommended for NBS in the U.S., Tennessee adopted statewide screening in 2017.
NBS for Fabry typically measures alpha-Gal A enzyme activity from a dried blood sample. This approach reliably detects affected boys, who usually have markedly reduced enzyme levels, but it may miss girls whose enzyme activity falls within or near the normal range due to X chromosome inactivation.
To evaluate how Fabry NBS performs in real-world clinical practice, particularly in girls, researchers analyzed statewide screening data from Tennessee along with records from the Vanderbilt Lysosomal Storage Disorders Database (VLSDD).
No false positives were identified among the 25 boys who tested positive for Fabry from 2017 to 2024. However, clinical data from the VLSDD showed that Fabry affected males and females at nearly equal rates, with 42 males and 39 females diagnosed from 2015 through 2024.
Of the 42 boys identified in the VLSDD, 62% were diagnosed through NBS. All males diagnosed outside screening were born before statewide screening was implemented.
In contrast, none of the 39 females was diagnosed through NBS. Instead, they received a diagnosis after developing symptoms (36%), through cascade testing after their sons were screened positive (33%), or because of a known family history (31%). The median age at diagnosis for females identified through cascade testing was 28.
Of the 22 mothers of boys identified through NBS, 59% were subsequently diagnosed with Fabry disease through cascade testing. None had initiated Fabry-specific treatment, though 69% reported symptoms.
Cumulative trends showed that before NBS was introduced, more females than males were diagnosed with Fabry. After 2017, diagnoses among males rose sharply, and by 2023, the total number of diagnosed males exceeded that of females.
Diagnoses for both sexes have increased since 2017. Among males diagnosed after 2017, 76% were identified through NBS, whereas 54% of newly diagnosed females were identified through cascade testing after a son was diagnosed.
“Our findings demonstrate that while NBS not only identifies affected males, it also indirectly facilitates the diagnosis of older female relatives, despite its failure to detect females with [Fabry disease] at birth,” the researchers wrote.
The team suggested refining screening strategies, including sex-specific enzyme cutoffs, improved screening algorithms, or incorporating genetic testing to allow earlier and more equitable detection in females.
