Newborn screening prone to miss Fabry disease in girls

Standard newborn screening tests for Fabry disease regularly miss female infants, leading to delays in their diagnosis and treatment compared with males, a new study reveals.

Because current screening relies on measuring enzyme activity, the test is generally less reliable for girls, who naturally maintain higher enzyme levels even when they carry the disease-causing genetic mutation. As a result, researchers are calling for a reevaluation of early-life screening strategies to eliminate these sex-based disparities.

The study, “Sex-Based Disparities in Fabry Disease Cause Challenges in Newborn Screening,” was published in Public Health Genomics.

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The genetic differences behind Fabry disease

Fabry disease is caused by mutations in the gene GLA, which instructs the body to make an enzyme called alpha-galactosidase A (alpha-Gal A). This enzyme is needed to break down certain fatty molecules. In people with Fabry, a deficiency of alpha-Gal A means these molecules cannot be broken down properly, so they build up to toxic levels in the body’s tissues, ultimately driving disease symptoms.

The GLA gene is located on the X chromosome, one of the two sex-determining chromosomes. With rare exceptions, females have two X chromosomes while males have one X and one Y chromosome.

Since males have only one X chromosome, they have only one copy of the GLA gene; as such, if that copy carries a Fabry-causing mutation, activity of the alpha-Gal A enzyme is usually severely decreased. However, since females have two X chromosomes and two copies of the GLA gene, a Fabry-causing mutation in one copy may be partially compensated by the other healthy copy. In practical terms, this means female Fabry patients have lower-than-normal alpha-Gal A enzyme activity, but their enzyme activity is usually not as dramatically decreased as in male patients.

Newborn screening, or NBS, is a public health initiative that systematically tests babies at birth for rare congenital disorders such as Fabry disease. The goal is to allow infants with these disorders to get diagnosed within the first weeks of life, so that appropriate care can be given as soon as possible. NBS programs for Fabry disease have been implemented in several countries worldwide. In most of the U.S., Fabry is not included in standard NBS testing, though a few states, like Tennessee and Illinois, do test for it.

NBS for Fabry disease generally works by collecting a blood sample and measuring alpha-Gal A enzyme activity, either in white blood cells or in plasma, which is the non-cellular portion of blood. Since female patients generally have higher enzyme activity than males, NBS is prone to miss female Fabry patients. However, there’s been almost no research directly assessing these sex-based differences in diagnostic accuracy and long-term outcomes.

To address this gap, a team of scientists analyzed data from the Fabry Disease Registry (NCT00196742), an ongoing research project sponsored by Sanofi that is collecting long-term data on thousands of people with Fabry disease. The team’s analysis covered data collected through 2023, representing a total of 3,740 male and 4,917 female patients.

Data reveals stark gaps in diagnosis and care

Even though there were more female patients overall, the researchers found that they were much less likely to be diagnosed by NBS. In fact, whereas 67 (1.8%) male patients were diagnosed by NBS, only six (0.1%) female patients were diagnosed via NBS.

“Despite females comprising the majority of the [Fabry Registry] cohort (57%), they were significantly under-identified by NBS … suggesting that a large proportion of affected females likely remain undetected by NBS,” the researchers wrote.

Among patients not diagnosed via NBS, female patients were generally older at symptom onset (median 18.1 vs. 11.1 years) and at diagnosis (median 35.5 vs. 30.8 years). Consistently, female patients were generally older when they started treatment.

The researchers noted that alpha-Gal A activity was generally much lower in male patients compared with female patients. Among female patients not diagnosed by NBS, median alpha-Gal A activity in white blood cells was just under half of normal, whereas plasma enzyme activity was about a third of normal. By contrast, most male patients had less than 5% normal enzyme activity in both white blood cells and plasma.

The study also included analyses of outcomes from a Tennessee NBS lab between 2017 and 2024. During that period, 25 male patients with Fabry were diagnosed by NBS, whereas no female patients were diagnosed.

“A stark sex disparity in NBS detection emerged across cohorts, underscoring a fundamental limitation of enzyme-based screening in females,” the researchers concluded.

Based on their findings, the scientists said that “the current NBS strategy should be reevaluated to improve early detection of females with” Fabry disease.

“Addressing this problem will require innovative diagnostic approaches aimed at improving the sensitivity and predictive value of NBS, to reduce sex-based disparities and enable earlier detection and intervention for affected females,” they concluded.