Screening Newborns for Enzyme Reveals Fabry Is More Common

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Measuring the activity of a certain enzyme whose levels are low or absent in Fabry disease may be a useful newborn screening blood test for its diagnosis, a five-year study in Italy suggests.

With the test, Fabry disease, which is more common among men than women, was found to occur in about one in every 4,000 male newborns. The findings suggest that the disease may be more frequent than originally estimated. “This is likely due to the recognition of previously undiagnosed later-onset forms of [Fabry disease],” researchers wrote.

The study, “Newborn screening for Fabry disease in northeastern Italy: results of five years of experience,” was published in the journal Biomolecules.

In some countries, as part of newborn screening, a blood spot test, also called a heel prick test, is performed on babies shortly after they are born to diagnose for different types of conditions, including Fabry disease.

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One way to do this is by using genetic testing to look for Fabry disease-causing mutations in GLA, the gene that carries instructions to make an enzyme called alpha-galactosidase A (alpha-galA). This enzyme is responsible for the breakdown of a fat molecule called globotriaosylceramide (Gb3) into smaller molecules that the body can use or discard. As a result of mutations in GLA, however, Gb3 is not degraded and builds up inside cells, leading to the symptoms of Fabry disease.

Other ways to diagnose Fabry disease in a newborn screening include blood tests to measure the activity of the alpha-galA enzyme or detect the presence of lyso-Gb3, a form of Gb3 that has been proposed as a specific biomarker of the disease.

During the study period, from September 2015 until March 2021, dried blood spots were collected from 173,342 babies — 89,485 males and 83,857 females — born in the northeastern region of Italy. Of those, 53 babies — 44 males and nine females — had low alpha-galA activity on their second day of life. A second test confirmed the low alpha-galA activity in 23 babies — 22 males (including two pairs of brothers) and one female. However, only the male babies were found to have a mutation in the GLA gene.

Thirteen (including two brothers) had known mutations linked to late-onset Fabry disease, four had unclassified mutations, four had a A143T mutation that may or may not be linked to late-onset Fabry disease, and one had a mutation that is considered not to cause the disease. All mothers carried the same mutation as their respective babies.

When the researchers compared alpha-galA activity by type of mutation, they found that babies with known disease-causing mutations had about half the level of activity as those with unclassified or A143T mutations.

Next, the researchers measured the levels of lyso-Gb3 on dried blood spots of 17 of the 22 male newborns carrying a GLA mutation. “We evaluated the use of this biomarker as a second-tier test,” the researchers wrote. They found that lyso-Gb3 levels were abnormally high in five newborns, all of whom had known mutations linked to late-onset Fabry disease. “A normal result cannot exclude [Fabry disease], and, therefore, cannot be used as a [second-tier] test.”

When they looked at a link between alpha-galA and lyso-Gb3, however, they found that the lower the activity of alpha-galA, the higher the levels of lyso-Gb3.

The researchers also measured the levels of lyso-Gb3 on plasma samples taken on a first visit to the clinic. They were abnormally high in 11 of the 21 tested male newborns, nine of whom had known disease-causing mutations. Again, the lower the activity of alpha-galA, the higher the levels of lyso-Gb3.

At the last visit, ages ranged between 10 days and 5.5 years. None of the patients had symptoms of, or had received specific treatment for, Fabry disease.

Based on the findings, the researchers proposed a new newborn screening algorithm, or set of rules. According to this algorithm, newborns with low alpha-galA and high lyso-Gb3 must be referred directly to a pediatric unit. Those with low alpha-galA and low lyso-Gb3, however, must be tested a second time before being referred to a pediatric unit for further molecular and genetic testing.

The findings suggest that Fabry disease may “be more frequent than previously estimated clinically” and that newborn screening “may help to improve the diagnosis of many unrecognized patients,” the researchers wrote.

According to the researchers, measurement of alpha-galA activity should be included in the national newborn screening program.

That’s why “the project is moving forward with the aim of gaining a better understanding of the disease and better care for the patients,” the researchers concluded.