Measuring lyso-Gb1 levels may aid diagnosis accuracy in Gaucher
New testing strategy could allow use of single blood sample in most cases
Measuring levels of lyso-Gb1, a fatty molecule often used as a biomarker of Gaucher disease (GD) severity, could help improve the accuracy of diagnostic tests for the rare condition, according to a new report from a South American research team.
While low activity of the glucocerebrosidase (GCase) enzyme is the diagnostic hallmark of Gaucher, unreliable results often require repeated testing. Now, researchers in Argentina have found that, in most cases, measuring lyso-Gb1 levels alongside GCase activity could help establish or rule out Gaucher with a single blood sample.
“Concomitant determination of [GCase] activity and Lyso-Gb1 levels … optimizes the diagnostic approach of individuals with suspicion of GD, independently of age and gender,” the team wrote, adding that “the implementation of [a] new algorithm [using both measures] would allow a faster and cheaper diagnosis of this disorder.”
Their study, “Addition of Lyso-Gb1 to enzyme activity to first-tier test for Gaucher in DBS improves diagnostic accuracy and reduces patient recall rate,” was published in the journal Clinica Chimica Acta. It was partly supported by Sanofi, with two of the four authors affiliated with the biopharma company.
In Gaucher disease, the GCase enzyme, which is needed to break down a fatty molecule called glucocerebroside (Gb1), is missing or abnormal. As a result, Gb1 and related molecules toxically accumulate to drive the symptoms of Gaucher, which can affect the body’s organs, blood, or bones.
The main way to diagnose Gaucher is through a test that measures GCase activity in a person’s blood sample. This is commonly done using dried blood spots, known as DBS, where a few drops of blood are collected and dried onto absorbent filter paper before being sent to the lab for analysis.
Testing often inconclusive; highlights need to improve diagnosis accuracy
DBS samples are easy to collect and transport, and require only a small amount of blood. However, they are not always of high quality, thus, in many cases, yielding inconclusive results that warrant repeat testing.
One option for improving DBS diagnostic performance is to measure another disease biomarker as a second-tier test. Lyso-Gb1, a metabolite of Gb1, accumulates to high levels in Gaucher and has emerged as a highly specific biomarker of disease severity.
In this study, the scientists tested whether adding lyso-Gb1 to their diagnostic algorithm could improve the accuracy of diagnosis for patients based on DBS samples. The team analyzed data from 4,651 people who were referred to their lab from 2018 to 2023 with clinical suspicion of Gaucher.
All participants’ blood samples were tested for the activity of GCase and beta-galactosidase (bGal), a control enzyme intended to evaluate the sample’s quality.
In participants with normal GCase activity levels, the researchers immediately ruled out Gaucher disease. For 326 people who had reduced or inconclusive GCase activity, the scientists measured lyso-Gb1 as a secondary test.
Researchers: Lyso-Gb1 measures could rule out Gaucher in most cases
When lyso-Gb1 levels were elevated above the established cutoff — which happened for about 14% of people — Gaucher was considered likely. Those people were referred for genetic testing or other evaluations to confirm the diagnosis.
Among the remaining individuals with normal lyso-Gb1, the activity level of bGal, the control enzyme, was used to determine what happened next.
About three-quarters of people had bGal levels that could suggest suboptimal DBS sample quality. Still, most were considered sufficient for the test to be considered normal, and Gaucher was ruled out.
However, bGal levels were critically low in 14 samples, and the researchers felt the results couldn’t be interpreted. A new DBS sample was required in those cases.
Overall, “determination of lyso-Gb1 levels in DBS was associated with a high accuracy rate and would lead to avoiding a second sample request in most cases, reducing both healthcare costs and anxiety due to genotyping [genetic testing],” the researchers wrote.
Still, the researchers emphasized that these test results should always be carefully considered, as there can be unusual cases that don’t fit the mold.
For example, the team faced one unique case in which a newborn whose mother had Gaucher underwent DBS testing two days after birth. The baby had borderline GCase activity levels and elevated lyso-Gb1. However, follow-up testing later on showed both biomarkers to be normal.
“This case highlights the importance of considering the limitations of early sampling in newborns from parents with confirmed [Gaucher disease],” the scientists wrote.
Determination of lyso-Gb1 levels in [a blood sample] was associated with a high accuracy rate and would lead to avoiding a second sample request in most cases, reducing both healthcare costs and anxiety due to genotyping [genetic testing].
Nevertheless, the findings indicate that lyso-Gb1 could rule out Gaucher in most cases where enzyme testing results are unreliable, according to the team. The researchers noted that larger studies are still needed to validate the approach.
Overall, however, the team suggested that the dual testing strategy would likely work better than taking a new sample.
“An eventual second DBS sample may lead to logistical issues that reduce the probability of a proper GD diagnosis; by contrast, the new algorithm may increase the diagnostic probability with a single sample,” the researchers wrote.
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