Blood biomarkers help identify individuals with fragile X syndrome
Patients with suspected fragile X syndrome (FXS) present higher levels of the two proteins metalloproteinase-9 (MMP9) and amyloid-beta protein precursor (APP) in their blood according to a recent study in Clinical Biochemistry. A research team in Egypt has demonstrated how these two biomarkers could assist in detecting FXS in cases where genetic testing is not possible.
Fragile X syndrome arises from an excess of repeats in a trio of DNA building blocks, known as the CGG triplet repeat, within the FMR1 gene. This disrupts the production of the FMRP protein, which is crucial for regulating numerous proteins associated with neurological function. The number of CGG repeats ranges from normal (5–44 repeats), or borderline (45–54 repeats), to fragile X-associated premutations (55–200 repeats) or full mutations (>200 repeats).
Individuals with premutations typically display no symptoms or mild symptoms, but these repeats can result in the presence of FXS in their children, whereas full mutations lead to the clinical symptoms of FXS. Despite being the second most common genetic cause of intellectual disability in children, FXS is often underdiagnosed.
The research team explained:
“Given their low cost, rapid turnaround time and easy technique, screening for serum biomarkers such as MMP9 and APP, especially in the absence of genetic diagnosis of FXS is a reasonable and justified approach. Both biomarkers are promising and can be used individually or together in this context.”
The team explored the possibility of MMP9 and APP acting as FXS blood biomarkers. Previous preclinical and clinical evidence has indicated that both proteins are disrupted in FXS.
“Our study is the first to evaluate both MMP9 and APP in FXS-suspected children in a clinical setting and to assess their correlation with disease presentation and severity.”
The team’s findings showed that in confirmed cases of FXS, whether full mutation or premutation, MMP9 levels were notably higher than in suspected children with a normal genotype. Additionally, MMP9 levels exhibited an upward trend with age and were highest in individuals experiencing speech or language defects alone. APP levels were also significantly greater in confirmed cases of FXS when compared with suspected cases with a normal genotype. APP levels were greatest in confirmed patients who had an isolated intellectual disability or form of neurodevelopmental delay.
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Additional experiments helped define the optimal clinical cut-off values for distinguishing FXS patients (full mutation and premutation cases) from patients presenting possible symptoms but possessing a normal genotype. While each protein exhibited reasonable accuracy in distinguishing between cases, the optimal identification of FXS cases was achieved by combining the two blood biomarkers, resulting in a sensitivity of 95.5%, implying that such a test would detect the majority of FXS cases in a clinical setting.
These findings suggest that the use of either biomarker or a combination of the two could provide viable alternatives for disease screening, especially in developing countries that lack readily available genetic testing.
