Disease Severity Tied to Two Neuroprostanes
Elevated levels of two neuroprostanes — markers of oxidative stress, a result of insufficient antioxidant defenses against toxic free radicals — are linked with symptom severity and type of mutations in people with Rett syndrome, a study reports.
These findings support the potential of the neuroprostanes as biomarkers to assess disease progression in Rett, scientists said.
The study, “Circulating 4-F4t-Neuroprostane and 10-F4t-Neuroprostane Are Related to MECP2 Gene Mutation and Natural History in Rett Syndrome,” was published in the International Journal of Molecular Sciences.
Accumulating research has indicated a crucial role of oxidative stress in Rett syndrome. In oxidative stress, free radicals, or reactive oxygen species (ROS), are harmful to cells, including nerve cells.
Neuroprostanes, formed from the metabolism of a fatty acid, are increasingly recognized as biomarkers of neurological diseases such as Rett syndrome. Among the neuroprostanes, 4-F4t-NeuroP and the 10-F4t-NeuroP are the most investigated.
Prior research suggested that the blood levels of these two molecules correlated with the severity of several neurological diseases.
In this study, researchers from Italy, France and Hong Kong assessed whether the levels of 4-F4t-NeuroP and 10-F4t-NeuroP are informative in Rett syndrome, specifically for people with mutations in the MECP2 gene, the most common cause of the disease.
They evaluated 77 Rett patients (age range 5 to 47 years), all with a confirmed mutation in MECP2, and at different stages of disease progression: 17 patients were stage II, 34 stage III and 26 were at stage IV.
In this classification, stage II refers to loss of previously acquired skills such as communication and gross motor skills function; stage III to disease stabilization with potential improvements; and stage IV, the last stage, to motor deterioration that can last decades.
A total of 45 healthy participants, matched for age and sex, also were recruited and served as controls.
Results showed that the levels of both neuroprostanes were significantly different according to the disease stage, being significantly higher in stages II and IV as compared to stage III.
This suggests that “the time-course for 4-F4t-NeuroP and 10-F4t-NeuroP formation appears to be parallel to the neurological impairment resulting in the clinical presentation,” the researchers wrote.
Additional analyses revealed that the levels of both neuroprostanes were significantly different according to the type of MECP2 mutation, as they varied in patients with so-called “hotspot” mutations.
Higher levels of both neuroprostanes were associated with deletions in the MECP2 gene, as well mutations leading to a shorter protein.
This variability in the amount of neuroprostanes remained when looking at the different domains of the MECP2 protein.
As for disease severity, evaluated with the Rett clinical severity scale (RCSS), the scientists found a significant correlation between increased neuroprostanes levels and four parameters of severity of the RCSS scale.
“In particular, walking deficiency was the RCSS item more strongly related to F4t-NeuroP levels,” they wrote.
Other parameters showing a significant association with higher levels of both molecules included deficits in verbal communication, in purposeful hand use, microcephaly (abnormally small head), and seizures.
These findings support the potential involvement of 10-F4t-NeuroP and 4-F4t-NeuroP “in the impact of different MECP2 mutations on ambulation, hand use, and language deficiencies,” the investigators wrote.
Overall, “this study indicates the biological significance of 4-F4t-NeuroP and 10-F4t-NeuroP as promising molecules to mark the disease progression” in Rett syndrome, they concluded.