Evidence for Three Subgroups of Female FMR1 Premutation Carriers Defined by Distinct Neuropsychiatric Features: A Pilot Study

Abstract

Over 200 Cytosine-guanine-guanine (CGG) trinucleotide repeats in the 5′ untranslated region of the Fragile X mental retardation 1 (FMR1) gene results in a “full mutation,” clinically Fragile X Syndrome (FXS), whereas 55 – 200 repeats result in a “premutation.” FMR1 premutation carriers (PMC) are at an increased risk for a range of psychiatric, neurocognitive, and physical conditions. Few studies have examined the variable expression of neuropsychiatric features in female PMCs, and whether heterogeneous presentation among female PMCs may reflect differential presentation of features in unique subgroups. In the current pilot study, we examined 41 female PMCs (ages 17–78 years) and 15 age-, sex-, and IQ-matched typically developing controls (TDC) across a battery of self-report, eye tracking, expressive language, neurocognitive, and resting state EEG measures to determine the feasibility of identifying discrete clusters. Secondly, we sought to identify the key features that distinguished these clusters of female PMCs. We found a three cluster solution using k-means clustering. Cluster 1 represented a psychiatric feature group (27% of our sample); cluster 2 represented a group with executive dysfunction and elevated high frequency neural oscillatory activity (32%); and cluster 3 represented a relatively unaffected group (41%). Our findings indicate the feasibility of using a data-driven approach to identify naturally occurring clusters in female PMCs using a multi-method assessment battery. CGG repeat count and its association with neuropsychiatric features differ across clusters. Together, our findings provide important insight into potential diverging pathophysiological mechanisms and risk factors for each female PMC cluster, which may ultimately help provide novel and individualized targets for treatment options.

Neuropsychiatric feature-based subgrouping reveals neural sensory processing spectrum in female FMR1 premutation carriers: A pilot study

“…Further, PMCs are at higher risk for exacerbation of underlying psychopathology by comorbidities associated with the premutation and external experiences (e.g., close relative with the full mutation) resulting in greater impact of the premutation on quality of life (Hall et al, 2016;Wheeler et al, 2017;Hagerman et al, 2018;Allen et al, 2020;Klusek et al, 2020). Female adult PMCs may experience impaired executive function and social processing difficulties in addition to increased neuropsychiatric risk (Schmitt et al, 2022). Executive dysfunction and social processing difficulties were previously noted in child PMCs, in addition to the developmental differences between PMCs and TD infants centered around abnormal sensory experiences and non-verbal communication (Wheeler et al, 2016).…”

“…Abnormal sensory processing is a common phenotypical feature of the FXS full mutation manifesting typically as sensory hyperreactivity (Ethridge et al, 2019). Few studies have addressed sensory sensitivity in PMCs and also fail to utilize measures of neural responses such as electroencephalography (EEG) to sensory stimulation (Hunter et al, 2008;Allen et al, 2020;Schmitt et al, 2022). Most prior evaluations focused on child PMCs from a developmental perspective, limiting commentary on how moderate FMR1 expansions impact sensory processing capacity later in the lifespan.…”

“…Previous studies in child PMCs have documented cooccurring sensory hyper-and hypo-responsivity that vary based on age (Wheeler et al, 2016;Raspa et al, 2018). Most studies of sensory processing abnormalities in adult PMCs focused on their relation to mood and anxiety (Allen et al, 2020;Schmitt et al, 2022). The neural basis of sensory processing alterations remain unclear, as is the mechanism by which alterations at the neural level are related to clinical presentation of neuropsychiatric symptoms in adult PMCs.…”

“…The second cluster (cluster 2) was characterized by increased executive dysfunction and higher resting gamma power suggesting a group more comparable to full mutation FXS. Finally, the third cluster (cluster 3) was comprised of members who were relatively unaffected by psychiatric or cognitive symptoms (Schmitt et al, 2022). However, this initial study did not examine or utilize sensory self-report or sensory EEG (such as sensory evoked potentials) measures or EEG measures directly related to mood and anxiety (e.g., frontal asymmetry) in deriving the cluster solution.…”

“…The current pilot study aimed to extend the work detailed in Schmitt et al (2022) by evaluating cluster membership in relation to task-based EEG parameters obtained during an auditory task, considering dynamic evaluations of oscillatory frequency bands in order to test the hypothesis that neuropsychiatric features are present in PMC populations supported by similar neural processes observed in full mutation FXS. Although the current study should be considered a pilot study and hypothesis generating due to the relatively small sample size and sparse literature on EEG in PMCs, we opted to also evaluate cluster differences across clinical measures as they related to variations in task-related frontal hemispheric asymmetry during the auditory task, as frontal asymmetry measures have previously been linked to variations in mood and anxiety hypothesized to map onto similar characteristics in PMCs (Allen et al, 2004;Coan and Allen, 2004;Thibodeau et al, 2006;Stewart et al, 2010;Smith et al, 2017;van der Vinne et al, 2017).…”