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

Abstract

IntroductionFragile X Syndrome (FXS) is rare genetic condition characterized by a repeat expansion (CGG) in the Fragile X messenger ribonucleoprotein 1 (FMR1) gene where individuals with greater than 200 repeats are defined as full mutation. FXS clinical presentation often includes intellectual disability, and autism-like symptoms, including anxiety and sensory hypersensitivities. Individuals with 55 to <200 CGG repeats are said to have the FMR1 premutation, which is not associated with primary characteristics of the full mutation, but with an increased risk for anxiety, depression, and other affective conditions, as well as and impaired cognitive processing differences that vary in severity. Defining subgroups of premutation carriers based on distinct biological features may identify subgroups with varying levels of psychiatric, cognitive, and behavioral alterations.MethodsThe current pilot study utilized 3 cluster subgroupings defined by previous k means cluster analysis on neuropsychiatric, cognitive, and resting EEG variables in order to examine basic sensory auditory chirp task-based EEG parameters from 33 females with the FMR1 premutation (ages 17–78).ResultsBased on the predefined, neuropsychiatric three-cluster solution, premutation carriers with increased neuropsychiatric features and higher CGG repeat counts (cluster 1) showed decreased stimulus onset response, similar to previous ERP findings across a number of psychiatric disorders but opposite to findings in individuals with full mutation FXS. Premutation carriers with increased executive dysfunction and resting gamma power (cluster 2) exhibited decreased gamma phase locking to a chirp stimulus, similar to individuals with full mutation FXS. Cluster 3 members, who were relatively unaffected by psychiatric or cognitive symptoms, showed the most normative task-based EEG metrics.DiscussionOur findings suggest a spectrum of sensory processing characteristics present in subgroups of premutation carriers that have been previously understudied due to lack of overall group differences. Our findings also further validate the pre-defined clinical subgroups by supporting links between disturbances in well-defined neural pathways and behavioral alterations that may be informative for identifying the mechanisms supporting specific risk factors and divergent therapeutic needs in individuals with the FMR1 premutation.

Region-Related Differences in Short-Term Synaptic Plasticity and Synaptotagmin-7 in Male and Female Hippocampus of a Rat Model of Fragile X Syndrome

“…Interestingly, the increase in synaptic facilitation seen in the VH of KO female rats occurred at an IPI of 25 ms that corresponds to 40 Hz, the typical frequency of gamma oscillation that fundamentally supports processing of neural information in the brain [96], including processing of visual information, attention and episodic memory. Thus, the alteration in PPR observed here may be related to the previously reported impairment in sensory processing in females [97,98].…”

"Tras las Huellas del Síndrome de cromosoma X Frágil: Experiencias y Desafíos en Ricaurte, Valle del Cauca, un estudio cualitativo”

“…Desde el punto de vista conductual, las características comunes son la hiperactividad, la ansiedad, las dificultades de socialización y la hipersensibilidad sensorial (Johnson et al, 2022). Además, las personas con la premutación del cromosoma X frágil pueden presentar dolor crónico, y las mujeres presentan más síntomas de dolor que los hombres, como alodinia, neuropatía periférica, migraña, fibromialgia y dolor de espalda (Norris et al, 2023)]. La presentación del síndrome puede variar considerablemente, y algunas personas que se encuentran dentro del rango de premutación presentan síntomas atípicos, como la corea generalizada, además de ataxia y deterioro cognitivo (Islam & Lee, 2020) Las principales preocupaciones a las que se enfrentan los familiares de pacientes con cromosoma X Frágil suelen tener que realizar un diagnóstico prolongado, lo que aumenta el estrés y repercute negativamente en la salud mental (Islam & Lee, 2020)los mismo autores plantean que tanto las madres como los padres necesitan un mayor apoyo para reducir sus problemas de salud mental y el estrés de la crianza de los hijos diagnosticados con la enfermedad.…”