Cerebellum neuropathology and motor skill deficits in fragile X syndrome

Abstract

Fragile X syndrome (FXS) is a leading form of inherited intellectual disability and single‐gene cause of autism spectrum disorder (ASD) and is characterized by core deficits in cognitive flexibility, sensory sensitivity, emotion, and social interactions. Motor deficits are a shared feature of FXS and autism. The cerebellum has emerged as one of the target brain areas affected by neurodevelopmental diseases. Alterations in the cerebellar structure, circuits, and function may be the key drivers of impaired fine and gross motor skills in FXS and fragile X‐associated tremor/ataxia syndrome (FXTAS). In this review, we briefly examined recent findings in FXS and present a discussion on the literature supporting motor skill deficits in FXS. Subsequently, we focused on neuropathological alterations in the cerebellum in FXS and FXTAS. We highlight studies that have directly examined the function of fragile X mental retardation protein and related epigenetic variations in the cerebellum. Overall, we obtained considerable supporting evidence for the hypothesis that cerebellar dysfunction is evident in FXS and FXTAS; however, compared with studies on other ASD models, studies on motor skills related to fragile X disorders are particularly rare and inconclusive. Hence, future research should address FXS‐related motor and behavioral trajectories and examine the underlying mechanisms at both the cell and circuit levels.

Synaptic cell adhesion molecules contribute to the pathogenesis and progression of fragile X syndrome

“…Recently, several synaptic CAMs, such as intercellular adhesion molecule 5 (ICAM5) ( Pei et al, 2020 ), neuroligin-1 ( Dahlhaus and El-Husseini, 2010 ; Lai et al, 2016 ), N-cadherin ( La Fata et al, 2014 ), L1-CAM ( Djabali et al, 1990 ), and calsyntenin 1 (CLSTN1) ( Cheng et al, 2019 ), have been found to aberrantly intervene in the pathological phenotype of fragile X syndrome (FXS), providing insights into the pathogenic mechanisms underlying FXS. As the most common intellectual developmental disorder ( Jacquemont et al, 2007 ; Hagerman and Hagerman, 2021 ) and the most common single-gene factor in autism spectrum disorder (ASD) ( Bagni et al, 2012 ; Deng and Klyachko, 2021 ; Chen Y. S. et al, 2022 ). FXS is often used to study neurodevelopmental disease mechanisms.…”

Combined extended reality and reinforcement learning to promote healthcare and reduce social anxiety in fragile X syndrome: a new assessment tool and a rehabilitative strategy

“…Behavioral difficulties, including poor eye contact, self-injury, aggression, and stereotypic, repetitive, and pervasive behaviors, are additionally reported (Marlborough et al, 2021 ; Niescier and Lin, 2021 ). Anxiety is also documented in FXS, with over 80% of the male subjects meeting the criteria for one anxiety disorder and over 60% of male subjects meeting the criteria for multiple anxiety disorders (Alusi et al, 2022 ; Chen Y. S. et al, 2022 ). The most frequent categories of anxiety disorders detectable in FXS are selective mutism and specific and/or social phobia.…”