Three Faces of Fragile X

Lieb-Lundell, Cornelia

doi:10.2522/ptj.20140430

Cited by 12 publications

(8 citation statements)

References 55 publications

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“…Consistent with the neurodevelopmental delays observed in FXS patients and animal models of the disease 9 , 21 , 32 , 36 , 98 – 102 , we observed a delay in the emergence of Up-states in ex vivo Fmr1 −/y circuits. The presence of a delay during ex vivo developmental further supports the notion that the lack of FMRP does indeed alter the temporal profile of the ontogenetic program underlying neurodevelopment.…”

Section: Discussionsupporting

confidence: 87%

Decreased reproducibility and abnormal experience-dependent plasticity of network dynamics in Fragile X circuits

Motanis

Buonomano

2020

Sci Rep

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fragile X syndrome is a neurodevelopmental disorder associated with a broad range of neural phenotypes. Interpreting these findings has proven challenging because some phenotypes may reflect compensatory mechanisms or normal forms of plasticity differentially engaged by experiential differences. To help minimize compensatory and experiential influences, we used an ex vivo approach to study network dynamics and plasticity of cortical microcircuits. in Fmr1 −/y circuits, the spatiotemporal structure of Up-states was less reproducible, suggesting alterations in the plasticity mechanisms governing network activity. chronic optical stimulation revealed normal homeostatic plasticity of Up-states, however, Fmr1 −/y circuits exhibited abnormal experience-dependent plasticity as they did not adapt to chronically presented temporal patterns in an interval-specific manner. These results, suggest that while homeostatic plasticity is normal, Fmr1 −/y circuits exhibit deficits in the ability to orchestrate multiple forms of synaptic plasticity and to adapt to sensory patterns in an experience-dependent manner-which is likely to contribute to learning deficits. Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disabilities, and reflects loss of function mutations in the RNA binding protein, Fragile X Mental Retardation Protein (FMRP) 1-4. Since the generation of the first mouse model of FXS 5 , a large number of neural phenotypes have been associated with the syndrome including: abnormalities in dendritic spine morphology and stabilization 6-12 , altered shortand long-term forms of synaptic plasticity 13-20 , abnormal axonal development 19,21,22 , changes in interneuronal connectivity 23,24 , channelopathies 16,25-31 , and imbalanced excitation/inhibition 24,32-44. The sheer diversity of reported neural phenotypes highlights the challenge in determining which phenotypes are a primary consequence of the absence of FMRP, from those that reflect indirect secondary neural phenotypes. These secondary neural phenotypes could reflect: (1) compensatory and homeostatic mechanisms, i.e., genetic redundancy and homeostatic plasticity engaged to compensate for the primary consequences of the lack of FMRP 44-46 ; or (2) normal forms of plasticity shaped by experiential differences, including differences in sensory exploration, social interactions and maternal care. Indeed, it is increasingly recognized that some of the neural phenotypes reported in animal models of FXS and autism spectrum disorder (ASD) may reflect compensatory mechanisms or differential developmental experiences 44,45. For example, it is well established that early differences in sensory experience, social interactions and maternal rearing, can alter numerous neural properties throughout life 47-53. As a result of decreased social interactions, young FMRP-deficient animals could in effect inhabit an impoverished sensory environment. Indeed, it is also well established that in mouse models of FXS and ASD, animals experience differences in so...

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Section: Discussionsupporting

confidence: 87%

Decreased reproducibility and abnormal experience-dependent plasticity of network dynamics in Fragile X circuits

Motanis

Buonomano

2020

Sci Rep

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“…There is a paucity of information regarding specific physical therapy interventions that could impact the characteristic musculoskeletal alterations affecting FXS children. However, rehabilitation therapies for these children are mainly focused on the neurodevelopmental aspects and motor delay, and less attention is paid to actual musculoskeletal alterations [33]. Studies aiming at classifying the different gait motor control impairments associated with FXS could therefore help in overcoming this limitation.…”

Section: Discussionmentioning

confidence: 99%

A Supervised Classification of Children with Fragile X Syndrome and Controls Based on Kinematic and sEMG Parameters

et al. 2022

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Fragile X syndrome (FXS) is caused by pathologic expansions of the CGG repeat polymorphic region of the FMR1 gene. There are two main categories of FMR1 mutations, “premutation” and “full mutation”, that are associated with different clinical phenotypes, and somatic mosaicism can represent a strong FXS phenotype modulator. FXS is the leading cause of inherited intellectual disability and autism, and it is characterized by musculoskeletal manifestations such as flexible flat feet, joint laxity and hypotonia. The former have been associated with altered joint kinematics and muscle activity during gait. The aim of this study was to use gait analysis parameters to classify FXS children from healthy controls and, within FXS children with full mutation, to classify children with mosaicism. Seven supervised machine learning algorithms were applied to a dataset of joint kinematics and surface electromyographic signals collected on twenty FXS children and sixteen controls. Results showed that the k-NN algorithm outperformed in terms of accuracy (100%) in classifying FXS children from controls, while CN2 rule induction obtained the best accuracy (97%) in classifying FXS children with mosaicism. The proposed pipeline might be used for developing assisted decision-making systems aiming at identifying and treating the musculoskeletal alterations associated with FXS.

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“…PT is the third most frequent intervention used by children with FXS [73]. Special treatment considerations for children with FXS are often given, which require intermittent assessment of motor development as well as hypotonia and joint hypermobility [85]. To address delays in walking skills and balance, physical therapists may recommend assistive devices such as orthotics to correct foot pronation or strollers for stability [85].…”

Section: Non-pharmacological Therapy Of Fxsmentioning

confidence: 99%

Fragile X Syndrome: From Molecular Aspect to Clinical Treatment

Protić

Aishworiya

Salcedo-Arellano

et al. 2022

IJMS

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Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome. Children with FXS are commonly co-diagnosed with Autism Spectrum Disorder, attention and learning problems, anxiety, aggressive behavior and sleep disorder, and early interventions have improved many behavior symptoms associated with FXS. In this review, we performed a literature search of original and review articles data of clinical trials and book chapters using MEDLINE (1990–2021) and ClinicalTrials.gov. While we have reviewed the biological importance of the fragile X mental retardation protein (FMRP), the FXS phenotype, and current diagnosis techniques, the emphasis of this review is on clinical interventions. Early non-pharmacological interventions in combination with pharmacotherapy and targeted treatments aiming to reverse dysregulated brain pathways are the mainstream of treatment in FXS. Overall, early diagnosis and interventions are fundamental to achieve optimal clinical outcomes in FXS.

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Three Faces of Fragile X

Cited by 12 publications

References 55 publications

Decreased reproducibility and abnormal experience-dependent plasticity of network dynamics in Fragile X circuits

Decreased reproducibility and abnormal experience-dependent plasticity of network dynamics in Fragile X circuits

A Supervised Classification of Children with Fragile X Syndrome and Controls Based on Kinematic and sEMG Parameters

Fragile X Syndrome: From Molecular Aspect to Clinical Treatment

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