Fragile X Syndrome (FXS) is a prevalent monogenic disease, often presenting with cognitive and neurological disorders including autism and epilepsy. The Fmr1 gene - transcriptionally silenced in FXS - normally encodes the Fragile X Mental Retardation Protein (FMRP), which acts as an activity dependent translational regulator at the base of dendritic spines. In an attempt to understand its role, dendritic spines in the dentate gyrus (DG) and cornu ammonis 1 (CA1) hippocampal regions of three-week old Fmr1- mice were analyzed and compared to wildtype (WT) littermate controls using electron microscopy. Dendritic spines with a continuous profile of the parent dendrite, spine neck, and spine head complete with synaptic components (presynaptic vesicles and postsynaptic densities) were included in our morphological analyses. We observed no changes in postsynaptic density length (DG: 5.69±0.30/6.18±0.85; SR: 7.55±0.87/6,96±0.33 µm/100 µm2; p=0.627/0.620), synapse density (DG: 32.3±3.8/30.3±1.9; SR: 34.4±1.8/30.7±0.5 synapses/100 µm2; p=0.655/0.270), spine head diameters (DG: 0.524±0.016/0.529±0.014; SR: 0.524±0.014/0.515±0.014 µm; p=0.098/0.20) or spine neck lengths (DG: 0.457±0.016/0.485±0.019; SR: 0.421 ± 0.015/0.425±0.017 µm; p=0.14/0.26), but found that in the DG spine necks were significantly narrower in the Fmr1- mice (0.193±0.0062/0.167±0.0064 µm; p=0.0002), whereas there were no changes in CA1 spine neck widths (0.162±0.0049/0.161±0.0061 µm; p=0.073). Estimated resistance calculated from spine necks morphologies revealed a ~1.7 fold increase in the Fmr1- DG compared to WT DG. These findings support that FMRP plays a role in granule cell spine neck structure and may influence synaptic signal compartmentalization and propagation in a regionally dependent manner. / Graduate

The dissertation is divided into two separate experiments that explore the effects of visual-spatial learning on PSD-95 dorsal hippocampal expression. Specifically, the aim of these studies was to explore the effect of learning an assay, the Hebb-Williams mazes, on the protein expression of PSD-95 in Fmr1 KO mice. PSD-95 is an important scaffolding protein hypothesized to be involved in learning and memory. In cellular models of Fragile X Syndrome it has been shown to be dysregulated but it has never been measured following behavioural learning. Establishment of a deficit using an ecologically valid behavioural assay could lead to the development of novel interventions. Study one employed a subset of the Hebb-Williams mazes of various levels of difficulty to evaluate PSD-95 protein expression in Fmrp intact and Fmr1 KO mice following learning. The results revealed significant increases in PSD-95 protein expression in control runners when compared to Fmr1 KO mice. There was a negative correlation between PSD-95 protein levels and mean total errors on the mazes meaning that as expression was increased, errors were decreased. The goals of study two were to reverse the molecular and behavioural deficits using pharmacological antagonist treatment shown to be effective in cellular models of Fragile X Syndrome. Fmr1 KO mice were treated with either saline or 20 mg/kg of a metabotropic glutamate receptor antagonist, 2-Methyl-6-(phenylethynyl) pyridine (MPEP). Relative to saline treated controls, drug treated Fmr1 KO mice made fewer errors on the same subset of Hebb-Williams mazes used in study one. Latency to complete these mazes did not differ between groups, indicating that MPEP treatment does not adversely affect motor functioning. Protein assessment revealed that PSD-95 was selectively rescued in MPEP treated mice and not saline controls. Similar to study one, a negative correlation between PSD-95 protein levels and mean total errors was observed. When taken together, these studies indicate that protein deficits are associated with a deficit of learning that can be reversed with a selective glutamate receptor antagonist. One of the strengths of the Hebb-Williams mazes is that performance is measurable without floor or ceiling effects, which plague other common behavioural assays. These data further suggest that pharmacological antagonist treatments may be promising in correcting the learning deficits in human Fragile X Syndrome patients.

Disordered communication between cortical neurons and glia underlies many of the characteristics of Fragile X syndrome (FXS), the most common monogenic form of intellectual disability and autism spectrum disorder (ASD). Despite extensive research, no effective treatments exist to comprehensively mitigate ASD- or FXS-related cognitive and motor disabilities, sensory hyperresponsivity, seizures, and other excitation-related symptoms. Glial-glial and glial-neuronal communication can be facilitated by purinergic signalling pathways, which utilize ATP, UTP, and their metabolites to influence both short-term and longer-term activation. The overall objective of this thesis work was to establish whether purinergic signalling is dysregulated within cortical astrocytes derived from the Fmr1 KO mouse model of FXS, and furthermore, to determine whether astrocyte purinergic dysregulations contribute to aberrant Fmr1 KO neuronal-glial interactions. Collectively, these studies provide the first reported evidence that P2Y receptor-driven purinergic signalling is elevated in Fmr1 KO cortical astrocytes, and suggest that this impacts the formation and activity of neuronal circuitry in a manner consistent with FXS symptomatology. Fmr1 KO cortical astrocyte dysregulations included elevated expression of P2Y2 and P2Y6 purinergic receptors, increased intracellular calcium release following P2Y activation, aberrant levels of intracellular purinergic signalling molecules, and increased ectonucleotidase glycosylation. UTP treatment promoted excess Fmr1 KO astrocyte expression and secretion of the synaptogenic protein TSP-1 to potentially influence neuronal connectivity, as well as increased phosphorylation of transcription factor STAT3 to likely drive cortical immune responses. Both exogenous UTP and the presence of Fmr1 KO astrocyte secretions promoted neurite outgrowth, while Fmr1 KO astrocyte-neuron co-cultures demonstrated elevated neuronal burst frequency that was normalized through chronic and selective P2Y2 antagonism. Together, these findings indicate novel and significant astrocyte P2Y-mediated purinergic upregulations within the Fmr1 KO mouse cortex, and suggest that astrocyte purinergic signalling should be further investigated in the search for innovative FXS treatments. / Thesis / Doctor of Philosophy (PhD) / Autism spectrum disorders (ASDs) have become a serious health concern in recent years due to rapidly rising rates of diagnosis. Despite extensive research, there are still no effective treatments for these disorders of brain development. It is therefore important that we study the cellular events contributing to ASDs in order to design new therapeutic strategies. The most common inherited form of ASD is Fragile X syndrome (FXS), which is characterized by cognitive and motor disabilities, sensory hyperresponsivity, attention deficits, hyperactivity, and seizures. Using the Fmr1 knockout (KO) mouse model of FXS, recent research has shown that many of these symptoms are related to disordered communication between brain cells within the cerebral cortex; specifically, between neurons and the helper-like cells known as astrocytes. One form of cellular signalling that supports this communication is known as the purinergic signalling pathway. Collectively, this thesis work is the first to show that purinergic signalling is increased in Fmr1 KO mouse cortical astrocytes and that it impacts FXS neuronal connections. Specifically, Fmr1 KO cortical astrocytes demonstrated increased communication using purinergic signalling, due to greater expression of P2Y2 and P2Y6 purinergic receptors and altered levels of the molecules that stimulate these receptors. Activation of Fmr1 KO astrocyte P2Y receptors promoted expression of the neuronal connection-forming protein TSP-1 and stimulated additional astrocyte signalling pathways. As a result of these changes, when Fmr1 KO neurons were grown in the presence of Fmr1 KO astrocytes, they grew longer extensions and demonstrated greater activity than wildtype controls, in a manner consistent with the excitation-related symptoms of FXS. Selectively targeting P2Y2-driven purinergic pathways with drug treatments corrected this activity, thereby revealing a potential new therapeutic approach for FXS. Understanding excess astrocyte P2Y-driven purinergic communication within the brain may therefore provide a foundation for the future development of new FXS treatments.

No description available.

The regulation of neural precursor cells (NPCs), which encompass neural progenitor and neural stem cells (NSCs), is fundamental for proper brain development and function. These cells are regulated by orchestrated signalling within their local environment. Aberrant aspects of cell proliferation, differentiation, survival, or integration have been linked to various neurological diseases including Fragile X syndrome (FXS)—a disorder characterized by intellectual and social changes due to the silencing of the gene encoding FMRP. The biology of hippocampal NPCs in FXS during early postnatal development has not been studied, despite high FMRP expression levels in the hippocampus at the end of the first postnatal week. In this thesis, the Fmr1-knockout (KO) mouse model was used to study hippocampal cell biology during early postnatal development. A tissue culture assay, used to study the effect of astrocyte-secreted factors on the proliferation of NSCs, indicated that astrocyte secreted factors from Fmr1-KO brains enhanced the proliferation of wild type, but not Fmr1-KO NSCs (Chapter 3). Next, the proliferation and cell cycle profiles of NPCs in vitro and in vivo studied with immunocytochemistry, Western blotting, and flow cytometry revealed decreased proliferation of NPCs in the Fmr1-KO hippocampus (Chapter 4). Finally, cells isolated from the P7 dentate gyrus and characterized by flow cytometry, showed a reduced proportion of NSCs and an increased proportion of neuroblasts—neuronal committed progenitors—in Fmr1-KO mice. Together, these results indicate that hippocampal NPCs show aberrant proliferation and neurogenesis during early postnatal development. This could indicate stem-cell depletion, increased quiescence, or a developmental delay in relation to lack of FMRP and uncovers a new role for FMRP in the early postnatal hippocampus. In turn, elucidating the mechanisms that underlie FXS will aid in the development of targeted treatments. / Thesis / Doctor of Philosophy (PhD) / Fragile X syndrome is the leading inherited cause of intellectual impairment and autism spectrum disorder. The syndrome is caused by a defect in one gene. This gene has been suggested to play a role in regulating the birth of new brain cells termed neural precursor cells. The importance of neural precursor cells stems from their ability to generate neurons and glia, the main cells in the brain. In this thesis, I focus on studying neural precursor cells from the hippocampus, a brain region important for learning and memory. A mouse model was used to compare neural precursor cells from healthy and Fragile X mice during early postnatal development. I found that neural precursor cells do not divide as much as they should in the Fragile X mouse hippocampus. The results help to determine the causes for learning and memory deficits in Fragile X and potentially open avenues for intervention.

by Zhao Zheng. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1995. / Includes bibliographical references (leaves 87-98). / Acknowledgements --- p.i / Abstract --- p.ii / List of Tables --- p.iii / List of Figures --- p.iv / Chapter Chapter 1 --- Introduction --- p.i / Chapter 1.1 --- History --- p.1 / Chapter 1.2 --- Chromosomal Fragile Sites --- p.2 / Chapter 1.3 --- Cytogenetics of the Fragile Site at Xq27.3 --- p.3 / Chapter 1.4 --- Clinical Findings in Fragile X --- p.5 / Chapter 1.5 --- Prevalence --- p.6 / Chapter 1.6 --- The Mode of Inheritance and the Sherman Paradox --- p.8 / Chapter 1.7 --- Molecular Genetics of the FMR-1 Gene --- p.11 / Chapter 1.7.1 --- The Mutation Locus and Linkage Analysis --- p.11 / Chapter 1.7.2 --- Abnormal DNA Methylation in the CpG Island --- p.12 / Chapter 1.7.3 --- Isolation of the FMR-1 Gene --- p.13 / Chapter 1.7.4 --- CGG Trinucleotide Repeats in FMR-1 --- p.13 / Chapter 1.7.5 --- DNA Instability and Mutational Mechanisms --- p.17 / Chapter 1.7.6 --- Gene Expression --- p.18 / Chapter 1.7.7 --- Resolution of the Sherman Paradox --- p.19 / Chapter 1.8 --- Methods of Detection for the Fragile X Mutation --- p.20 / Chapter 1.8.1 --- Cytogenetic Analysis --- p.20 / Chapter 1.8.2 --- Diagnosis by Direct DNA Analysis --- p.21 / Chapter 1.8.2.1 --- Southern Blot Analysis --- p.22 / Chapter 1.8.2.2 --- PCR Analysis --- p.27 / Chapter 1.9 --- Studies of the Fragile X Syndrome in Mainland China --- p.29 / Chapter Chapter 2 --- Objectives of the Project --- p.33 / Chapter Chapter 3 --- Materials and Methods --- p.34 / Chapter 3.1 --- Chemical Materials --- p.34 / Chapter 3.1.1 --- Enzymes --- p.34 / Chapter 3.1.2 --- DNA Markers --- p.34 / Chapter 3.1.3 --- Reagent Kits --- p.34 / Chapter 3.1.4 --- Primers for Polymerase Chain Reaction --- p.35 / Chapter 3.1.5 --- Chemical Reagents --- p.35 / Chapter 3.1.6 --- Nylon Membranes --- p.36 / Chapter 3.1.7 --- Radioisotopes --- p.36 / Chapter 3.1.8 --- Buffers and Solutions --- p.36 / Chapter 3.2 --- Clinical Materials --- p.38 / Chapter 3.2.1 --- Control Subjects --- p.38 / Chapter 3.2.2 --- Fragile X Patients --- p.39 / Chapter 3.2.3 --- Mentally Retarded Patients --- p.39 / Chapter 3.3 --- Methods --- p.40 / Chapter 3.3.1 --- Blood Collection --- p.40 / Chapter 3.3.2 --- DNA Isolation --- p.43 / Chapter 3.3.2.1 --- The Salting-out Method --- p.43 / Chapter 3.3.2.2 --- DNA Quantitation --- p.44 / Chapter 3.3.3 --- Labelling of StB12.3 Probe by [α-32P]-dCTP --- p.44 / Chapter 3.3.3.1 --- The Random Priming Method --- p.44 / Chapter 3.3.3.2 --- Purification of Radioactive StB12.3 Probe --- p.45 / Chapter 3.3.3.3 --- Assessment of [α-32P] Incorporation in StB12.3 --- p.45 / Chapter 3.3.4 --- Southern Blot Analysis --- p.46 / Chapter 3.3.4.1 --- Preparation of DNA Fragments --- p.46 / Chapter 3.3.4.2 --- Blotting by Capillary Action --- p.46 / Chapter 3.3.4.3 --- Southern Hybridization --- p.47 / Chapter 3.3.5 --- PCR Amplification and Detection of PCR Products --- p.48 / Chapter 3.3.5.1 --- PCR Amplification --- p.48 / Chapter 3.3.5.2 --- Labelling of (CGG)5 Probe and HpaII Digested pBR322 DNA Marker --- p.49 / Chapter 3.3.5.3 --- Detection of the PCR Products --- p.50 / Chapter Chapter 4 --- Results --- p.52 / Chapter 4.1 --- Amplification of the FMR-1 Gene --- p.52 / Chapter 4.2 --- Analysis of the FRAXA Site by Southern Hybridization --- p.52 / Chapter 4.3 --- Distribution of CGG Repeat Sizes in Normal Unrelated Chinese Subjects in Hong Kong --- p.55 / Chapter 4.4 --- Comparison of CGG Repeat Patterns Among Normal Subjects from Different Parts of China --- p.61 / Chapter 4.5 --- CGG Repeat Pattern in Mildly Mentally Retarded Children in Hong Kong --- p.65 / Chapter 4.6 --- Investigation of Suspected Fragile X Families --- p.69 / Chapter Chapter 5 --- Discussions --- p.73 / Chapter 5.1 --- Distribution of CGG Repeats in Normal Chinese Population --- p.73 / Chapter 5.2 --- Overlap Between the Normal and Premutation Alleles --- p.78 / Chapter 5.3 --- CGG Allele Distribution in Mildly MR Patients --- p.79 / Chapter 5.4 --- Molecular Analysis of Fragile X Syndrome Families --- p.80 / Chapter 5.5 --- Somatic Instability of CGG Repeats --- p.82 / Chapter Chapter 6 --- Conclusions --- p.85 / Bibliography --- p.87

Résumé: Mémoire présenté à la Faculté de médecine et des sciences de la santé en vue de l’obtention du diplôme de maître sciences (M.Sc.) en biochimie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4. Le document présent est un mémoire par article, lequel explorera la fonction d'une protéine liant l'ARN, FMRP, dans la différenciation cellulaire. Cette protéine joue un rôle de premier plan puisque son absence conduit à des anomalies développementales durant la neurogenèse et à une plasticité synaptique déficiente. Ces anomalies sont observées chez la souris KO pour le gène FMR1, mais également dans le cerveau des individus avec le syndrome du X fragile (SXF). Ces derniers dont le gène FMR1 est muté présentent une déficience intellectuelle (DI). Puisque la DI est la principale manifestation du SXF, et que les neurones « normaux » expriment FMRP à des niveaux supérieures à ceux des autres tissus corporels, son rôle a presqu'exclusivement été étudié dans les cellules neuronales. Pourtant, FMRP est une protéine hautement conservée et est exprimée dans presque toutes les cellules du corps. Logiquement, FMRP devrait jouer un rôle important dans tous les tissus l’exprimant à des niveaux de base, bien que son absence dans les tissus ne se manifeste pas cliniquement. Cette polyvalence fonctionnelle est encore plus probable de par le fait que plusieurs ARNm différents ont la possibilité d’interagir avec FMRP puisqu’elle identifie ses cibles par reconnaissance de motifs. L'étude présentée se fonde sur l'hypothèse que FMRP effectue des fonctions de base critiques au développement de tous types de tissus humains, et non seulement dans les neurones. L’hypothèse sera davantage développée. Puis, un modèle innovateur de la différenciation cellulaire non-neuronal sera présenté pour l'étude de FMRP. L'enquête sur la distribution subcellulaire et les interactions dynamiques de cette protéine sera détaillée durant les différents changements morphologiques de la spécialisation et de la maturation cellulaire. Les résultats des expériences seront analysés en profondeur. Puis, un retour sur l'hypothèse en guise des résultats expérimentaux permettra de constater que FMRP semble bien jouer un rôle durant la différenciation cellulaire non-neuronale. Ce rôle est intimement lié à la réorganisation du cytosquelette et à la synthèse protéique locale, régulée dans les complexes mRNPs composés de FMRP et ses cibles d'ARNm qui sont régulés, stabilisés et transportés vers les régions en maturation. Ultimement, plusieurs éléments indiquent que FMRP doit interagir correctement avec de nombreuses molécules, décrites dans ce mémoire, afin de permettre aux cellules de se spécialiser et d'acquérir les caractéristiques désirées au cours d’une différenciation normale. / Abstract: The present article-based memoire will explore the involvement of an important RNA-binding protein, FMRP, in cellular differentiation. This protein is well-known for the developmental anomalies during neurogenesis as well as the loss of synaptic plasticity which occur when its gene, FMR1, is mutated. Since FMRP expression is most pronounced in neurons and because the absence of its expression results in the intellectual deficiency known as the Fragile X Syndrome, FMRP has nearly always been studied in neurons alone. However, FM RP is a highly conserved protein, expressed ubiquitously across the body. Additionally, its influence in cells can be vast since its motif - based RNA recognition renders it capable of binding a variety of transcripts. Logically speaking, FMRP should play a role of first rate importance in the other tissues where it is present. The clinical manifestation of its impact in those tissues is likely to be lessened only by the lower levels of FMRP expressed in the average human cell. The main hypothesis of the current study is that FMRP performs critical but basic functions involved in the development of all human tissues where it is present at basal levels, rather than exerting an impact limited to the nervous system alone. The hypothesis will be further elaborated. An innovative non-neuronal model will be presented for the study of FMRP throughout the differentiation process. The behaviour and dynamic interactions of FMRP during cell specialization and morphological maturation will be investigated. An in-depth analysis of the experimental results will follow. Returning to the hypothesis of the study with these results at hand, it will be concluded that FMRP does indeed appear to play a major role in the differentiation of non-neuronal cells. In fact, FMRP's function seems to be closely linked to cytoskeletal reorganization, as well as local protein synthesis through the formation of mRNP complexes with its target mRNAs, which are stabilized, regulated and transported towards the active areas of the cell in differentiation. Ultimately, it is clear that proper interaction between FMRP and certain types of molecules, described in this memoire, is required for cells to specialize and acquire the characteristics of mature cells through normal differentiation.

Reduced activity of Fragile X mental retardation protein (FMRP) in brain neurons results in the most common form of heritable mental retardation in humans, Fragile X Syndrome (FXS). FMRP is a selective RNA-binding protein that is implicated in the translational regulation of specific mRNAs in neurons. Although very few direct targets of FMRP have been identified and verified in vivo, FXS is thought to result from the aberrant regulation of potentially hundreds of mRNAs causing defects in neuron morphology and synapse function. Identifying additional targets will be important for elucidating the mechanism of FMRP regulation as well as the etiology of FXS. Drosophila melanogaster offers a unique and powerful system for studying the function of FMRP. Flies with loss of FMRP activity have neuronal and behavioral defects similar to those observed in humans with FXS. Importantly, FMRP regulates common target mRNAs in neurons in both mice and flies. Here, I will describe our discovery of a previously unknown requirement for Drosophila FMRP (dFMRP) during the cleavage stage of early embryonic development. First, we identified a requirement for dFMRP for proper cleavage furrow formation and found that dFMRP functions to regulate the expression of specific target mRNAs during the cleavage stage. Among these is trailer hitch (tral) mRNA, which encodes a translational regulator as well, and represents a new in vivo target of dFMRP translational regulation. In addition, I have identified twenty-eight proteins that change in expression in the absence of dFMRP using a comparative proteomics based screen for dFMRP targets. One of these is the Chaperonin containing tcp-1 complex (CCT), a previously unidentified target, which I found is itself also required for cleavage furrow formation. Finally, we have identified a new dFMRP protein-binding partner, Caprin, and found that together dFMRP and Caprin are required for the proper timing of the MBT. This set of work has led to a better understanding of the mechanism of dFMRP-dependent regulation of cellular morphogenesis in early embryos and has the potential to lead to a better understanding of the etiology of FXS. / text

The prevalence of Autism Spectrum Disorder (ASD) and its defining features has been increasingly investigated in genetic syndromes associated with intellectual disability, with syndrome specific profiles reported. The experience of catatonia and other movement disorders in people with ASD has been increasing highlighted within both research and diagnostic guidelines. However, these issues have not typically been investigated alongside other features of ASD within research into genetic syndromes. The first paper in this thesis provides a review of the literature on movement disorders in genetic syndromes associated with ASD, which focuses on the prevalence of reported movement disorders, the methods of assessment used, and the quality of research to date. An empirical study is reported in Paper 2. Within a cohort of individuals with Cornelia de Lange and Fragile X syndromes the prevalence of attenuated behaviour [autistic catatonia] is examined, based on parent/carer report, and the extent to which features of ASD predict later attenuated behaviour is investigated. Paper 3 provides a critical reflection on the first two papers as well as some wider considerations on undertaking research in this area. The results of both the literature review and the empirical study indicated that across a number of genetic syndromes (Angelman syndrome, Cornelia de Lange syndrome, Fragile X syndrome and Rett syndrome) attenuated behaviour [autistic catatonia] and/or movement disorders affect a substantial proportion of individuals. Furthermore, repetitive behaviours, one of the characteristic features of ASD, appear to predict later attenuated behaviour in Cornelia de Lange and Fragile X syndromesThe results presented in this thesis have important implications for the way services support individuals with specific genetic syndromes. Paper 1 confirms the high prevalence of movement problems in Angelman and Rett syndromes, and Paper 2 provides a new insight into movement problems in Cornelia de Lange and Fragile X syndromes. Movement disorders are reported to impact negatively on wellbeing and quality of life in people with ASD, and are likely to have a similar impact on the lives of people with genetic syndromes. Greater awareness and recognition of movement problems in CdLS and FXS is required, and although specialist services may already be aware of some of the above issues, there should be an increased emphasis on ensuring that community services are aware of the needs of individuals with genetic syndromes, including the implications of movement problems for support needs and quality of life.

Raising a child with a pervasive developmental disorder (PDD), particularly that of Fragile X Syndrome (FXS), is challenging, as it comes with parental stressors for both mothers and fathers. Research on these stressors has been limited to only the stressors that mothers of children with a PDD experience and has failed to thoroughly examine the experiences and stressors of fathers of children with a PDD, particularly that of FXS. Using Hill's ABC-X family stress theory, this quantitative research study investigated the effects of marital satisfaction due to the amount of shared childcare responsibilities and parental stress among the mothers and fathers of children diagnosed with FXS. This study also examined whether significant differences exist among these parents, who were recruited through the use of flyers, notices, and handouts that were randomly passed out to parents at the FXS Alliance of Texas located in the southwest region of Texas. Participants for this study were 128 parents of children with FXS, each of whom completed a demographic questionnaire, the Kansas Marital Satisfaction Scale, and The Sharing of Childcare Responsibilities Scale and Parental Stress Level Scale. An independent samples t test and multiple linear regression statistical analysis was employed. The results of the study indicated that parental stress associated with the amount of shared childcare responsibilities accounted for a significant degree of the variance in marital satisfaction. Yet the study did not find a significant mean difference in the level of parental stress that was experienced uniquely across gender. Potential social changes may include future development and improvements in treatment, therapeutic approaches, and predicted outcomes in efforts to enhance parental stress interventions so as to improve stress-related outcomes for parents of children with FXS.