Browsing by Author "Hagerman, Randi (7006679292)"

There is increasing recognition of the heterogeneity of origin of cases of autism spectrum disorder (ASD) with multiple forms of ASD having been identified over the decades. Among these, a genetic etiology can be identified in 20–40% of cases when a full genetic work-up is completed. The Fragile X premutation state (characterized by the presence of 55–200 CGG repeats in the FMR1 gene) is a relatively newly identified disease state that has since been associated with several disorders including fragile X-associated tremor ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI) and most recently, fragile X-associated neurodevelopmental disorders (FXAND) which commonly includes anxiety and depression. In addition to these associated disorders, extant literature and clinical observations have suggested an association between the premutation state and ASD. In this paper, we review the literature pertinent to this and discuss possible molecular mechanisms that may explain this association. This includes lowered levels of the FMR1 Protein (FMRP), GABA deficits, mitochondrial dysfunction and secondary genetic abnormalities that is seen in premutation carriers as well as their increased vulnerability to environmental stressors. Understanding these mechanisms can facilitate development of targeted treatment for specific sub-groups of ASD and premutation disorders in future. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.

There is increasing recognition of the heterogeneity of origin of cases of autism spectrum disorder (ASD) with multiple forms of ASD having been identified over the decades. Among these, a genetic etiology can be identified in 20–40% of cases when a full genetic work-up is completed. The Fragile X premutation state (characterized by the presence of 55–200 CGG repeats in the FMR1 gene) is a relatively newly identified disease state that has since been associated with several disorders including fragile X-associated tremor ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI) and most recently, fragile X-associated neurodevelopmental disorders (FXAND) which commonly includes anxiety and depression. In addition to these associated disorders, extant literature and clinical observations have suggested an association between the premutation state and ASD. In this paper, we review the literature pertinent to this and discuss possible molecular mechanisms that may explain this association. This includes lowered levels of the FMR1 Protein (FMRP), GABA deficits, mitochondrial dysfunction and secondary genetic abnormalities that is seen in premutation carriers as well as their increased vulnerability to environmental stressors. Understanding these mechanisms can facilitate development of targeted treatment for specific sub-groups of ASD and premutation disorders in future. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.

Fragile X syndrome (FXS) is a global neurodevelopmental disorder caused by the expansion of CGG trinucleotide repeats (≥200) in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene. FXS is the hallmark of Fragile X-associated disorders (FXD) and the most common monogenic cause of inherited intellectual disability and autism spectrum disorder. There are several animal models used to study FXS. In the FXS model of Drosophila, the only ortholog of FMR1, dfmr1, is mutated so that its protein is missing. This model has several relevant phenotypes, including defects in the circadian output pathway, sleep problems, memory deficits in the conditioned courtship and olfactory conditioning paradigms, deficits in social interaction, and deficits in neuronal development. In addition to FXS, a model of another FXD, Fragile X-associated tremor/ataxia syndrome (FXTAS), has also been established in Drosophila. This review summarizes many years of research on FXD in Drosophila models. © 2022 by the authors.

Fragile X syndrome (FXS) is a global neurodevelopmental disorder caused by the expansion of CGG trinucleotide repeats (≥200) in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene. FXS is the hallmark of Fragile X-associated disorders (FXD) and the most common monogenic cause of inherited intellectual disability and autism spectrum disorder. There are several animal models used to study FXS. In the FXS model of Drosophila, the only ortholog of FMR1, dfmr1, is mutated so that its protein is missing. This model has several relevant phenotypes, including defects in the circadian output pathway, sleep problems, memory deficits in the conditioned courtship and olfactory conditioning paradigms, deficits in social interaction, and deficits in neuronal development. In addition to FXS, a model of another FXD, Fragile X-associated tremor/ataxia syndrome (FXTAS), has also been established in Drosophila. This review summarizes many years of research on FXD in Drosophila models. © 2022 by the authors.

Background: The fragile X premutation carrier state (PM) (55–200 CGG repeats in the fragile X messenger ribonucleoprotein 1, FMR1 gene) is associated with several conditions, including fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor ataxia (FXTAS), with current literature largely primarily investigating older PM individuals. The aim of this study was to identify the prevalence of fragile X-associated neurodevelopmental disorders (FXAND) in a sample of young PM individuals. Methods: This was a retrospective study conducted through a medical record review of PM individuals who were seen either for clinical concerns (probands, 45.9%) or identified through the cascade testing (non-probands, 54.1%) of an affected sibling with fragile X syndrome. Information on the presence of autism spectrum disorder, attention deficit hyperactivity disorder, anxiety, depression, long-term psychiatric medication intake, and cognitive function, based on standardized assessments, was obtained. Molecular data, including CGG repeat number and FMR1 mRNA levels, were also available for a subset of participants. Analysis included descriptive statistics and a test of comparison to describe the clinical profile of PM individuals pertinent to FXAND. Results: Participants included 61 individuals (52 males and 9 females) aged 7.8 to 20.0 years (mean 12.6 ± 3.4) with a mean full-scale IQ of 90.9 ± 22.7. The majority (N = 52; 85.2%) had at least one mental health disorder, with anxiety being the most common (82.0% of subjects), followed by ADHD (66.5%), and ASD (32.8%). Twenty-seven (87.1%) of non-probands also had at least one mental health condition, with probands having lower cognitive and adaptive skills than non-probands. ASD was present in 20 participants (17/52 males and 3/9 females; 15 probands) with significantly lower FSIQ in those with ASD (mean 73.5 vs. 98.0, p < 0.001). Participants with ASD had a higher number of long-term medications compared to those without (2.32 vs. 1.3, p = 0.002). Conclusions: Our findings indicate a high rate of FXAND diagnoses within a cohort of young PM individuals, including those identified via cascade testing, although this was not a population sample. An awareness of the entity of FXAND and the early recognition of the symptoms of associated conditions may facilitate timely and appropriate care for PM individuals. © 2022 by the authors.

Background: The fragile X premutation carrier state (PM) (55–200 CGG repeats in the fragile X messenger ribonucleoprotein 1, FMR1 gene) is associated with several conditions, including fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor ataxia (FXTAS), with current literature largely primarily investigating older PM individuals. The aim of this study was to identify the prevalence of fragile X-associated neurodevelopmental disorders (FXAND) in a sample of young PM individuals. Methods: This was a retrospective study conducted through a medical record review of PM individuals who were seen either for clinical concerns (probands, 45.9%) or identified through the cascade testing (non-probands, 54.1%) of an affected sibling with fragile X syndrome. Information on the presence of autism spectrum disorder, attention deficit hyperactivity disorder, anxiety, depression, long-term psychiatric medication intake, and cognitive function, based on standardized assessments, was obtained. Molecular data, including CGG repeat number and FMR1 mRNA levels, were also available for a subset of participants. Analysis included descriptive statistics and a test of comparison to describe the clinical profile of PM individuals pertinent to FXAND. Results: Participants included 61 individuals (52 males and 9 females) aged 7.8 to 20.0 years (mean 12.6 ± 3.4) with a mean full-scale IQ of 90.9 ± 22.7. The majority (N = 52; 85.2%) had at least one mental health disorder, with anxiety being the most common (82.0% of subjects), followed by ADHD (66.5%), and ASD (32.8%). Twenty-seven (87.1%) of non-probands also had at least one mental health condition, with probands having lower cognitive and adaptive skills than non-probands. ASD was present in 20 participants (17/52 males and 3/9 females; 15 probands) with significantly lower FSIQ in those with ASD (mean 73.5 vs. 98.0, p < 0.001). Participants with ASD had a higher number of long-term medications compared to those without (2.32 vs. 1.3, p = 0.002). Conclusions: Our findings indicate a high rate of FXAND diagnoses within a cohort of young PM individuals, including those identified via cascade testing, although this was not a population sample. An awareness of the entity of FXAND and the early recognition of the symptoms of associated conditions may facilitate timely and appropriate care for PM individuals. © 2022 by the authors.

Background: Fragile X syndrome, with an approximate incidence rate of 1 in 4000 males to 1 in 8000 females, is the most prevalent genetic cause of heritable intellectual disability and the most common monogenic cause of autism spectrum disorder. The full mutation of the Fragile X Messenger Ribonucleoprotein-1 gene, characterized by an expansion of CGG trinucleotide repeats (>200 CGG repeats), leads to fragile X syndrome. Currently, there are no targeted treatments available for fragile X syndrome. In a recent large multi-site trial, FXLEARN, the effects of the mGluR5 negative allosteric modulator, AFQ056 (mavoglurant), were investigated, but did not show a significant impact of AFQ056 on language development in children with fragile X syndrome aged 3–6 years. Objectives: The current analyses from biospecimens collected in the FXLEARN study aimed to determine whether AFQ056 affects the level of potential biomarkers associated with Akt/mTOR and matrix metalloproteinase 9 signaling in young individuals with fragile X syndrome. Previous research has indicated that these biomarkers play crucial roles in the pathophysiology of fragile X syndrome. Design: A double-blind placebo-controlled parallel-group flexible-dose forced titration design. Methods: Blood samples for biomarkers were collected during the FXLEARN at baseline and subsequent visits (1- and 8-month visits). Biomarker analyses included fragile X messenger ribonucleoprotein-1 genotyping by Southern blot and PCR approaches, fragile X messenger ribonucleoprotein-1 mRNA levels determined by PCR, matrix metalloproteinase 9 levels’ detection using a magnetic bead panel, and targets of the Akt/mTOR signaling pathway with their phosphorylation levels detected. Results: This research revealed that administering AFQ056 does not affect the expression levels of the investigated blood biomarkers in young children with fragile X syndrome. Conclusion: Our findings of the lack of association between clinical improvement and biomarkers’ levels in the treatment group are in line with the lack of benefit observed in the FXLEARN study. These findings indicate that AFQ056 does not provide benefits as assessed by primary or secondary endpoints. Registration: ClincalTrials.gov NCT02920892. © The Author(s) 2024.

Fragile X syndrome is the most common monogenetic cause of inherited intellectual disability and syndromic autism spectrum disorder. Fragile X syndrome is caused by an expansion (full mutation ≥200 CGGs repeats, normal 10-45 CGGs) of the fragile X mental retardation 1 (FMR1) gene, epigenetic silencing of the gene, which leads to reduction or lack of the gene’s product: the fragile X mental retardation protein. In this cross-sectional study, we assessed general and pharmacotherapy knowledge (GK and PTK) of fragile X syndrome and satisfaction with education in neurodevelopmental disorders (NDDs) among senior medical students in Serbia (N=348), Georgia (N=112), and Colombia (N=58). A self-administered 18-item questionnaire included GK (8/18) and PTK (7/18) components and self-assessment of the participants education in NDDs (3/18). Roughly 1 in 5 respondents had correct answers on half or more facts about fragile X syndrome (GK>PTK), which ranged similarly 5-7 in Serbia, 6-8 in Georgia, and 5-8 in Colombia, respectively. No cohort had an average value greater than 9 (60%) that would represent passing score “cut-off.” None of the participants answered all the questions correctly. More than two-thirds of the participants concluded that they gained inadequate knowledge of NDDs during their studies, and that their education in this field should be more intense. In conclusion, there is a major gap in knowledge regarding fragile X syndrome among senior medical students in these three developing countries. The finding could at least in part be generalized to other developing countries aimed toward increasing knowledge and awareness of NDDs and fostering an institutional collaboration between developed and developing countries. © 2021.