Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cognitive and behavioral improvement in adults with fragile X syndrome treated with metformin-two cases.

ABSTRACT:

Background

The majority of individuals with fragile X syndrome (FXS) have intellectual disability, behavioral problems, autism, and language deficits. IQ typically declines with age in boys with the full mutation. The results of preclinical studies demonstrated that metformin, a biguanide used to treat type 2 diabetes, rescues multiple phenotypes of FXS in both Drosophila and mouse models. Preliminary studies of patients with FXS demonstrated improvements in behavior.

Methods

Here, we present two cases of individuals who have been treated with metformin clinically for one year.

Results

Both patients demonstrated significant cognitive and behavioral improvements. They also improved eating habits and normalization of their weight percentiles.

Conclusion

Metformin may be a candidate drug for treatment of several types of symptoms in individuals with FXS.

SUBMITTER: Protic D

PROVIDER: S-EPMC6625129 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Cognitive and behavioral improvement in adults with fragile X syndrome treated with metformin-two cases.

Protic Dragana D Aydin Elber Y EY Tassone Flora F Tan Maria M MM Hagerman Randi J RJ Schneider Andrea A

Molecular genetics & genomic medicine 20190518 7

<h4>Background</h4>The majority of individuals with fragile X syndrome (FXS) have intellectual disability, behavioral problems, autism, and language deficits. IQ typically declines with age in boys with the full mutation. The results of preclinical studies demonstrated that metformin, a biguanide used to treat type 2 diabetes, rescues multiple phenotypes of FXS in both Drosophila and mouse models. Preliminary studies of patients with FXS demonstrated improvements in behavior.<h4>Methods</h4>Here ...[more]

PMID: 31104364

Similar Datasets

Cognitive and behavioral correlates of caudate subregion shape variation in fragile X syndrome.

Project description:Individuals with fragile X syndrome (FXS) exhibit frontal lobe-associated cognitive and behavioral deficits, including impaired general cognitive abilities, perseverative behaviors, and social difficulties. Neural signals related to these functions are communicated through frontostriatal circuits, which connect with distinct regions of the caudate nucleus (CN). Enlargement of the CN is the most robust and reproduced neuroanatomical abnormality in FXS, but very little is known on how this affects behavioral/cognitive outcomes in this condition. Here, we investigated topography within focal regions of the CN associated with prefrontal circuitry and its link with aberrant behavior and intellect in FXS. Imaging data were acquired from 48 individuals with FXS, 28 IQ-matched controls without FXS (IQ-CTL), and 36 typically developing controls (TD-CTL). Of the total participant count, cognitive and behavioral assessment data were obtained from 44 individuals with FXS and 27 participants in the IQ-CTL group. CN volume and topography were compared between groups. Correlations were performed between CN topography and cognitive as well as behavioral measures within FXS and IQ-CTL groups. As expected, the FXS group had larger CN compared with both IQ-CTL and TD-CTL groups. Correlations between focal CN topography and frontal lobe-associated cognitive and behavioral deficits in the FXS group supported the hypothesis that CN enlargement is related to abnormal orbitofrontal-caudate and dorsolateral-caudate circuitry in FXS. These findings deepen our understanding of neuroanatomical mechanisms underlying cognitive-behavioral problems in FXS and hold promise for informing future behavioral and psychopharmacological interventions targeting specific neural pathways.

| S-EPMC6869464 | biostudies-literature

Adaptive, behavioral, and cognitive outcomes in individuals with fragile X syndrome with varying autism severity.

Project description:This study aimed to determine the association between severity of autism spectrum disorder (ASD) and cognitive, behavioral, and molecular measures in individuals with fragile X syndrome (FXS). Study inclusion criteria included individuals with FXS and (1) age 6-40 years, (2) full-scale IQ < 84, and (3) language ≥3-word phrases. ASD symptom severity was determined by Autism Diagnostic Observation Schedule-2 (ADOS-2). Other measures identified non-verbal IQ, adaptive skills, and aberrant behaviors. Molecular measures included blood FMR1 and CYFIP1 mRNA levels, FMRP and MMP9 levels. Analysis of variance (ANOVA) and Spearman's correlations were used to compare ASD severity groups. Data from 54 individuals was included with no/mild (N = 7), moderate (N = 18), and severe (N = 29) ASD. Individuals with high ASD severity had lower adaptive behavior scores (47.48 ± 17.49) than the no/mild group (69.00 ± 20.45, p = 0.0366); they also had more challenging behaviors, lethargy, and stereotypic behaviors. CYFIP1 mRNA expression levels positively correlated with the ADOS-2 comparison score(r2 = 0.33, p = 0.0349), with no significant correlations with other molecular markers. In conclusion, autism symptom severity is associated with more adverse cognitive and adaptive skills and specific behaviors in FXS, whereas CYFIP1 mRNA expression levels may be a potential biomarker for severity of ASD in FXS.

| S-EPMC10868665 | biostudies-literature

Metformin treatment in young children with fragile X syndrome.

Project description:BackgroundMetformin is a drug commonly used in individuals with type 2 diabetes, obesity, and impaired glucose tolerance. It has a strong safety profile in both children and adults. Studies utilizing the Drosophila model and knock out mouse model of fragile X syndrome (FXS) have found metformin to rescue memory, social novelty deficits, and neuroanatomical abnormalities. These studies provided preliminary evidence that metformin could be used as a targeted treatment for the cognitive and behavioral problems associated with FXS. Previously, a case series of children and adults with FXS treated with metformin demonstrated improvements in irritability, social responsiveness, language, and hyperactivity.MethodsHere, we present nine children with FXS between 2 and 7 years of age who were treated clinically with metformin and monitored for behavioral and metabolic changes.ResultsParent reports and developmental testing before and after metformin are presented. There were improvements in language development and behavior (such as lethargy and stereotypy) in most of the patients.ConclusionThese results support the need for a controlled trial of metformin in children with FXS under 7 years old whose brains are in a critical developmental window and thus may experience a greater degree of clinical benefit from metformin.

| S-EPMC6825840 | biostudies-literature

The association between mosaicism type and cognitive and behavioral functioning among males with fragile X syndrome.

Project description:Mosaicism in fragile X syndrome (FXS) refers to two different FMR1 allele variations: size mosaicism represents different numbers of CGG repeats between the two alleles, such that in addition to a full mutation allele there is an allele in the normal or premutation range of CGG repeats, while methylation mosaicism indicates whether a full-mutation allele is fully or partially methylated. The present study explored the association between mosaicism type and cognitive and behavioral functioning in a large sample of males 3 years and older (n = 487) with FXS, participating in the Fragile X Online Registry with Accessible Research Database. Participants with methylation mosaicism were less severely cognitively affected as indicated by a less severe intellectual disability rating, higher intelligence quotient and adaptive behavior score, and lower social impairment score. In contrast, the presence of size mosaicism was not significantly associated with better cognitive and behavioral outcomes than full mutation. Our findings suggest that methylation mosaicism is associated with better cognitive functioning and adaptive behavior and less social impairment. Further research could assess to what extent these cognitive and behavioral differences depend on molecular diagnostic methods and the impact of mosaicism on prognosis of individuals with FXS.

| S-EPMC10948005 | biostudies-literature

Differential cognitive and behavioral development from 6 to 24 months in autism and fragile X syndrome

Project description: Not available

| S-EPMC10953146 | biostudies-literature

Concomitant fragile X-associated tremor ataxia syndrome and Parkinson's disease: a clinicopathological report of two cases.

Project description: Not available

| S-EPMC4516009 | biostudies-literature

Early metformin treatment: An effective approach for targeting fragile X syndrome pathophysiology.

Project description:Fragile X syndrome (FXS) is the most common genetic cause of autism spectrum disorder engendered by transcriptional silencing of the fragile X messenger ribonucleoprotein 1 (FMR1) gene. Given the early onset of behavioral and molecular changes, it is imperative to know the optimal timing for therapeutic intervention. Case reports documented benefits of metformin treatment in FXS children between 2 and 14 y old. In this study, we administered metformin from birth to Fmr1-/y mice which corrected up-regulated mitogen-2 activated protein kinase/extracellular signal-regulated kinase and mammalian/mechanistic target of rapamycin complex 1 signaling pathways and specific synaptic mRNA-binding targets of FMRP. Metformin rescued increased number of calls in ultrasonic vocalization and repetitive behavior in Fmr1-/y mice. Our findings demonstrate that in mice, early-in-life metformin intervention is effective in treating FXS pathophysiology.

| S-EPMC11295030 | biostudies-literature

Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome.

Project description:Recent advances in neurobiology have provided several molecular entrees for targeted treatments for Fragile X syndrome (FXS). However, the efficacy of these treatments has been demonstrated mainly in animal models and has not been consistently predictive of targeted drugs' response in the preponderance of human clinical trials. Because of the heterogeneity of FXS at various levels, including the molecular level, phenotypic manifestation, and drug response, it is critically important to identify biomarkers that can help in patient stratification and prediction of therapeutic efficacy. The primary objective of this study was to assess the ability of molecular biomarkers to predict phenotypic subgroups, symptom severity, and treatment response to metformin in clinically treated patients with FXS. We specifically tested a triplex protein array comprising of hexokinase 1 (HK1), RAS (all isoforms), and Matrix Metalloproteinase 9 (MMP9) that we previously demonstrated were dysregulated in the FXS mouse model and in blood samples from patient with FXS. Seventeen participants with FXS, 12 males and 5 females, treated clinically with metformin were included in this study. The disruption in expression abundance of these proteins was normalized and associated with significant self-reported improvement in clinical phenotypes (CGI-I in addition to BMI) in a subset of participants with FXS. Our preliminary findings suggest that these proteins are of strong molecular relevance to the FXS pathology that could make them useful molecular biomarkers for this syndrome.

| S-EPMC7349631 | biostudies-literature

Targeted therapy of cognitive deficits in fragile X syndrome.

Project description:Breaking an impasse in finding mechanism-based therapies of neuropsychiatric disorders requires a strategic shift towards alleviating individual symptoms. Here we present a symptom and circuit-specific approach to rescue deficits of reward learning in Fmr1 knockout mice, a model of Fragile X syndrome (FXS), the most common monogenetic cause of inherited mental disability and autism. We use high-throughput, ecologically-relevant automated tests of cognition and social behavior to assess effectiveness of the circuit-targeted injections of designer nanoparticles, loaded with TIMP metalloproteinase inhibitor 1 protein (TIMP-1). Further, to investigate the impact of our therapeutic strategy on neuronal plasticity we perform long-term potentiation recordings and high-resolution electron microscopy. We show that central amygdala-targeted delivery of TIMP-1 designer nanoparticles reverses impaired cognition in Fmr1 knockouts, while having no impact on deficits of social behavior, hence corroborating symptom-specificity of the proposed approach. Moreover, we elucidate the neural correlates of the highly specific behavioral rescue by showing that the applied therapeutic intervention restores functional synaptic plasticity and ultrastructure of neurons in the central amygdala. Thus, we present a targeted, symptom-specific and mechanism-based strategy to remedy cognitive deficits in Fragile X syndrome.

| S-EPMC7612812 | biostudies-literature

Mavoglurant in Fragile X Syndrome: Results of two open-label, extension trials in adults and adolescents.

Project description:Fragile X syndrome (FXS) is the most common monogenic cause of inherited intellectual and developmental disabilities. Mavoglurant, a selective metabotropic glutamate receptor subtype-5 antagonist, has shown positive neuronal and behavioral effects in preclinical studies, but failed to demonstrate any behavioral benefits in two 12-week, randomized, placebo-controlled, double-blind, phase IIb studies in adults and adolescents with FXS. Here we report the long-term safety (primary endpoint) and efficacy (secondary endpoint) results of the open-label extensions. Adolescent (n = 119, aged 12-19 years) and adult (n = 148, aged 18-45 years) participants received up to 100 mg bid mavoglurant for up to 34 months. Both extension studies were terminated prematurely due to lack of proven efficacy in the core studies. Mavoglurant was well tolerated with no new safety signal. Five percent of adults and 16.9 percent of adolescents discontinued treatment due to adverse events. Gradual and consistent behavioral improvements as measured by the ABC-CFX scale were observed, which were numerically superior to those seen in the placebo arm of the core studies. These two extension studies confirm the long-term safety of mavoglurant in FXS, but further investigations are required to determine whether and under which conditions the significant preclinical results obtained with mGluR5 inhibition can translate to humans.

| S-EPMC6242849 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data