scholarly journals Consumption of Breast Milk Is Associated with Decreased Prevalence of Autism in Fragile X Syndrome

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1785
Author(s):  
Cara J. Westmark
Keyword(s):  
Breast Milk ◽  
Fragile X Syndrome ◽  
Study Design ◽  
Early Life ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Research Database ◽  
Retrospective Survey ◽  
Fold Reduction

Breastfeeding is associated with numerous health benefits, but early life nutrition has not been specifically studied in the neurodevelopmental disorder fragile X syndrome (FXS). Herein, I evaluate associations between the consumption of breast milk during infancy and the prevalence of autism, allergies, diabetes, gastrointestinal (GI) problems and seizures in FXS. The study design was a retrospective survey of families enrolled in the Fragile X Online Registry and Accessible Research Database (FORWARD). There was a 1.7-fold reduction in the prevalence of autism in FXS participants who were fed breast milk for 12 months or longer. There were strong negative correlations between increased time the infant was fed breast milk and the prevalence of autism and seizures and moderate negative correlations with the prevalence of GI problems and allergies. However, participants reporting GI problems or allergies commenced these comorbidities significantly earlier than those not fed breast milk. Parsing the data by sex indicated that males exclusively fed breast milk exhibited decreased prevalence of GI problems and allergies. These data suggest that long-term or exclusive use of breast milk is associated with reduced prevalence of key comorbidities in FXS, although breast milk is associated with the earlier development of GI problems and allergies.

scholarly journals Consumption of Breast Milk Is Associated With Decreased Prevalence of Autism in Fragile X Syndrome

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 930-930
Author(s):  
Cara Westmark
Keyword(s):  
Breast Milk ◽  
Fragile X Syndrome ◽  
Early Life ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Research Database ◽  
Retrospective Survey ◽  
Funding Sources ◽  
Fold Reduction

Abstract Objectives Breastfeeding is associated with numerous health benefits in infants, but early life nutrition has not been specifically studied in the neurodevelopmental disorder fragile X syndrome (FXS). Herein, we evaluate associations between the consumption of breast milk during infancy and the prevalence of autism, allergies, diabetes, gastrointestinal (GI) problems and seizures in participants with FXS. Methods The study design was a retrospective survey of families enrolled in the Fragile X Online Registry and Accessible Research Database (FORWARD). Results There was a 73% rate of breastfeeding in the enrolled participants with an 81% rate for at least 3 months, 73% for 6 months and 41% for 12 months of age or longer. There was a 1.7-fold reduction in the prevalence of autism in participants with FXS who were fed breast milk for 12 months or longer and a 1.9-fold decrease in autism in participants reporting no use of any infant formula (P < 0.05). The most common reasons for cessation of breastfeeding were reduced milk production and age of the child. There were strong negative correlations between increased time the infant with FXS was fed breast milk and the prevalence of autism and seizures and moderate negative correlations with the prevalence of GI problems and allergies. However, participants reporting GI problems or allergies commenced these comorbidities significantly earlier than participants that were not fed breast milk. Parsing the data by sex indicated that males exclusively fed breast milk exhibited decreased prevalence of GI problems and allergies. Conclusions These data suggest that long-term or exclusive use of breast milk is associated with reduced prevalence of key comorbidities in FXS including autism, GI problems and allergies, although breast milk is associated with the earlier development of GI problems and allergies. Funding Sources NICHD.

scholarly journals Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in fragile X syndrome

2019 ◽  
Author(s):  
Kagistia Hana Utami ◽  
Niels H. Skotte ◽  
Ana R. Colaço ◽  
Nur Amirah Binte Mohammad Yusof ◽  
Bernice Sim ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Embryonic Stem ◽  
Neural Progenitor Cell ◽  
Integrative Analysis ◽  
Network Activity ◽  
Neural Cells ◽  
Molecular Signatures ◽  
Neurodevelopmental Abnormalities

AbstractFragile X syndrome (FXS) is an incurable neurodevelopmental disorder with no effective treatment. FXS is caused by epigenetic silencing ofFMR1and loss of FMRP expression. To investigate the consequences of FMRP deficiency in the context of human physiology, we established isogenicFMR1knockout (FMR1KO) human embryonic stem cells (hESCs). Integrative analysis of the transcriptomic and proteomic profiles of hESC-derived FMRP-deficient neurons revealed several dysregulated pathways important for brain development including processes related to axon development, neurotransmission, and the cell cycle. We functionally validated alterations in a number of these pathways, showing abnormal neural rosette formation and increased neural progenitor cell proliferation inFMR1KO cells. We further demonstrated neurite outgrowth and branching deficits along with impaired electrophysiological network activity in FMRP-deficient neurons. Using isogenicFMR1KO hESC-derived neurons, we reveal key molecular signatures and neurodevelopmental abnormalities arising from loss of FMRP. We anticipate that theFMR1KO hESCs and the neuronal transcriptome and proteome datasets will provide a platform to delineate the pathophysiology of FXS in human neural cells.

scholarly journals Impaired inhibitory control of cortical synchronization in fragile X syndrome

2011 ◽  
Vol 106 (5) ◽  
pp. 2264-2272 ◽  
Author(s):  
Scott M. Paluszkiewicz ◽  
Jose Luis Olmos-Serrano ◽  
Joshua G. Corbin ◽  
Molly M. Huntsman
Keyword(s):  
Fragile X Syndrome ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Synaptic Inhibition ◽  
Cortical Interneuron ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Functional Defect

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by severe cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes contributes to these deficits. In this study we show specific inhibitory circuit dysfunction in layer II/III of somatosensory cortex of Fmr1 KO mice. We demonstrate reduced activation of somatostatin-expressing low-threshold-spiking (LTS) interneurons in response to the group I metabotropic glutamate receptor (mGluR) agonist 3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice, resulting in impaired synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, indicating a weakened LTS interneuron network in Fmr1 KO mice. Together, these findings reveal a functional defect in a single subtype of cortical interneuron in Fmr1 KO mice. This defect is linked to altered activity of the cortical network in line with the FXS phenotype.

scholarly journals Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Carlo Brighi ◽  
Federico Salaris ◽  
Alessandro Soloperto ◽  
Federica Cordella ◽  
Silvia Ghirga ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Cortical Neurons ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Functional Characterization ◽  
Model Systems ◽  
Network Activity ◽  
Knock Out ◽  
2D And 3D

AbstractFragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models; however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show an increased number of GFAP positive cells, likely astrocytes, increased spontaneous network activity, and depolarizing GABAergic transmission. Cortical brain organoid models show an increased number of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.

scholarly journals An “Omic” Overview of Fragile X Syndrome

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 433
Author(s):  
Olivier Dionne ◽  
François Corbin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Medical Problems ◽  
Biochemical Alterations ◽  
Fragile X Mental Retardation ◽  
Wide Range

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with a wide range of cognitive, behavioral and medical problems. It arises from the silencing of the fragile X mental retardation 1 (FMR1) gene and, consequently, in the absence of its encoded protein, FMRP (fragile X mental retardation protein). FMRP is a ubiquitously expressed and multifunctional RNA-binding protein, primarily considered as a translational regulator. Pre-clinical studies of the past two decades have therefore focused on this function to relate FMRP’s absence to the molecular mechanisms underlying FXS physiopathology. Based on these data, successful pharmacological strategies were developed to rescue fragile X phenotype in animal models. Unfortunately, these results did not translate into humans as clinical trials using same therapeutic approaches did not reach the expected outcomes. These failures highlight the need to put into perspective the different functions of FMRP in order to get a more comprehensive understanding of FXS pathophysiology. This work presents a review of FMRP’s involvement on noteworthy molecular mechanisms that may ultimately contribute to various biochemical alterations composing the fragile X phenotype.

Abnormal neurogensis in the hippocampus of a mouse model of fragile X syndromes

2007 ◽  
Vol 30 (4) ◽  
pp. 80
Author(s):  
B Eadie ◽  
B Christie
Keyword(s):  
Mouse Model ◽  
Learning And Memory ◽  
Fragile X Syndrome ◽  
Knockout Mice ◽  
Fragile X ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Fmr1 Gene ◽  
Learning Impairment

Fragile X syndrome is the most common inherited form of mental retardation. It is a neurodevelopmental disorder that is similar in clinical presentation to autism spectrum disorder. However, unlike autism, Fragile X syndrome is caused by the silencing of a single gene, and in recent years, a mouse model of Fragile X syndrome has been generated by deletion of the Fmr1 gene. Surprisingly, a clear neurobiological basis for the learning impairment observed in both these knockout mice and patients has been difficult to elucidate. We hypothesized that neurogenesis, a process that continues into adulthood in the hippocampus, may be abnormal in this syndrome. Support for such a hypothesis comes from the findings that these new neurons may disproportionately contribute to synaptic plasticity in networks engaged during learning and memory. We have shown that the survival of new cells in the hippocampus of young Fmr1 knockout mice is significantly decreased in the ventral hippocampus, a sub-region which may be more involved with emotional, rather than, spatial memory. Further experiments are being conducted to assess the differentiation of these new cells into neurons and glia. We are also characterizing the normal expression of the Fmr1 gene product, FMRP, across the phases of neurogenesis in control mice. In conclusion, we have discovered a clear impairment in a process that may be critical to emotionally-significant learning and memory in a mouse model of Fragile X syndrome.

scholarly journals Fragile X syndrome: Lessons learned from the most translated neurodevelopmental disorder in clinical trials

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Phan Q. Duy ◽  
Dejan B. Budimirovic
Keyword(s):  
Clinical Trials ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Full Range ◽  
Autism Spectrum ◽  
Lessons Learned ◽  
Success Story ◽  
Negative Results ◽  
Neural Signaling

AbstractFragile X syndrome (FXS) is the leading genetic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID) worldwide. Preclinical successes in understanding the biology of FXS have led to numerous translational attempts in human clinical trials of therapeutics that target the excitatory/inhibitory neural signaling imbalances thought to underlie FXS. Despite the preclinical success story, the negative results of the human clinical trials have been deemed to be at least in part disappointing by the field. In this commentary, we contend that such negative studies results in clinical trials may actually propel the FXS field forward by serving as important lessons for designing and implementing improved future clinical trials such that can objectively assess the full range of responses to new therapeutics.

scholarly journals Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models

2016 ◽  
Vol 10 ◽  
Author(s):  
Catherine H. Choi ◽  
Brian P. Schoenfeld ◽  
Aaron J. Bell ◽  
Joseph Hinchey ◽  
Cory Rosenfelt ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Camp Signaling ◽  
Multiple Drug ◽  
Long Term Memory ◽  
Term Memory ◽  
Drug Treatments
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