Fragile X and autism: Intertwined at the molecular level leading to targeted treatments

Fragile X syndrome (FXS) is caused by an expanded CGG repeat (> 200 repeats) in the 5' untranslated portion of the fragile mental retardation 1 gene (FMR1), leading to deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA carrier protein that controls the translation of several other genes that regulate synaptic development and plasticity. Autism occurs in approximately 30% of FXS cases, and pervasive developmental disorder, not otherwise specified (PDD-NOS) occurs in an additional 30% of cases. Premutation repeat expansions (55 to 200 CGG repeats) may also give rise to autism spectrum disorders (ASD), including both autism and PDD-NOS, through a different molecular mechanism that involves a direct toxic effect of the expanded CGG repeat FMR1 mRNA. RNA toxicity can also lead to aging effects including tremor, ataxia and cognitive decline, termed fragile X-associated tremor ataxia syndrome (FXTAS), in premutation carriers in late life. In studies of mice bearing premutation expansions, there is evidence of early postnatal neuronal cell toxicity, presenting as reduced cell longevity, decreased dendritic arborization and altered synaptic morphology. There is also evidence of mitochondrial dysfunction in premutation carriers. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in autism without fragile X mutations. Research regarding dysregulation of neurotransmitter systems in FXS, including the metabotropic glutamate receptor (mGluR)1/5 pathway and γ aminobutyric acid (GABA)A pathways, have led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism

Treatment of Fragile X Syndrome with Cannabidiol: A Case Series Study and Brief Review of the Literature.

Fragile X syndrome (FXS) is an X-linked dominant disorder caused by a mutation in the fragile X mental retardation 1 gene. Cannabidiol (CBD) is an exogenous phytocannabinoid with therapeutic potential for individuals with anxiety, poor sleep, and cognitive deficits, as well as populations with endocannabinoid deficiencies, such as those who suffer from FXS. The objective of this study was to provide a brief narrative review of recent literature on endocannabinoids and FXS and to present a case series describing three patients with FXS who were treated with oral CBD-enriched (CBD+) solutions. We review recent animal and human studies of endocannabinoids in FXS and present the cases of one child and two adults with FXS who were treated with various oral botanical CBD+ solutions delivering doses of 32.0 to 63.9 mg daily. Multiple experimental and clinical models of FXS combine to highlight the therapeutic potential of CBD for management of FXS. All three patients described in the case series exhibited functional benefit following the use of oral CBD+ solutions, including noticeable reductions in social avoidance and anxiety, as well as improvements in sleep, feeding, motor coordination, language skills, anxiety, and sensory processing. Two of the described patients exhibited a reemergence of a number of FXS symptoms following cessation of CBD+ treatment (e.g., anxiety), which then improved again after reintroduction of CBD+ treatment. Findings highlight the importance of exploring the therapeutic potential of CBD within the context of rigorous clinical trials

Modulation of the GABAergic pathway for the treatment of fragile X syndrome.

Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further studies are needed to determine the safety and efficacy of GABAergic treatments for FXS

Plasma Biomarkers for Monitoring Brain Pathophysiology in FMR1 Premutation Carriers.

Premutation carriers have a 55-200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene. Currently, 1.5 million individuals are affected in the United States, and carriers are at risk of developing the late-onset neurodegenerative disorder Fragile X-associated tremor ataxia syndrome (FXTAS). Limited efforts have been made to develop new methods for improved early patient monitoring, treatment response, and disease progression. To this end, plasma metabolomic phenotyping was obtained for 23 premutation carriers and 16 age- and sex-matched controls. Three biomarkers, phenylethylamine normalized by either aconitate or isocitrate and oleamide normalized by isocitrate, exhibited excellent model performance. The lower phenylethylamine and oleamide plasma levels in carriers may indicate, respectively, incipient nigrostriatal degeneration and higher incidence of substance abuse, anxiety and sleep disturbances. Higher levels of citrate, isocitrate, aconitate, and lactate may reflect deficits in both bioenergetics and neurotransmitter metabolism (Glu, GABA). This study lays important groundwork by defining the potential utility of plasma metabolic profiling to monitor brain pathophysiology in carriers before and during the progression of FXTAS, treatment efficacy and evaluation of side effects

Developmental aspects of FXAND in a man with the FMR1 premutation.

BackgroundFragile X mental retardation 1 (FMR1) premutation can cause developmental problems including autism spectrum disorder (ASD), social anxiety, depression, and attention deficit hyperactivity disorder (ADHD). These problems fall under an umbrella term of Fragile X-associated Neuropsychiatric Disorders (FXAND) and is separate from Fragile X-associated Tremor/Ataxia syndrome (FXTAS), a neurodegenerative disorder.Methods/clinical caseA 26-year-old Caucasian male with the Fragile X premutation who presented with multiple behavior and emotional problems including depression and anxiety at 10 years of age. He was evaluated at 13, 18, and 26 years old with age-appropriate cognitive assessments, psychiatric evaluations, and an MRI of the brain.ResultsThe Autism Diagnostic Observation Scale (ADOS) was done at 13 years old and showed the patient has autism spectrum disorder (ASD). An evaluation at 18 years old showed a full-scale IQ of 64. A Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) performed at 26 years old confirmed the previous impression of social anxiety disorder, agoraphobia disorder, and selective mutism. His MRI acquired at 26 years old showed enlarged ventricles, increased frontal subarachnoid spaces, and hypergyrification.ConclusionThis is an exemplary case of an FMR1 premutation carrier with significant psychiatric and cognitive issues that demonstrates Fragile X-associated Neuropsychiatric Disorders (FXAND) as separate from the other well-known premutation disorders

Early intervention combined with targeted treatment promotes cognitive and behavioral improvements in young children with fragile x syndrome.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability due to an expansion in the full mutation range (>200 CGG repeats) of the promoter region of the FMR1 gene leading to gene silencing. Lack of FMRP, a critical protein for dendritic spine formation and maturation, will cause FXS. Early environmental enrichment combined with pharmacological intervention has been proven to rescue dendritic spine abnormalities in the animal model of FXS. Here we report on 2 young children with FXS who were treated early with a combination of targeted treatment and intensive educational interventions leading to improvement in their cognition and behavior and a normal IQ

Modulation of the GABAergic pathway for the treatment of fragile X syndrome

Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further studies are needed to determine the safety and efficacy of GABAergic treatments for FXS

Rift Valley Fever: An Economic Assessment of Agricultural and Human Vulnerability

This research focused on the assessment of the U.S. agricultural sector and human vulnerability to a Rift Valley Fever (RVF) outbreak and the implications of a select set of alternative disease control strategies. Livestock impact assessment is done by using an integrated epidemic/economic model to examine the extent of RVF spread in the Southeast Texas livestock population and its consequences plus the outcome of implementing two different control strategies: emergency vaccination and larvicide vector control separately plus when they are used simultaneously. Human impact assessment utilized an inferential procedure, which comprises of a cost of illness calculation to assess the dollar cost of human illnesses and deaths, as well as a Disability Adjusted Life Year calculation to give an estimate of the burden of disease on public health as a whole. Results indicate substantial potential losses to the U.S., where combined livestock and human national costs ranged from $121 million to$2.3 billion.Rift Valley Fever, Outbreak, Welfare, Vaccination, Larvicide., Environmental Economics and Policy, Food Consumption/Nutrition/Food Safety, Food Security and Poverty, Health Economics and Policy,

Effects of Sertraline Treatment for Young Children with FXS

Phenotypic manifestations for young children with fragile X syndrome (FXS) include: anxiety, sensory processing challenges, global language and communication deficits and intellectual and developmental disabilities. Many of these symptoms can be treated with medications, including selective serotonin reuptake inhibitors (SSRIs). However to date a clinical trial has not been conducted for children under five years old. This study investigated the following question: Are there group differences on developmental outcome measures for those children treated with sertraline compared to placebo