State-of-the-art therapies for fragile X syndrome.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a full mutation (> 200 CGG repeats) in the FMR1 gene. FXS is the leading cause of inherited intellectual disabilities and the most commonly known genetic cause of autism spectrum disorder. Children with FXS experience behavioral and sleep problems, anxiety, inattention, learning difficulties, and speech and language delays. There are no approved medications for FXS; however, there are several interventions and treatments aimed at managing the symptoms and improving the quality of life of individuals with FXS. A combination of non-pharmacological therapies and pharmacotherapy is currently the most effective treatment for FXS. Currently, several targeted treatments, such as metformin, sertraline, and cannabidiol, can be used by clinicians to treat FXS. Gene therapy is rapidly developing and holds potential as a prospective treatment option. Soon its efficacy and safety in patients with FXS will be demonstrated. WHAT THIS PAPER ADDS: Targeted treatment of fragile X syndrome (FXS) is the best current therapeutic approach. Gene therapy holds potential as a prospective treatment for FXS in the future.

An Update on Psychopharmacological Treatment of Autism Spectrum Disorder.

While behavioral interventions remain the mainstay of treatment of autism spectrum disorder (ASD), several potential targeted treatments addressing the underlying neurophysiology of ASD have emerged in the last few years. These are promising for the potential to, in future, become part of the mainstay treatment in addressing the core symptoms of ASD. Although it is likely that the development of future targeted treatments will be influenced by the underlying heterogeneity in etiology, associated genetic mechanisms influencing ASD are likely to be the first targets of treatments and even gene therapy in the future for ASD. In this article, we provide a review of current psychopharmacological treatment in ASD including those used to address common comorbidities of the condition and upcoming new targeted approaches in autism management. Medications including metformin, arbaclofen, cannabidiol, oxytocin, bumetanide, lovastatin, trofinetide, and dietary supplements including sulforophane and N-acetylcysteine are discussed. Commonly used medications to address the comorbidities associated with ASD including atypical antipsychotics, serotoninergic agents, alpha-2 agonists, and stimulant medications are also reviewed. Targeted treatments in Fragile X syndrome (FXS), the most common genetic disorder leading to ASD, provide a model for new treatments that may be helpful for other forms of ASD.

Impact of FMR1 Premutation on Neurobehavior and Bioenergetics in Young Monozygotic Twins.

Mitochondrial dysfunction (MD) has been identified in lymphocytes, fibroblasts and brain samples from adults carrying a 55-200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene (premutation; PM); however, limited data are available on the bioenergetics of pediatric carriers. Here we discuss a case report of three PM carriers: two monozygotic twins (aged 8 years) harboring an FMR1 allele with 150-180 CGG repeats, with no cognitive or intellectual issues but diagnosed with depression, mood instability and ADHD, and their mother (asymptomatic carrier with 78 CGG repeats). Fibroblasts and lymphocytes from the twins presented a generalized OXPHOS deficit, altered mitochondrial network, accumulation of depolarized mitochondria, and increased mitochondrial ROS production, outcomes distinct and more severe than the mother's ones, suggesting the involvement of modulatory effects mediated by CGG expansion, X-activation ratio, sex hormones and epigenetic factors (chronic inflammation, consequence of Lyme disease). The degree of the severity of MD appeared to segregate with the morbidity of the phenotype. The mitochondrial ROS-mediated HIF-1α stabilization was identified as a key player at contributing to the MD, pointing it as a novel target for future therapeutical intervention.

Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome.

Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABAB receptor agonist. However, none of the trials has been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical trials. FXS is at the forefront of efforts to develop drugs for neurodevelopmental disorders, and lessons learned in the process will also be important for such disorders.

Premutation in the Fragile X Mental Retardation 1 (FMR1) Gene Affects Maternal Zn-milk and Perinatal Brain Bioenergetics and Scaffolding.

Fragile X premutation alleles have 55-200 CGG repeats in the 5' UTR of the FMR1 gene. Altered zinc (Zn) homeostasis has been reported in fibroblasts from >60 years old premutation carriers, in which Zn supplementation significantly restored Zn-dependent mitochondrial protein import/processing and function. Given that mitochondria play a critical role in synaptic transmission, brain function, and cognition, we tested FMRP protein expression, brain bioenergetics, and expression of the Zn-dependent synaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (Shank3) in a knock-in (KI) premutation mouse model with 180 CGG repeats. Mitochondrial outcomes correlated with FMRP protein expression (but not FMR1 gene expression) in KI mice and human fibroblasts from carriers of the pre- and full-mutation. Significant deficits in brain bioenergetics, Zn levels, and Shank3 protein expression were observed in the Zn-rich regions KI hippocampus and cerebellum at PND21, with some of these effects lasting into adulthood (PND210). A strong genotype × age interaction was observed for most of the outcomes tested in hippocampus and cerebellum, whereas in cortex, age played a major role. Given that the most significant effects were observed at the end of the lactation period, we hypothesized that KI milk might have a role at compounding the deleterious effects on the FMR1 genetic background. A higher gene expression of ZnT4 and ZnT6, Zn transporters abundant in brain and lactating mammary glands, was observed in the latter tissue of KI dams. A cross-fostering experiment allowed improving cortex bioenergetics in KI pups nursing on WT milk. Conversely, WT pups nursing on KI milk showed deficits in hippocampus and cerebellum bioenergetics. A highly significant milk type × genotype interaction was observed for all three-brain regions, being cortex the most influenced. Finally, lower milk-Zn levels were recorded in milk from lactating women carrying the premutation as well as other Zn-related outcomes (Zn-dependent alkaline phosphatase activity and lactose biosynthesis-whose limiting step is the Zn-dependent ß-1,4-galactosyltransferase). In premutation carriers, altered Zn homeostasis, brain bioenergetics and Shank3 levels could be compounded by Zn-deficient milk, increasing the risk of developing emotional and neurological/cognitive problems and/or FXTAS later in life.

Emotion potentiated startle in fragile X syndrome.

Social avoidance and anxiety are prevalent in fragile X syndrome (FXS) and are potentially mediated by the amygdala, a brain region critical for social behavior. Unfortunately, functional brain resonance imaging investigation of the amygdala in FXS is limited by the difficulties experienced by intellectually impaired and anxious participants. We investigated the relationship between social avoidance and emotion-potentiated startle, a probe of amygdala activation, in children and adolescents with FXS, developmental disability without FXS (DD), and typical development. Individuals with FXS or DD demonstrated significantly reduced potentiation to fearful faces than a typically developing control group (p < .05). However, among individuals with FXS, social avoidance correlated positively with fearful-face potentiation (p < .05). This suggests that general intellectual disability blunts amygdalar response, but differential amygdala responsiveness to social stimuli contributes to phenotypic variability among individuals with FXS.

Neural substrates of executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS): a brain potential study.

Executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS) has been suggested to mediate other cognitive impairments. In the present study, event-related potentials and neuropsychological testing were combined to investigate the brain mechanisms underlying the executive dysfunction in FXTAS. Thirty-two-channel electroencephalography was recorded during an auditory "oddball" task requiring dual responses. FXTAS patients (N= 41, mean age= 62) displayed prolonged latencies of N1 and P3 and reduced amplitudes of P2 and P3, whereas their N2 measures remained within the normal range, indicating relatively preserved early-stage auditory attention but markedly impaired late-stage attention and working memory updating processes (as indexed by P3). Topographical mapping revealed a typical parietal P3 peak preceded by a prominent fronto-central P3 in normal control subjects (N= 32), whereas FXTAS patients had decreased parietal P3 amplitude and diminished fronto-central positivities with a delayed onset (∼50 ms later than controls, P < 0.002). The P3 abnormalities were associated with lower executive function test (e.g., BDS-2) scores. Smaller P3 amplitudes also correlated with increased CGG repeat length of fragile X mental retardation 1 (FMR1) gene and higher FMR1 mRNA levels. These results indicate that abnormal fronto-parietal attentional network dynamics underlie executive dysfunction, the cardinal feature of cognitive impairment in FXTAS.

Prepulse inhibition in patients with fragile X-associated tremor ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder that affects carriers of the fragile X premutation, typically after age 50. Common symptoms include intention tremor, ataxia, neuropathy, autonomic dysfunction, cognitive decline, and dementia. The objectives of this study were to determine if patients with FXTAS have altered prepulse inhibition (PPI; a measure of sensorimotor gating), and to study possible correlations between PPI, molecular status, and cognitive performance. A passive acoustic PPI paradigm was applied in 163 subjects; 121 carriers of the fragile X premutation, and 42 healthy controls. There were significant differences in PPI between premutation carriers with FXTAS and controls at PPI 60 ms, and at 120 ms. This effect was more prominent in the male FXTAS patients. There was a tendency to an impaired PPI in female premutation carriers at the 120 ms condition. There was a significant correlation between the PPI deficit and a higher CGG repeat number. The results show an impairment in sensorimotor gating processes in male carriers of the fragile X premutation, which is more prominent in patients with FXTAS.

Prepulse inhibition in fragile X syndrome: feasibility, reliability, and implications for treatment.

Pharmacological rescue of behavioral, cognitive and synaptic abnormalities in the animal models of fragile X syndrome (FXS) has prompted the initiation of clinical trials of targeted treatments in humans with this condition. Objective, well-validated outcome measures that are reflective of FXS deficits and can be modeled similarly in animal and human studies are urgently needed. A protocol measuring prepulse inhibition (PPI) of the startle reflex, including measures of test-retest stability, was evaluated in 61 individuals with the fragile X full mutation (40 males and 21 females; 19.18 +/- 7.18 years) and 63 age-matched normal controls (35 males and 28 females; 20.83 +/- 6.96 years) across two laboratory sites with identical equipment and protocols. Relative to controls, the fragile X group had PPI impairment of 26%, 22%, and 28% for 60, 120, and 240 ms prepulse interval trial types, respectively, P = 0.000002. PPI test-retest reliability in 29 of the participants was excellent for the 120 ms prepulse interval trials (intraclass correlations: FXS, 0.85; controls, 0.88, 0.89 overall). This study demonstrates the feasibility and reliability of PPI measurement in a developmentally disabled population and highlights its potential as an outcome measure to test the efficacy of targeted neurotherapeutic agents.