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

Abstract

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.

Graphical Abstract

Fragile X syndrome (FXS) is caused by a full mutation (> 200 CGG repeats) in the FMR1 gene, which is located on chromosome Xq27.3. In the FMR1 gene, the normal range of CGG trinucleotide repeats ranges from 5 to 44; the gene encodes the FMR1 protein (FMRP).¹ FMRP has a multifaceted role and it is crucial for neurological development and functioning. FMRP binds to ribosomes and oversees the translation of messenger RNA (mRNA), which is integral to the formation of neuronal synapses.^2-4 Investigations have underscored FMRP’s role as an ‘immediate early protein’ at synapses, orchestrating aspects of synaptic development and adaptability.^5,6 Furthermore, FMRP regulates RNA stability and transport within cells,⁷ while also forming connections with several ion channels to modulate their activity.^2,8 The expanded CGG triplet repeats in the fully mutated FMR1 gene are hypermethylated with consequent transcriptional gene silencing, which results in a reduction or absence of FMRP in individuals with FXS.⁹ However, a recent study revealed that this is not always true. Researchers found that some patients with a fully mutated FMR1 gene may produce limited amounts of 217-bp mRNA, which is abnormally spliced; typically, no FMRP is produced.¹⁰ If 217-bp mRNA is eliminated using an antisense oligonucleotide (ASO), then the FMR1 gene starts producing normal levels of full-length FMR1 mRNA and subsequently normal levels of FMRP.¹⁰ This is a paradigm shift in our usual understanding of the molecular basis of FXS and warrants further study; it is a hopeful finding for early gene manipulation using ASOs to treat FXS.

The prevalence of FXS is estimated at 1 in 5000 males and 1 in 8000 females.¹¹ Although the clinical presentation of FXS can vary between the sexes, with females generally exhibiting milder symptoms because of the presence of a second X chromosome, it leads to a range of cognitive, behavioral, and physical challenges. The clinical presentation of FXS can vary widely, but there are common features and characteristics associated with the syndrome. Individuals with FXS exhibit varying levels of intellectual disability depending on how much FMRP is produced.¹² Disabilities can include difficulties in learning and language development. Speech and language development is typically delayed or impaired in individuals with FXS. They might have trouble with speech articulation, using complex language structures, and understanding social communication. The severity of these challenges can range from mild to severe. Individuals with FXS usually show shyness and social or general anxiety. Repetitive behaviors (e.g. hand flapping, repetitive speech, and intense preoccupation with specific objects or interests), sleep problems, and sensitivity to sensory stimuli, such as being overly sensitive to certain sounds, textures, or lights, are frequently observed in individuals with FXS. Attention-deficit/hyperactivity disorder (ADHD) symptoms are also common in FXS. ADHD symptoms include hyperactivity, impulsiveness, and difficulties with sustained attention and focus. Autism spectrum disorder is relatively common in individuals with FXS. Estimates of the prevalence of autism spectrum disorder in individuals with FXS can vary in different studies, but approximately 50% to 60% of males with FXS and 20% of females with FXS also have a co-occurring diagnosis of autism spectrum disorder. In addition, individuals with FXS might have physical features that are characteristic of the syndrome. These features may include a long face, large ears, a prominent jaw or forehead, high palate, joint hypermobility, and macroorchidism at puberty and thereafter.^13,14

Currently, there is no cure for FXS, but there are several interventions and treatments aimed at managing the symptoms and improving the quality of life of individuals with the condition. Treatment for FXS typically involves a combination of non-pharmacological (behavioral) therapies, educational interventions, and symptomatic or targeted pharmacotherapy.¹⁵ Finally, gene therapy is developing and clinical trials are expected to demonstrate its efficacy and safety in humans. This review presents an overview of the treatment strategies available for individuals with FXS.

NON-PHARMACOLOGICAL INTERVENTIONS IN FXS

Early diagnosis and intervention in FXS are crucial. Early interventions and therapies can improve developmental outcomes and provide families with guidance and support. Behavioral and educational interventions are very useful in individuals with FXS.¹⁶ Among others, these interventions include applied behavior analysis and speech and language therapy.^17,18 They can help address challenging behaviors, improve communication skills and language development, and teach social and adaptive skills. Occupational and physical therapy can enhance fine motor skills, sensory processing, and activities of daily living.^18,19 Mindfulness meditation techniques, which may reduce overall psychological symptomatology by emphasizing detached observation and heightened awareness of consciousness content, can serve as a potent cognitive behavioral coping strategy.²⁰ Cognitive behavioral therapy can contribute to high functioning in individuals with FXS by dealing with anxiety, ADHD, social challenges, and depression using individualized therapy.²¹ Tailored educational programs and individualized education plans can provide structured learning environments to accommodate the needs of the individuals.²² Training and support for parents and caregivers can help them learn effective strategies for managing challenging behaviors, promoting communication, and supporting their child’s development.^13,22 Finally, collaboration between health care providers, therapists, educators, and families is essential to develop a comprehensive and effective treatment strategy for individuals with FXS. Early intervention and a supportive environment can significantly improve the outcomes and quality of life of individuals with FXS.¹⁵

PHARMACOTHERAPY IN FXS

Currently, there is no cure for FXS. The aim of pharmacotherapy is to treat ADHD symptoms, anxiety, aggression, and sleep problems.

Selective serotonin reuptake inhibitors

Anxiety is frequently observed in people with FXS, affecting around 70% to 80% of individuals.²³ Selective serotonin reuptake inhibitors, such as sertraline, are highly effective in treating anxiety.^24,25 Selective serotonin reuptake inhibitors work by reducing the reabsorption of serotonin at nerve terminals, leading to increased serotonin levels in the brain. Serotonin has a crucial role in regulating mood in the central nervous system.²⁶ Sertraline can be used to manage anxiety even in young individuals and provides additional benefits, including improved language and motor development, in addition to its anxiety-reducing effects.²⁷ Sertraline is generally well tolerated. In children, there may be occasional activation symptoms, characterized by restlessness and agitation, especially when the medication is rapidly adjusted.^13,27-29

Antipsychotics

In individuals with FXS, particularly during their teenage years, behaviors such as aggression, self-harm, and explosive temper tantrums are often observed. To address these symptoms, medications like risperidone or aripiprazole, which are atypical antipsychotic drugs, can be beneficial.³⁰ These medications work by affecting dopamine and serotonin receptors, although the precise mechanism of action is not completely understood.^31,32 Both medications are generally safe and well tolerated, but they can lead to weight gain. This is crucial to consider when treating individuals with FXS because obesity is prevalent in 30% to 60% of individuals with FXS.^13,29,33

Stimulants

Stimulants are the preferred choice for managing ADHD symptoms in children aged 5 years and older. Stimulants increase the levels of dopamine and norepinephrine in the prefrontal cortex at the neurotransmitter level.³⁴ Both neurotransmitters are helpful in enhancing attention and motivation, and in impulse control. Stimulants are effective in approximately 70% of individuals with ADHD symptoms; they work effectively at similar doses in individuals with FXS as they do in the general population.^35,36 Stimulants are divided into two categories: methylphenidate or amphetamine derivatives. They are generally well tolerated in individuals with FXS, especially those older than 5 years.³⁵ Serious adverse effects, such as palpitations and elevated blood pressure, are rare. Several studies showed that there is no increased risk of sudden cardiac-related death because of stimulants in individuals with FXS compared to the general population.^13,29 Stimulant doses are usually kept relatively low in FXS because high doses can suppress language; this is an important side effect to be avoided in patients with low language abilities or in individuals who are nonverbal.

Alpha 2-adrenergic receptor agonists

These agonists occupy alpha 2-adrenergic receptors in the prefrontal cortex, leading to increased norepinephrine levels, resulting in positive effects on the regulation of attention. In individuals with FXS, they have a calming effect on hyperarousal. These medications are particularly beneficial for individuals who do not respond well to or cannot tolerate stimulants, such as children under the age of 5 years.³⁷ Alpha 2-adrenergic receptor agonists, specifically clonidine and guanfacine, can potentially improve ADHD symptoms with an overall calming effect.^38,39 Clonidine can be advantageous in children with FXS who also experience sleep disturbances and sleep-related issues because it is the more sedating of the two medications.⁴⁰ Guanfacine, on the other hand, induces less sedation than clonidine, making it the preferred choice for managing daytime behavior.^39,41 Potential side effects of both medications include sedation and low blood pressure after treatment initiation. Both medications are available in a long-acting form, so that they can be given once a day. Abrupt discontinuation of these medications should be avoided to minimize the risk of rebound hypertension.^13,29

Other pharmacotherapy

Children with FXS present mild-to-moderate difficulties with sleep duration and sleep quality.⁴² Melatonin, short-acting or long-acting, is the first-choice drug for sleep issues. If melatonin is ineffective, treatment options can include clonidine and guanfacine.^13,29 In addition, levetiracetam and oxcarbazepine are commonly used as first-line treatment for seizures in individuals with FXS.⁴³ In individuals with FXS experiencing significant adverse effects, it is advisable to consider transitioning them to alternative anticonvulsant medications. This decision aligns with the availability of an array of drugs characterized by favorable safety profiles.^13,29

TARGETED TREATMENTS

Progress in understanding the neurobiology of FXS has pinpointed several pathways that are disrupted when FMRP is absent. These pathways are potential targets for new medications that can reverse the neurobiological changes due to a lack of FMRP; thus, they are targeted treatments for FXS.⁴⁴ The adoption of quantitative outcome measures to gauge effectiveness in numerous investigations enhanced the overall quality of recent clinical trials.⁴⁵ We discuss some medications that can be defined as targeted treatments for FXS.

Metformin

Metformin is a widely used antihyperglycemic medication and serves as a primary treatment for type 2 diabetes mellitus. Its mechanisms of action involve both adenosine monophosphate-activated, protein kinase-dependent and independent pathways.⁴⁶ Additionally, metformin has shown promise in addressing the upregulation of the mGluR/mTORC1-ERK cascade in animal models of FXS, leading to improvements in social behavior, cognition, and other FXS-related issues.⁴⁷

Clinical studies demonstrated that metformin is well tolerated in individuals with FXS and can result in positive behavioral changes, including reduced irritability, social avoidance, and aggression, as well as appetite suppression and weight control.⁴⁸ In young children with FXS, metformin has shown potential for enhancing language development and reducing undesirable behaviors.⁴⁹ It even improved IQ scores in two adult males with FXS after 1 year of treatment.⁵⁰ Metformin’s ability to block the development of macroorchidism, as observed in FXS animal models, has also been observed in clinical cases.⁵¹ An open-label study involving 15 individuals with FXS demonstrated that metformin was well tolerated, safe, and may have had a positive impact on γ-aminobutyric acid-mediated inhibition, a key aspect of FXS pathology.⁵² These findings suggest the potential of metformin as a therapeutic option for FXS.⁴⁴ Results from a double-blind, controlled trial of metformin in children and adults with FXS is expected in 2024.

Cannabidiol

Cannabidiol (CBD) is used to manage anxiety, sleep issues, and tantrums in children with FXS or autism spectrum disorder.^53,54 CBD has several effects on the endocannabinoid system, influencing natural ligands like anandamide and 2-arachidonoylglycerol for cannabinoid receptors (CB1 and CB2).⁵⁵ In FXS, where FMRP is lacking, the endocannabinoid system is dysregulated, disrupting the balance of inhibitory and excitatory neurotransmitters. CBD helps by increasing 2-arachidonoylglycerol availability, preventing CB1 receptor internalization,^56-58 boosting anandamide levels,⁵⁹ binding to serotonin 1A receptors,⁶⁰ acting as a dopamine partial agonist,⁶¹ and positively modulating γ-aminobutyric acid subtype A receptors.⁶² These effects restore the balance between excitatory and inhibitory pathways, thereby improving FXS behavior. In a double-blind, randomized, controlled trial of a topical CBD ointment in children with FXS aged 3 to 18 years, efficacy was observed with significant improvement in the social avoidance subtest of the Aberrant Behavior Checklist questionnaire for individuals with FXS with a full mutation and 100% methylation.⁶³ The first open-label study showed significant improvement in behaviors like hyperactivity, aggression, anxiety, and tantrums with a topical CBD ointment.⁶⁴ The preliminary results indicate CBD’s potential benefit for most individuals with FXS, especially those with a fully methylated FMR1 gene.⁵⁵

BPN14770 as a phosphodiesterase-4D inhibitor

A deficit in FMRP influences cyclic adenosine monophosphate (cAMP) levels in the brain; FXS is associated with low cAMP levels.⁶⁵ cAMP is hydrolysed by phosphodiesterases (PDEs); PDE inhibitors have been shown to rescue phenotypes in FXS preclinical models.⁶⁶ For example, pharmacological inhibition of PDE2A normalized communicative, social, and cognitive impairments in a rat model of FXS,⁶⁷ while TAK-063, a PDE10A inhibitor, had positive effects on normalizing electroencephalography biomarkers in a mouse model of FXS.⁶⁸ Based on the results of preclinical research, a promising therapeutic approach involving PDE inhibitors can be used in individuals with FXS. The ‘cAMP theory’ has been successfully applied to clinical studies examining the effects of the PDE4D inhibitor BPN14770, which also prevents the breakdown of cAMP, resulting in increased cAMP levels.⁶⁹ The results of the study⁷⁰ showed cognitive improvement in 30 adult males (18–45 years old) with FXS who participated in a controlled trial where BPN14770 was administered at a dose of 25mg twice daily (ClinicalTrials.gov registration: NCT03569631). After 14 weeks of treatment with the PDE4D inhibitor, improvements were observed in oral reading recognition, picture vocabulary, and cognition crystallized composite scores from the National Institutes of Health toolbox. Caregivers also reported significant improvements in language skills and daily functioning using a visual analog scale. Importantly, the medication was well tolerated, safe, and with no significant adverse effects compared to placebo.⁷⁰

Minocycline

Minocycline is a second-generation tetracycline derivative; it has central anti-inflammatory properties that inhibit molecules like cyclooxygenase-2, inducible nitric oxide synthase, and p38 mitogen-activated protein kinase. It has antiapoptotic effects by inhibiting caspases, which make it neuroprotective.⁷¹ Early studies in a Drosophila model of FXS showed that minocycline effectively restored normal synaptic structure in several brain regions.⁷² It also reversed abnormal social communication in Fmr1 knockout mice by reducing matrix metalloproteinase-9 levels, as shown by changes in mating-related vocalizations.⁷³ In a randomized crossover trial involving pediatric patients with FXS aged 3 years 6 months to 16 years, minocycline improved overall functioning as measured using global improvement on the Clinical Global Impression Scale; parents noted improvements in anxiety and mood-related behaviors.⁷⁴ Additionally, after at least 3 months of minocycline treatment, electrocortical responses to auditory stimuli showed improved habituation.⁷⁵

Several targeted treatments for FXS are undergoing clinical trials, offering a hopeful outlook for the development of new therapeutic options in the future.⁴⁴

GENE THERAPY

There are no approved medications for FXS. The current strategy entails pharmacotherapeutic interventions consisting of different groups of medications. These treatments are used to address the symptomatic manifestation of comorbid behaviors and psychiatric challenges; yet, they do not address the fundamental source of FXS.¹³

Several treatment strategies are being investigated for FMR1 gene activation. These strategies include ASO therapy, adeno-associated virus (AAV) vector therapy, and clustered regularly interspaced short palindromic repeats. Currently, none of these methods have advanced to trials in FXS, necessitating further investigation to ascertain their safety, compatibility, and efficacy.

The potential of gene therapy using AAV to reinstate FMRP expression is a promising therapeutic strategy.^76,77 However, prevailing AAV gene therapy assessments for FXS have solely relied on nonhuman FMRP driven by promoters distinct from the human FMR1 promoter.^78-81 A more pertinent approach for clinical application would encompass human FMRP within appropriate cell types and at physiologically relevant levels, as directed by the human FMR1 promoter. Jiang et al.⁸² created two efficacious subdomains of the human FMR1 promoter capable of orchestrating gene expression. Both human FMRP isoforms showed expression patterns across the brain reminiscent of murine FMRP when AAVs carrying human FMRP isoforms under the governance of a human FMR1 promoter subdomain were administered into the bilateral ventricles of neonatal male Fmr1 knockout and wild-type mice. Importantly, human FMRP mitigated deficits in social behavior, stereotyped and repetitive behaviors, and reversed dysmorphic dendritic spines in Fmr1 knockout mice, all the while leaving the behaviors of wild-type mice unaffected. These findings underscore the effectiveness potential of the human FMR1 promoter in driving human FMRP expression in the brain, alleviating deficits in Fmr1 knockout mice. This bolsters the notion of using AAV gene therapy as a viable avenue for FXS treatment.⁸²

Similarly, another study revealed the potential therapeutic value of AAV-based gene therapy, highlighting the benefits associated with human FMRP isoform 17 orthologs. Using AAV vectors controlled by a methyl CpG binding protein 2 mini-promoter (AAV9 serotype), researchers successfully distributed FMRP transgenes in the telencephalon and diencephalon of neonatal Fmr1 knockout rats and mice. This transgene expression, predominantly within non-GABAergic neurons, partially rescued Fmr1 knockout rat phenotypes, such as improved social dominance in treated females and correction of abnormal slow wave activity during sleep-like states in males.⁸³

Diacylglycerol kinase κ (DGK-κ) is a prominent mRNA target of FMRP within cortical neurons and a pivotal controller of lipid signaling. It was downregulated in the brain of knockout mice, where FMRP was absent.^84,85 Building on this, Habbas et al.⁸⁶ presented evidence that the introduction of a modified form of DGK-κ, which functions independently of FMRP through the AAV vector delivery mechanism, rectified abnormal cerebral diacylglycerol/phosphatidic acid equilibrium. Furthermore, this correction extends to FXS-relevant behavioral traits observed in the knockout mouse model. These findings suggested the pivotal involvement of DGK-κ in the pathogenesis of FXS and showed preclinical validation that the replacement of DGK-κ holds potential as a viable therapeutic strategy for FXS.⁸⁶ However, this therapeutic approach should be applied cautiously because of contrasting data on DGK-κ expression in the mouse brain. Although Tabet et al.⁸⁴ demonstrated that cells expressed DGK-κ in different regions of the cortex (including the somatosensory cortex, entorhinal cortex, limbic structures, and the ventral hippocampus in the mouse brain), other data showed that this gene is expressed only in a few brain regions (http://mousebrain.org/). Further research is needed to elucidate the role of the DGKK gene in the FXS phenotype and its role in potential gene therapy.

In addition, the formation of ‘R-loops’ (three-stranded nucleic acid structures) within extended CGG repeats in FXS cells can lead to significant FMR1 reactivation, ranging from 40% to 100%. Given the potential reversal of FXS cellular traits through FMR1 reinstatement, an emerging avenue for future FXS treatment might involve addressing R-loops to trigger trinucleotide repeat contraction and subsequent re-expression of absent FMRP within neuronal cells. The results of the study⁸⁷ offer initial indications that the mechanism prominently observed in induced pluripotent stem cells is also present in neuronal cells. Subsequent endeavors in this field will be geared toward refining the contraction process in ex vivo neuronal models and in vivo scenarios, focusing on its therapeutic implications.

The next promising gene therapy for FXS is the use of ASOs. ASO therapy is a targeted approach to treat genetic disorders by using short synthetic molecules known as ASOs (18–30 bp long) to modulate gene expression. These molecules are designed to bind to specific RNA sequences in a complementary manner, thereby influencing several cellular processes related to gene expression and protein production. The basic principle of ASO therapy involves the introduction of synthetic oligonucleotides into the body, which then selectively interact with the RNA transcribed from a target gene.⁸⁸ The study conducted by Shah et al.¹⁰ presented evidence of widespread incorrect expression and splicing of many mRNAs in both the white blood cells and brain tissue of individuals with FXS. They observed limited transcription of the FMR1 gene in over 70% of patients with FXS. This remarkable discovery found that the FMR1 gene produces an mRNA that is abnormally spliced, that is, 217-bp mRNA; because of this abnormal splicing, protein expression is blocked. Specifically, in all FXS tissues expressing FMR1, FMR1 RNA undergoes mis-splicing in a CGG expansion-dependent manner, giving rise to a little known FMR1 mRNA isoform (217-bp mRNA). This FMR1 mRNA variant includes FMR1 exon 1 along with a pseudo-exon located in intron 1. Expression of FMR1 217-bp mRNA has also been detected in skin fibroblasts and brain tissue from individuals carrying the FMR1 premutation. However, the investigation revealed that in cells where FMR1 RNA is mis-spliced, ASO treatment results in a reduction of FMR1 217-bp mRNA, restoration of full-length FMR1 RNA, and normalization of FMRP levels. Briefly, this study showed that if this abnormal mRNA splicing event is blocked using an ASO, then the FMR1 gene produces normal mRNA that in turn produces normal protein. For individuals expressing FMR1 217-bp mRNA, ASO treatment emerges as a prospective therapeutic strategy to ameliorate the condition.¹⁰

The clustered regularly interspaced short palindromic repeat method is also a powerful new tool that can be used to precisely demethylate and reactivate the FMR1 gene. Liu et al.⁸⁹ successfully achieved complete activation of the FMR1 gene by eliminating the methylation of CGG repeats in neurons derived from induced pluripotent stem cells affected by the full mutation of the FMR1 gene. Electrophysiological abnormalities were rescued in neurons derived from methylation-edited, FXS-induced pluripotent stem cells. Furthermore, the wild-type phenotype in mutant neurons was restored, while expression of the FMR1 gene in edited neurons was maintained in vivo after engrafting into the mouse brain.⁸⁹

The gene therapy closest to human clinical trials uses a modified FMRP linked to a TAT polypeptide that can cross the blood–brain barrier when given intravenously.⁹⁰ This FMRP-TAT protein complex rescued the phenotype in knockout mouse; human trials are planned although testing in a primate model first may be needed along with additional studies before US Food and Drug Administration approval. However, treatment in patients with FXS would need recurrent weekly infusions at a minimum.

Current limitations of gene therapy

Delivery of gene therapy components to the brain presents several challenges and limitations. The method of delivery is crucial for the success of gene therapy; developing minimally invasive and effective delivery methods is an ongoing area of research.⁹¹ The blood–brain barrier is a major obstacle that restricts the entry of many therapeutic agents, including gene therapy vectors, into the brain.⁹² In addition, the distribution of gene therapy vectors within brain tissue can be uneven, leading to incomplete coverage of the target area. Achieving widespread and uniform distribution remains a challenge, especially in large or deep brain structures.⁹³ Also, some viral vectors used in gene therapy may have inherent toxicity that can damage brain cells.^94,95 Ensuring sustained and regulated expression of therapeutic genes over the long term is also challenging. Specifically, gene therapy vectors may have off-target effects, resulting in unintended consequences. This could lead to the expression of therapeutic genes in nontarget cells or tissues, potentially causing adverse effects.⁹⁶ Researchers continue to explore innovative strategies to address these limitations and improve the efficacy, safety, and precision of gene therapy for neurological disorders. Advances in nanotechnology, viral vector design, and delivery techniques are expected to contribute to overcoming these challenges in the future.⁹¹

The timing of FMRP restoration through gene therapy is a crucial aspect to consider in clinical trials because the developmental stage of the individual can impact the effectiveness of the intervention. It involves balancing the potential benefits of early intervention with the challenges of ensuring the safety and efficacy of the treatment. Ideally, gene therapy could be applied before birth or even during conception to ensure that the developing fetus receives the corrected genetic material.⁹⁷ Administering gene therapy in the early stages of childhood, before the full manifestation of symptoms, may also be beneficial.⁹⁸ Furthermore, in some cases, gene therapy may need to be administered throughout an individual’s life to maintain adequate levels of FMRP.⁹⁹ Decisions about when to intervene must involve ethical aspects and careful consideration of the potential risks and benefits.

CONCLUSION

Gene therapy or molecular manipulations of the FMR1 gene will become available in the near future for patients with FXS because successful studies in animals and human cells have already been carried out. However, before this takes place, there are several targeted treatments that can be used by clinicians to treat FXS in childhood and adulthood. Studies of metformin and CBD treatment have shown positive results that can be translated to the clinic, while the use of sertraline for anxiety and guanfacine or stimulants for ADHD are in common use for individuals with FXS. Atypical antipsychotics, such as aripiprazole and risperidone, should be reserved for significant aggression or behavior disruption that does not respond to other treatments. The use of psychotropic medications should be combined with individualized therapies from psychology, speech and language therapy, occupational therapy, and physical therapy, along with special educational help via the school system. Counseling for the caregiver and other family members regarding the premutation and treatments for many premutation problems may also help children with FXS indirectly by reducing anxiety and stress for the whole family.¹⁵

Figure 1 illustrates the therapeutic pyramid of treatment approaches in FXS. This is a schematic representation of several treatment strategies. It could prove highly valuable for the daily clinical practices of medical professionals who work with patients with FXS.

Figure 1:

The therapeutic pyramid of treatment approaches in FXS. Abbreviations: ADHD, attention-deficit/hyperactivity disorder; fragile X syndrome.

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.

ABBREVIATIONS

AAV

adeno-associated virus

ASO

antisense oligonucleotide

cAMP

cyclic adenosine monophosphate

CBD

cannabidiol

DGK-κ

diacylglycerol kinase κ

FMRP

FMR1 protein

FXS

fragile X syndrome

PDE

phosphodiesterase