Molecular mechanisms for targeted treatments in fragile X syndrome
1MIND Institute, University of California Davis Health, Sacramento, CA 95817, USA.
2Department of Pediatrics, University of California Davis Health, Sacramento, CA 95817, USA.
Correspondence to: Dr. Randi Hagerman, MIND Institute, University California Davis Health, 2825 50th street, Sacramento, CA 95817, USA.E-mail:
Fragile X syndrome (FXS) is caused by a full mutation (> 200 repeats) in the 5’untranslated region of the Fragile X Messenger Ribonucleoprotein 1 gene (FMR1 gene), which leads to methylation and silencing of expression, generating the total or partial absence of its product, FMR1 protein (FMRP). When the repetitions are between 55 and 200 cytosine-guanine-guanine (CGG) repeats, it is called a premutation, which is related to a wide spectrum of conditions such as Fragile X-associated tremor ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND). High levels of FMR1 mRNA are implicated in premutation pathophysiology, which differs from the deficiency or absence of FMRP in FXS. In recent years, numerous attempts have been made to find treatments that can counteract the effects of the absence of FMRP and improve symptoms associated with the condition such as intellectual disability, anxiety, autism, stereotypies, language delay, and aggressive behavior. Here, we review current treatments in addition to targeted treatments that can reverse some of the neurobiological abnormalities in those with FXS. We also review molecular interventions that will hopefully lead to a promising future for those affected by FXS and their families.
Much progress has been made in the diagnosis and management of FXS since it was first described in 1943 and then known as Martin-Bell Syndrome. In a large meta-analysis, the frequency of the full mutation
FXS is the most frequent cause of intellectual disability (ID) and autism of hereditary origin, caused by an expansion of the sequence of CGG trinucleotides repeats to ≥ 200 in the region of the promoter of the FMR1 located on the long arm of the X chromosome at Xq27.3. This full mutation generates silencing through methylation of the gene, leading to the total or partial loss of its product, FMRP. This protein is mainly expressed throughout the brain and in the testes, but also in almost all other tissues and organs.
The premutation is 55 to 200 CGG repeats in the promoter region of FMR1 and it is usually not methylated. Carriers of the premutation usually produce normal levels of FMRP and they are not intellectually impaired; however, they do exhibit elevated levels of FMR1 mRNA. The elevated levels of mRNA lead to toxicity to the neuron and other cells and this causes clinical problems including FXPOI meaning menopause before age 40, FXTAS, a neurodegenerative disorder, and FXAND affecting approximately 50% of carriers.
FMRP binds messenger RNAs, including brain cytoplasmic RNAs and microRNAs, to regulate their transport and translation, interacts with nuclear and cytoplasmic proteins, modulates ionic channels, and is present in synaptic compartments, where it controls the translation of specific mRNAs. Structurally, it has three main regions: N-terminal region, central region, and C-terminal region. Each of these regions can bind to RNA molecules and FMRP’s role in mRNA transport, splicing, and metabolism is important for brain development and aging.
The symptoms and signs related to the total or partial loss of FMRP are variable but usually compromise all areas of development: cognitive, behavioral, sensory, verbal, and motor, which have lifelong consequences. In addition, characteristic physical manifestations such as the elongated face, prominent ears, joint hypermobility, soft skin, and macroorchidism in puberty occur in FXS. The features of FXS require complex management in treatment, which should be addressed by a multidisciplinary team. Here, we present a review of the literature to try to encompass the current optimal therapeutic intervention strategies for these children, adults, and their families affected by fragile X conditions. The literature was selected for controlled medication trials in FXS, the inclusion of systematic reviews in this field of study, key search engines, and follow-up studies. Single-case or abstract conference studies were excluded.
Molecular mechanisms of fragile X syndrome
FMRP is a multi-functional mRNA binding protein that travels to and from the cell nucleus, with a role in the translation, stability, editing, and intracellular transport of hundreds of mRNAs. FMRP also directly interacts with proteins and regulates their function. Additionally, FMRP can regulate RNA synthesis by either controlling the expression of or modulating the activities of transcription factors and chromatin-modifying enzymes, many of which are involved in neurodevelopment and the maintenance of neural connections. In the synaptic space, FMRP is associated with the activation of glutamate receptors, both metabotropic (group 1 mGluR 1 and 5) and ionotropic (AMPA and NMDA). Its deficit, therefore, translates into abnormal growth and synaptic plasticity. The expression of these receptors is increased in the hippocampus of animals lacking FMRP. Despite the successful use of glutamate receptor inhibitors to correct symptoms such as seizures, hyperreactivity, and neural structural changes in knockout (KO) mouse, studies in fully-methylated FXS patients with an antagonist of mGluR5 were not successful in adults or children with FXS[13,14].
The endocannabinoid system is also regulated by FMRP and endogenous cannabinoid ligands such as anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol (2-AG), are postulated to play a role in neuronal development and function. These ligands bind to cannabinoid receptors type 1 and 2 (CB1 and CB2) and modulate synaptic activity. CB1 is expressed in the brain and is present at lower concentrations in a variety of peripheral tissues and cells. CB2 receptors are expressed primarily in the immune and hematopoietic system, as well as in the brain, pancreas, and bone. CB1 can be found at high levels in inhibitory terminals (GABAergic interneurons) and at lower levels in excitatory terminals (glutamatergic) and both play a role in mood and behavior modulation. 2-AG is the most abundant endocannabinoid in the brain and is produced in dendritic spines by activating mGLUR1 receptors. The absence of FMRP in FXS reduces the production of 2-AG, thereby decreasing the activation of CB1 receptors in the central nervous system (CNS). Administration of cannabidiol (CBD) appears to increase 2-AG availability, thereby increasing CB1 receptor activation and attenuating reduced endogenous cannabinoid signaling.
In another aspect, FMRP modulates the activation of sodium-potassium channels and calcium channels[19,20], its absence alters the transport and/or translation of specific mRNAs that can influence neuronal excitability.
The GABAergic system is also affected in FXS, leading to an excitatory-inhibitory imbalance, because of reduced expression of subunits at GABA receptors and a reduction in GABAergic interneuronal signaling, which play a central role in the presence of autism spectrum disorder (ASD) and FXS. FMRP is broadly expressed in GABAergic neuron populations. The GABAergic system normally mediates the inhibitory neurotransmission in the CNS and the lack of FMRP disrupts this system and it was implicated in the pathogenesis of FXS based on studies of GABA-A receptor expression in Fmr1 KO mice. These alterations increase neuronal excitability and further enhance the imbalance of excitation and inhibition. This imbalance leads to enhanced sensitivity to repeated sensory stimuli, a lack of habituation to repetitive stimuli, and subsequent sympathetic hyperactivation, causing anxiety in these patients[23,24].
The normal morphology of dendritic spines also derives from physiological processes modulated in part by FMRP activity. Its absence or decrease leads to a pathological hyperabundance of long, thin immature dendritic protrusions, which result in an abnormal post-synaptic maturation and a failure in the synapse elimination process.
Another association studied is the relationship between FMRP and metalloproteinase 9 (MMP9) levels. MMP9 is an enzyme that encodes an endopeptidase important for the maturation of dendritic spines and synaptic formation. MMP9 levels are elevated in FXS because FMRP, which inhibits the translation of the MMP9 mRNA, is missing. However, MMP9 levels can be lowered to normal with minocycline treatment[27,28]. In fact, in the Fmr1-KO mouse, treatment with minocycline improved the maturation of dendritic spines, synapse formation, anxiety levels, and cognitive performance, as well as ultrasonic vocalizations[29,30]. In addition, metformin may decrease MMP9 levels in the Fmr1-KO mouse. Such studies led to the successful trial of minocycline in the treatment of FXS.
This knowledge has made it possible to generate therapeutic interventions with multiple medications that can already be applied in clinical practice or are in clinical trials.
Coping with FXS and their family inheritance and social environment
The complexity of the child affected by FXS and the impact on their family and social environment requires that this condition be addressed by a multidisciplinary team guided by a developmental specialist (Pediatrician, Neurologist, or Child Psychiatrist), ideally with experience in FXS.
Treatment will then require pharmacological and non-pharmacological therapy such as speech and language therapy, occupational therapy (OT), physical therapy (PT), counseling, or behavioral interventions such as applied Behavior analysis (ABA) and a healthy lifestyle. The inheritance of the fragile X mutation through the pedigree needs to be explained to the family. If a child has the full mutation, the mother is always the carrier because the expansion to ≥ 200 CGG repeats only occurs when passed on by the mother. The mother usually has a premutation, but on occasion, she may have a full mutation, so she needs the fragile X DNA test herself. She has approximately a 50% chance of passing on the full mutation to her children because rarely do both X chromosomes carry the mutation. If her premutation is over 90 CGG repeats, then the repeat expansion will expand to a full mutation in the next generation. For premutation carriers with repeats between 55 and 90, there is an increasing risk of going to a full mutation as the repeat number increases. Usually, after every 10 CGG repeats, there is an AGG anchor, and if one or two anchors are present in the mother, this will decrease the risk of expanding to the full mutation up until 90 to 100 repeats when the risk goes to 100% when that mutation is passed on to the next generation[33,34].
If the family has a male premutation carrier, often the father of the mother, then this male will pass on the premutation to all his daughters. Therefore, it is helpful to order fragile X DNA testing for the grandparents because if the grandfather is the carrier, then all of the mother’s sisters will be carriers and they will be at high risk of having children with FXS. In addition, premutation carriers need to know the risk of premutation disorders. FXPOI occurs in about 20% of female carriers; FXTAS occurs in about 40% of aging male carriers and 16% of aging female carriers, and FXAND, which encompasses depression, anxiety, insomnia, chronic pain, and chronic fatigue and social deficits, occurs in up to 50% of carriers, typically in adulthood, but sometimes also in childhood[7,36,37].
Cognitive-behavioral challenges and neurological symptoms
Patients with FXS may present with significant behavioral problems, which usually manifest with greater intensity as they advance in their development, including tactile defensiveness, poor eye contact, hand flapping, hand-biting, clothes chewing, hyperactivity, impulsivity, anxiety, aggressive behavior, and sensory over-reactivity from the second year of life onward. The manifestations of these problems include overfilling or stuffing their mouths with food, and this often translates into obesity. Autism (50%-60% of men, 20% of women) or social deficits and attention deficits with/without hyperactivity (80% of boys and 30% of girls) are also more frequent than in the general population. Often, in early childhood, sleep difficulties can be seen as well. Physical therapy, occupational therapy, speech therapy and ABA for ASD are essential within non-pharmacological interventions.
ABA is a behavioral intervention commonly used as a therapeutic treatment for ASD. Its premise is to reinforce the positive socially-involved actions of the child. The Early Start Denver Model (ESDM), another model of behavioral intervention, has ABA principles, but focuses on verbal and social skills through interactions with young children ages 1 to 3 in the family environment[40,42,43].
Anxiety is a cardinal symptom in FXS, especially after age 2, and can increase with age and it can also correlate with ASD. Low doses of sertraline, a selective serotonin reuptake inhibitor (SSRI), which then prevents the reuptake of serotonin from the synaptic space, has shown significant improvement in anxiety and in visual perception, fine motor coordination, and better T score on the Mullen scale for development in a controlled trial of young children with FXS ages 2 to 6 years old. Those who do not respond to SSRIs, or who exhibit aggressive behaviors (potentially harming others or themselves), or who exhibit violent reactions may respond well to the use of an atypical antipsychotic such as aripiprazole or risperidone, both of which are approved for aggression and irritability in ASD. These atypical antipsychotics can block dopamine but also stimulate the serotonin receptors, leading to improvement in aggression and irritability, decreased hyperactivity, and less anxiety in FXS. Cognitive behavioral therapy has proven helpful for emotional dysregulation in FXS[47,48].
Other neuropsychiatric manifestations include social or specific phobias, ritualistic and compulsive behaviors, restricted interests, aggressiveness, stereotypies, and self-harming behaviors. Early and intensive psychological and environmental interventions can play a positive role in the management of anxiety, ADHD, social challenges, and depression.
Most men with FXS have ID; however, up to 15% (predominantly those with mosaicism) and 70% of women may have an IQ that is normal or close to normal, but still have learning problems and emotional control issues. Cognitive abilities in FXS are known to decline with age in childhood and adolescence. Most men with FXS in adulthood have cognitive abilities around an IQ of 40 unless they are mosaic with the partial lack of methylation in the full mutation or a significant percentage of cells with the premutation. The size or methylation mosaicism is associated with a higher IQ than those with a full mutation that is fully methylated because these mosaic individuals are producing a higher level of FMRP[50,51]. This is the case of females with a full mutation because their normal X produces FMRP and the amount of FMRP depends on the activation ratio (AR), meaning the percentage of cells with the normal X as the active X usually measured in blood. So, an AR of 0.75 means that 75 percent of her white blood cells have the active X as the normal X, and usually the IQ is relatively high. Approximately 1/3 of girls with the full mutation have an IQ less than 70, 1/3 have an IQ in the borderline range (70 to 85) and 1/3 have an IQ in the normal range (above 85).
By late adulthood, with aging, up to 17% of men with FXS may develop Parkinsonian symptoms, often combined with some additional cognitive impairment.
Seizures and ASD
Seizures can also be associated with FXS, usually complex partial, although they can evolve into generalized tonic-clonic seizures or absence seizures. Seizures are common in FXS and up to 14% of males and 6% of females have seizures. Seizures often begin between ages 4 and 10 years and data showed that autism was significantly associated with seizures as a co-occurring condition. For treatment, Levetiracetam and oxcarbazepine are used as the first line of treatment. Valproate can be another choice and has a mood-stabilizing effect, allowing the improvement of symptoms of aggression or lack of control in some cases.
Growth, connective tissue, and involvement of other systems
People affected by FXS may have different associated medical conditions from the spectrum of connective tissue disorders. These include flat feet, scoliosis, joint subluxations, mitral valve prolapse, dilated ureters, and vesicoureteral reflux. It is important to rule out aortic root dilation (25%) or mitral valve prolapse (MVP) (3%-20%) if a murmur is heard on auscultation. Another possible finding of the cardiovascular system is the decrease in parasympathetic vagal tone, especially in children who are hyperaroused. Hypertension is common in obese patients and in adulthood, and this may be related to enhanced anxiety. If hypertension or a murmur is heard, then referral to cardiology, where an evaluation including an ultrasound, is carried out that can document MVP or other cardiac problems. It is worth mentioning that carriers of the premutation may also present with cardiovascular symptoms such as arrhythmias and dysautonomia.
Obesity occurs in about 35% of those with FXS before they reach adolescence, especially in those with hyperphagia and a lack of satiation after meals. In about 10%, these behavioral features can lead to a Prader-Willi-like phenotype with severe obesity and this has a biomarker of low cytoplasmic FMRP interacting protein (CYFIP) levels reported by Nowicki et al.. These children present with severe hyperphagia and early obesity (6-9 years) and typically have small genitalia and delayed puberty. Knowing the increased risk of obesity, it is important to encourage regular physical exercise, ideally daily, and to promote a healthy diet by avoiding foods rich in saturated fats and sugar. The therapy is complex and requires multidisciplinary support from experts in the field for behavioral interventions and medications.
Annual pediatric health checkups should include otoscopy and appropriate treatment of otitis media which is often recurrent in the first years of life. It is recommended to have early and frequent hearing screens, especially if there is a history of recurrent ear infections, to avoid a greater impact on language acquisition. Children with FXS may have difficulty communicating discomfort or pain, so in the face of otitis, they may hit their head, and this may be the only outward symptom of infection. Recurrent otitis media infections often require insertion of Pressure Equalizer tubes (PE tubes) and sometimes adenoidectomy and/or tonsillectomy.
An evaluation by an ophthalmologist is recommended between 3 and 4 years of age to evaluate and correct visual acuity problems (astigmatism, hypermetropia, strabismus). If strabismus is noted (occurs in about 20% of FXS patients), it should be evaluated as early as possible to avoid the development of amblyopia. Nystagmus, convergence insufficiency, and eyelid ptosis have also been reported, but are less common[54,56].
In the gastrointestinal sphere, loose stools are usually the norm in FXS, but in some rare cases, constipation may occur. Toilet training is typically delayed because of sensory issues and cognitive deficits, but the biggest problem is training them to wipe themselves successfully after a bowel movement. OT therapy is often helpful in addressing this problem. Gastro-esophageal reflux is more common in infants with FXS (leading to frequent emesis) than in the general population. These symptoms should be screened carefully, diagnostic studies performed, and treatment implemented if appropriate.
Almost all young children with FXS need early intervention beginning by 2 years old or earlier and they benefit from speech and language therapy, OT, and PT. In general, motor involvement is one of the first findings noticed in early development. Most children affected by FXS are hypotonic, which will translate into delayed onset of motor milestones such as the ability to sit without support and the onset of walking. In the neonatal and infant period, they may have difficulties in sucking and frequent regurgitation. Physical therapy and occupational therapy are important for supporting motor development.
They usually have poor language development and some children, especially boys and those with comorbidity with autism, may be completely nonverbal for several years. Speech problems of males with FXS include variability in rate and stuttering-like repetition of sounds. Also notable among the features displayed by males is perseveration on a word, phrase, or topic in conversation, which is probably related to the hyperarousal and frontal-lobe-executive function deficits. Speech therapy is incorporated as a central element of intervention in the first years of life. PROMPT therapy can be helpful for the nonverbal child at
School integration programs with special education are necessary for these children when accessing the school system. Resources or plans for these children can be found on online portals such as www.fragileX.org; www.fragilex.org.uk; or www.fragilex.org.au.
Attention deficit hyperactivity disorder and treatment
As previously noted, ADHD can be diagnosed in approximately 80% of boys and about 30% of girls with FXS. However, the usual treatment of ADHD with stimulants can cause irritability when given to children less than 5 years old with FXS. For those who are 5, and older stimulants are usually tolerated well, especially the long-acting preparations when once-a-day dosing in the morning leads to a stable level in blood during the day. These First-Line medications improve norepinephrine and dopamine levels at the synapse in the prefrontal cortex, which play a role in improving motivation, attention, and impulse control. For children under 5 years of age with excessive hyperactivity, guanfacine or clonidine may be considered. Clonidine is especially helpful for sleep problems when given at bedtime because of its sedative effect. Guanfacine has an overall calming effect, which calms down hyperactivity and hyperarousal when given in the morning and in the afternoon after school. In some countries, such as Italy, stimulants are not authorized, so an alternative for attention deficit symptoms is L-acetylcarnitine or valproic acid[65,66].
In general, the use of stimulants such as methylphenidate or mixed amphetamine salts should start at a low dose and then follow-up visits should follow weight and vitals, particularly blood pressure, since both can be affected in children with FXS. If weight loss occurs, then the dose should be lowered or even discontinued on weekends, and increased food intake can occur before bed when the medication has worn off. In general, the stimulants are well tolerated; however, it is important to note that at higher doses, they can have a quieting effect on language. Therefore, it is advisable to avoid administering high doses.
At each medical visit, it is suggested to check sleep quality and time for sleep because these parameters influence the development, learning, and functioning of any child, including those affected by FXS. Children under 3 years old with FXS often have wakefulness at night and they may get up and search for parents. Seizures can also occur at night in about 15% of young children with FXS. Sleep apnea also can occur in young children, especially if there is a history of snoring and obstruction heard at night by the parents. Referral to an Ear Nose and Throat (ENT) specialist and a sleep study can clarify if sleep apnea is occurring, and an adenoidectomy/tonsillectomy typically eliminates sleep apnea in a young child with FXS.
The use of melatonin is the most effective medication as a primary treatment of sleep wakening in young children with FXS. Not only does melatonin play a role as a sleep inducer, but it also has antioxidant properties and it facilitates neuronal plasticity. Melatonin should not be given in the daytime because it can cause drowsiness during the day.
Targeted treatments for fragile X syndrome
Most of these treatments, promoted in the last decade, are supported by research conducted in FXS animal models with a KO of FMR1 and the neurobiological effect that this entails. The current objective is to be able to, on the one hand, reactivate the damaged gene and, on the other hand, replace the effects of the absence of the FMRP protein.
Early attempts used negative modulators of mGluR5 receptors (mGluR antagonists) since this pathway is upregulated in FXS. Favorable results have been shown in animal studies using these antagonists, but in humans, the results have been negative[70-72]. Even the use of the mGluR5 antagonist AFQ056 in young children with FXS combined with parent-implemented language intervention (PILI) has not demonstrated efficacy over a prolonged period of time in a controlled trial.
GABA-A and GABA-B receptor agonists can reverse some of the symptoms in the animal model of FXS and would be useful under the theory that GABA pathways are also affected in individuals with FXS and that problems such as seizures and sleep disturbances are associated with this pathway. FMRP acts as a modulator of these GABA receptors. Clinical studies with Arbaclofen (selective GABA-B agonist) showed improvement in the symptoms of social isolation and behavioral problems reported by parents of patients with FXS, compared to placebo; however, in phase III studies with adolescents and adults, Arbaclofen did not show improvement. In the group of 5 to 11 years, an observable improvement was maintained in the application of the ABC FX test (Aberrant Behavior Checklist-community Edition, factored for FXS), so arbaclofen will be studied again in FXS by the Allos company. Acamprosate (positive allosteric modulator of the GABA-A receptor) and metadoxine (an indirect GABA activator) have been tested in small placebo-control groups of FXS individuals. Metadoxine has shown improvement when evaluated with the Vineland Daily Living Skills subscale and in the computerized cognitive Test of Attentional Performance for Children (KiTAP) test (executive function tasks) compared with individuals who received placebo. Ganaxolone has shown improvement in anxious symptoms in a specific subgroup of participants with greater severity of anxiety, but it was not efficacious for the overall group of FXS. A placebo-free study of 3 doses of Gaboxadol, a GABA-a receptor agonist, was carried out in 28 adolescent and adult males with FXS, and there was a 60% response rate, suggesting that further studies are warranted in a controlled trial with placebo.
Minocycline, an antibiotic of the tetracycline family acts by lowering matrix metalloproteinase-9 (MMP9) expression and activity levels, which, in turn, can improve the maturity and strength of synaptic connections in the Fmr1-KO mouse. One controlled study demonstrated significant improvement in behavior in children with FXS measured with the Clinical Global Impression Scale and the Visual Analogue Scale. Thus, this medication is used in clinics to help with behavioral problems, anxiety, and attention in children with FXS at times. Other benefits of minocycline are its antioxidant power and anti-apoptotic effects. Unfortunately, it has certain side effects such as the permanent darkening of the teeth (when used in children under 8 years) and also, sometimes increasing the levels of antinuclear antibodies (ANA), which can trigger a Lupus-Like syndrome with rash or inflammation of joints (reversible when treatment is stopped). Therefore, if minocycline is used in treatment, then the ANA should be tested every 6 months or once a year if the patient is stable without side effects.
Another drug is trofinetide, a terminal analog of the tripeptide of the insulin-like growth factor that can decrease abnormal ERK and AKT activity, normalizing the phenotype in the KO mouse. An exploratory, phase 2, multicenter, double-blind, placebo-controlled, parallel-group study of the safety and tolerability of orally administered trofinetide to adolescent and adult males with FXS was performed. Trofinetide was well tolerated and showed a consistent signal of efficacy at the higher dose observed by caregiver and clinician assessments despite the relatively short duration of treatment.
Lovastatin, a statin, is another drug under study, which, in in vitro studies, has corrected excessive protein synthesis at the level of the hippocampus of the Fmr1-KO mouse and, when administered orally or injected, was able to inhibit the expression of audiogenic-induced seizures. Being a drug already FDA-approved and widely used in adults and children for the management of hypercholesterolemia, it was exciting to continue testing it as a specific therapeutic alternative for FXS. Unfortunately, a controlled trial of lovastatin combined with an open-label treatment of a PILI in youth with FXS did not show greater benefit than the use of PILI alone.
Another specific targeted treatment for FXS is metformin, a first-line medication in the treatment of type 2 diabetes that acts by decreasing the hepatic production of glucose, decreasing absorption of glucose at the intestinal level and increasing insulin sensitivity, which leads to lower plasma glucose levels. Metformin in the fmr1-KO mouse has been shown to reduce ERK signaling and decrease levels of phosphorylated EIF4E and MMP9. Metformin can also alleviate features of FXS in the Drosophila model of FXS by lowering the up-regulation of the mTOR pathway that is seen in FXS. Metformin is also known to reduce obesity, especially in children or adults with ASD who have gained weight because of antipsychotic use. Initially, metformin was tried in patients with FXS and the Prader-Willi-like phenotype with obesity and it helped to reduce the obesity. In addition, it was tried in FXS without obesity and the families saw an improvement in language and conversational abilities. In young children 3 to 7 years, an open-label trial of metformin improved both behavior and cognitive abilities on the Mullen Scales of Early Learning compared to the early development of FXS documented in the literature. Subsequent cases of FXS have demonstrated improvement in IQ in two adult males treated clinically with metformin and another case where macroorchidism did not develop when metformin was started before puberty. Currently, a controlled trial of metformin treatment over 4 months for individuals with FXS from ages 8 to 45 is taking place at three centers, including the MIND Institute at UC Davis and at the University of Edmonton in Canada and St Justine Hospital in Montreal. Results should be available in early 2024. Because of clinical reports demonstrating its benefits, metformin is often used clinically and we all await the results of the controlled trial.
CBD has an antioxidant, anti-inflammatory, and neuroprotective effect, so it could be useful in patients with neurodevelopmental disorders where neuro-inflammation and immune dysregulation would play a role in pathogenesis, such as in ASD. Moreover, its anxiolytic effect, via GABA enhancement and activation of the cannabinoid type 1 receptor, has been shown to improve anxious symptoms in patients with autism. Its positive medicinal effects include the control of seizures in children with Lennox Gastaut syndrome and Dravet syndrome. Moreover, parents of children with refractory epilepsy reported improvement in attention and behavior when treated with CBD.
Zynerba has manufactured CBD that is free of THC and has carried out a twelve-week controlled trial of this topical ointment in children with FXS at a dose of 250 mg to 500 mg (weight dependent) rubbed on the shoulder skin twice a day. This topical preparation of CBD demonstrated significant benefit for the primary outcome measure of Social Avoidance, a subtest of the Aberrant Behavioral Checklist for Fragile X (ABC FX) in those children who had > 90% methylation. However, because it did not demonstrate efficacy for those with FXS who were mosaic, the FDA asked Zynerba to carry out a second treatment study where the molecular subgroups were further studied and this trial, called RECONNECT, is currently ongoing at multiple international sites. CBD not only improved social avoidance but also benefited anxiety and outburst behavior so that the Quality of Life was improved for the families, and they found that they could go on outings with their children without severe behavioral manifestations. However, this medication is not available from marijuana stores presently, and the closest alternative is hemp-derived CBD, which has a very low level of THC (< 1%) and is typically available in tinctures or gummies. CBD may also be helpful for premutation carriers who often have symptoms of insomnia, anxiety, and chronic pain associated with FXAND.
Phosphodiesterase 4D inhibitor: BPN14770
Perhaps the most exciting treatment study in FXS was the use of BPN14770, which inhibits the breakdown of cAMP because cAMP is deficient in FXS. The use of this inhibitor raised cAMP levels and improved cognition substantially in a controlled trial. Thirty adults with FXS were treated for 14 weeks with either a placebo or BPN14770 at a dose of 25 mg twice a day. The cognitive outcome measure was the NIH toolbox, which had been modified by Dr. David Hessl and his team to be useful in individuals with ID. They found that multiple measures on the NIH toolbox improved in those treated with BPN14770 compared to placebo including Oral Reading Recognition, Picture Vocabulary, and the Cognition Crystallized Composite Score in addition to the parents’ documentation of improvements in language and daily functioning on the Visual Analogue Scale. Such significant improvements in cognition in adults with FXS have never been seen before, so this medication has brought hope to the fragile X field that cognitive deficits can be improved even in adulthood. Currently, phase III controlled trials of BPN14770 are being carried out in adolescents and adults with FXS at multiple centers, and by the end of 2023, such trials will likely take place in children with FXS.
Advances in DNA technology have been used to correct CGG expansions with pluripotent cells. Eventually, in the future, these cells can enter into the CNS of patients affected with FXS to correct the expansion. Recently, an approach to correct the genetic defect in FXS was described via recruitment of endogenous repair mechanisms that then drive excision of the long CGG repeat. FMRP restoration through de novo transcription, can be induced by demethylation and resolution of the aberrant R-loops in the FMR1 gene in cellular models, identifying a potential method of treating FXS in the future. Another study that sought to deliver ASOs into the brain of FXTAS affected mouse models showed reduced inclusion formation, improved motor response, and correction of gene expression profiling. These studies raised hope for the development of future curative treatments, and it is exciting to witness the development of therapeutic alternatives that until recently were unthinkable.
Animal models and advances in understanding the molecular dysregulation present in FXS have led to several targeted treatments described here that have improved the lives of many patients with FXS. Support and intervention for patients should extend to their family and environment. The quality of life of each of these individuals will be affected differently depending on the level of ID, behavioral challenges, the presence of aggressiveness or disruptive behaviors, and the comorbidity present in both the patient and their caregivers. Parents can be affected emotionally, having to assume the responsibility of ensuring the health of the child, and battling chronic stress or major depression, especially those caregivers who have the premutation with FXAND and/or FXPOI. Family support is a fundamental pillar in therapeutic approaches. PILI is an alternative that strengthens communication channels between parents and children. It is recommended to have counseling, parent group support, educational alternatives, and psychological and/or psychiatric- intervention when necessary.
We acknowledge the patients and their families who have been our power inspiration to work in this field and our own families who have provided the encouragement to keep moving forward.Authors’ contributions
Wrote the first draft of this paper: Miranda I
Added additional information and edits: Hagerman RAvailability of data and materials
Not applicable.Financial support and sponsorship
Support for this research comes from the Azrieli Foundation, private donors, and the Intellectual and Developmental Research Center at the MIND Institute NICHD (grant P50 HD103526).Conflicts of interest
Dr Hagerman has been funded by Zynerba to carry out a controlled trial of CBD in individuals with Fragile X Syndrome. The Azrieli Foundation has funded Dr Hagerman to carry out a controlled trial of metformin in individuals with Fragile X Syndrome. Dr Miranda has no conflicts pertinent to this paper.Ethical approval and consent to participate
Not applicable.Consent for publication
© The Author(s) 2023.
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Cite This Article
Miranda I, Hagerman R. Molecular mechanisms for targeted treatments in fragile X syndrome. Rare Dis Orphan Drugs J 2023;2:20. http://dx.doi.org/10.20517/rdodj.2023.21
Miranda I, Hagerman R. Molecular mechanisms for targeted treatments in fragile X syndrome. Rare Disease and Orphan Drugs Journal. 2023; 2(4): 20. http://dx.doi.org/10.20517/rdodj.2023.21
Miranda, Isabel, Randi Hagerman. 2023. "Molecular mechanisms for targeted treatments in fragile X syndrome" Rare Disease and Orphan Drugs Journal. 2, no.4: 20. http://dx.doi.org/10.20517/rdodj.2023.21
Miranda, I.; Hagerman R. Molecular mechanisms for targeted treatments in fragile X syndrome. Rare. Dis. Orphan. Drugs. J. 2023, 2, 20. http://dx.doi.org/10.20517/rdodj.2023.21
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