Introduction

Fragile X Syndrome (FXS) is a genetic condition which causes mild-to-moderate intellectual disability and characteristic physical features such as a long narrow face, protruding ears, flat feet, enlarged testicles and hyperflexibility. It results from a mutation in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene in the X chromosome that affects the synthesis of FMR1 protein, which is necessary for adequate brain development. FXS is present in about 1 in 6000 live births with people assigned male at birth (AMAB) being affected twice as frequently.¹

FXS is often associated with delays in intellectual and language development, which can highly interfere with learning, interpersonal communication and performance of daily tasks. In addition, it is frequently accompanied by neuropsychiatric conditions such as anxiety, social phobias, Autism Spectrum Disorder (ASD), and Attention-Deficit Hyperactivity Disorder (ADHD). In 10-15% of individuals also experience recurrent seizures which if not managed properly can pose serious health risks. As such, Fragile X Syndrome can be a severe burden for patients and families, potentially leading to emotional stress, social isolation, caregiving demands and financial strain. Psychosocial interventions such as support groups, social welfare networks and raising community awareness can minimise these barriers and promote the development of new research and treatments.²

This article aims to provide a summary of the latest research and emerging therapeutic strategies for Fragile X Syndrome and how they might hopefully improve health outcomes and foster well-being in patients and families.

What is fragile x syndrome

Fragile X Syndrome results from a mutation in the gene that encodes the protein FMR1, usually characterised by too many CGG repeats which leads to the methylation, that is silencing, of the gene. This causes an inability to produce FMR1 protein, which plays an important role in the development of connections between neurons, thus resulting in alterations in brain circuits that can cause neurological, developmental and psychiatric abnormalities. It was originally believed that the mutation followed a typical X-linked dominant inheritance pattern and therefore everyone with the mutation would develop the disease.³ 

However, studies have shown it might be more complex as some individuals appear to be asymptomatic carriers that show CGG expansion but not enough to cause methylation of the gene. They can pass down the disease to their offspring though due to increases in the number of CGG repeats with new generations. In addition, since people assigned female at birth (AFAB) have two X chromosomes, they can undergo inactivation of one of their X chromosomes if the mutation is present, resulting in normal translation of the other allele.⁴ 

Features of Fragile X Syndrome in children and adults are:

• Mild-to-moderate learning disability, which causes difficulties in problem-solving and language skills
• Specific facial features such as a long face, large ears and prominent jaw and chin
• Enlarged testicles in post-pubertal males (macroorchidism)
• Connective tissue abnormalities, particularly flat feet, hypermobile fingers and high-arched palate (high-arched roof of the mouth)
• Neuropsychiatric conditions such as ASD, ADHD, anxiety and social phobia/withdrawal
• Seizures ³

In children with developmental delays and/or with other characteristic symptoms of FXS, diagnosis can be confirmed with genetic testing to look for the number of CGG repeats in the FMR1 gene on chromosome X. Alternatively, if there is a high risk in the family, doctors can order a prenatal test in which a sample of placental tissue or amniotic fluid is taken from the mother's uterus to test the genome present. 

There is no known cure for Fragile X Syndrome, instead, management is aimed at promoting quality of life, addressing special care needs and alleviating specific symptoms. Individualised learning support plans, school accommodations and help from professionals in special needs education can address intellectual difficulties. In addition, cognitive and occupational therapy as well as support groups for patients and families can mitigate FXS-associated emotional problems and mental health impacts of disability. Pharmacological therapies often also play an important role, these can include anti-seizure medication and drugs used to manage common comorbid psychiatric disorders such as Anxiety and ADHD.⁵

Current research in fragile x syndrome

Research in the genetic and molecular biology of Fragile X Syndrome has proposed different mechanisms as to how a loss of function mutation in the FMR1 gene can occur. Usually, individuals have 5-55 CGG repeats. In FXS, however, a CGG expansion causes patients to have over 200, which leads to the methylation of the gene, essentially silencing it and preventing the translation of the FMR1 protein. 

Fragile X Messenger Ribonucleoprotein 1 (FMR1) is involved in the transport of mRNA molecules into synapses (the connections between neurons), which are responsible for regulating the expression of receptors that bind to the neurotransmitter Glutamate. Researchers have found that a deficiency in FMR1 results in abnormalities in neuronal receptor expression, with respective increases and decreases in different Glutamate receptor types. In turn, this can affect the shape of neurons and synapses and the appropriate development of neural circuits. 

Overall, these changes in neurotransmission most likely underlie the learning and cognitive difficulties seen in FXS patients.⁶ In addition, studies have found this may result in behavioural and emotional abnormalities, with as much as 73% of individuals with FXS fitting a diagnosis for ADHD. ASD, anxiety, social withdrawal, self-injurious behaviour and isolation are also common.⁷ 

Emerging treatments for fragile x syndrome

Current pharmacological interventions for FXS include medications used in anxiety and ADHD such as antidepressants and psychostimulants. However, research has identified the possibility for new disease-modifying pharmacotherapies, most notably a new class of compounds known as mGlu5 inhibitors. These drugs antagonise the mGlu5 receptor which is believed to be overexpressed in FXS and have yielded promising results in ameliorating animal models of cognitive deficits.⁸ Other targeted therapies being investigated include Acamprosate, a drug traditionally used to treat alcoholism which interacts with Glutamate receptors and has been found to improve both intellectual and emotional difficulties in FXS; and the antibiotic Minocycline, which can affect levels of neuroproteins and rescue normal behaviour in studies with mice lacking the FMR1 gene.⁹ 

In recent years, researchers have also been investigating the possibility of directly altering the genome to correct mutations, including Fragile X Syndrome. CRISPR is a genetic editing technique in which an enzyme is used to slice portions of DNA with unwanted mutations and replace them with a scientifically designed genetic sequence to normalise or alter gene expression. In FXS, CRISPR can be used to correct the FMR1 gene through injection directly into the brain of a virus containing the splicing enzyme and an engineered functioning FMR1 gene. More research is still needed. However, to understand how this can be carried out and the potential risks associated.¹⁰

FAQs

Q1: What is fragile x syndrome? 

A: Fragile X Syndrome (FXS) is a genetic disorder caused by a mutation of the FMR1 gene on the X chromosome. Symptoms of FXS can include intellectual disability, speech and language delays, psychiatric problems and distinct physical features such as a long face, large ears, and flexible joints.¹

Q2: How is fragile x syndrome diagnosed? 

A: FXS is diagnosed through genetic testing, specifically a DNA test called the FMR1 DNA test, which can detect the mutation responsible for the syndrome. This test is typically recommended for individuals showing signs of developmental delays and/or other symptoms associated with FXS. 

Q4: Can fragile x syndrome be cured? 

A: Currently, there is no cure for FXS. However, various treatments and therapies can help manage symptoms and improve quality of life. These include educational interventions, behavioural therapies, speech and occupational therapies, and medications to address specific symptoms such as anxiety, ADHD and seizures.⁵

Q5: Are there any new treatments or research developments for fragile x syndrome? 

A: Yes, ongoing research is focused on developing new treatments, including pharmacological treatments, gene therapy, and behavioural interventions. Clinical trials are testing new drugs that target the underlying mechanisms of FXS, and advances in genetic research hold promise for potential future therapies.

Summary

Fragile X Syndrome is a potentially debilitating genetic disorder that is characterised by a mutation in the FMR1 gene on Chromosome X. FXS causes learning disability and characteristic physical features, often accompanied by psychiatric problems and, more rarely, seizures.

Fragile X Syndrome can affect developmental milestones and cause severe occupational and language disabilities, as well as lead to emotional strain, social isolation and financial burden for those affected and their loved ones. However, there is still no known treatment or cure and awareness of the disease among the general public remains low. As such there is a need for more research on the pathophysiology of the condition and potential new treatments. On the other hand, researchers, over the past decades have made some important advances and there is hope for emerging treatments, including gene editing, new pharmaceuticals and behavioural interventions.