Introduction

Fragile X Syndrome (FXS) is a genetic condition that results in various behavioural and physical symptoms, many of which coincide with characteristics seen in those with Autism Spectrum Disorder (ASD). Research has shown that these two conditions are being increasingly co-diagnosed, which is no surprise due to the similarities in disruption to synaptic function and neuronal connectivity.¹ Given the recent surges in global autism diagnoses, research into understanding the pathophysiology of ASD is only becoming more pressing, therefore focusing research into comorbid conditions like FXS will be immensely valuable in improving interventions and support for these individuals.

What is Fragile X Syndrome?

Fragile X Syndrome is caused by mutation in a single gene, resulting in  developmental and intellectual disabilities in the affected individual. FXS affects males more (and more severely) than females: approximately 1 in 4000 males are affected with FXS compared to 1 in 8000 females.² The symptoms that occur from this syndrome are lifelong and most people with FXS aren’t able to live independently. This highlights the importance of increased research and awareness into FXS, so that the condition can be detected earlier and interventions can begin earlier, in order to improve the quality of these individuals’ lives.

Cause

FXS is an X-linked condition as the mutated gene that causes the syndrome is located on the X chromosome. This disease-causing gene is known as FMR1 and its role is for synthesising FMRP, a regulatory protein. FMRP is necessary in regulating the production of other proteins and is important in synaptic development.

The genetic problem in FXS is a stutter mutation in the FMR1 gene. This is because the FMR1 gene normally has a CGG triplet repeated 5-40 times, however those with FXS have the triplet repeated more than 200 times.² This mutation leads to a change in the base sequence, leading to the silencing of the gene. Therefore, FMR1 can no longer be transcribed and translated into FMRP.

The consequence of this is that there is now less FMRP, resulting in changes in synaptic development. This will disrupt the transmission of electrical impulses, leading to a change in the nervous system’s functioning. These consequences are then observed as the symptoms of FXS.

Symptoms

The disruption to the nervous system in various FXS can result in physical, cognitive or behavioural symptoms. These can include:

• Developmental delays
• Intellectual disabilities
• Social problems
• Hyperactivity
• Sleeping difficulties
• Anxiety
• Impulsiveness

Developmental delays can be detected early on in a child’s life by noticing if the child takes longer to walk, sit or talk compared to other children the same age. Intellectual disabilities can also be identified if the child is having difficulty learning new skills (e.g. slower at learning to read than others their age).³ It is important to note that the range of cognitive impairments can vary largely amongst individuals with FXS, which is why early detection and diagnosis is important to give a personalised care plan and support for the child.

Diagnosis and management

Often genetic testing methods and screening protocols are used to help with the detection of FXS. The main method used to diagnose FXS is using a blood sample.⁴ This will test for a potentially mutated FMR1 gene. It is important that this test be done as early as possible in a child’s life in order to intervene early. For this to happen, parents and carers need to be aware of the signs and symptoms to recognise in their children, so then they’ll be able to seek for the most appropriate support.

Currently, there is no cure for FXS. There are only medications or therapies that can be given to help manage and control some of the symptoms of the syndrome. For example, Risperidone  (Risperdal) can be given to help control aggression, and other medications may be given to control hyperactivity or mood instability. Other interventions include special education, physiotherapies, speech and language therapies.⁵

All of these are interventions that are similarly used in supporting individuals with autism.

What is Autism Spectrum Disorder?

The World Health Organisation describes Autism Spectrum Disorder as ‘a diverse group of conditions related to the development of the brain’ and is often characterised by ‘some degree of difficulty with social interaction and communication’.⁶

These characteristics usually begin early in childhood but the age at which individuals are diagnosed can vary largely. Unlike FXS, there is no specific cause of ASD, as there are various genetic and environmental factors that can result in disruption to neuronal connectivity- leading to the features of ASD. This is one of the reasons why ASD presents very differently in individuals, resulting in a ‘spectrum’ of characteristics.  The complexity of the ASD’s etiology can make it difficult in detection and diagnosis as it is not simple as a DNA blood test.

Cause

Research has shown that ASD can be caused by environmental influences, neurobiological factors or genetic factors. Environmental factors include: if the developing foetus is exposed to a maternal immune response in the womb, birth complications or even prenatal exposure to air pollution can be a risk factor.⁷ There are also many studies that suggests genetics being a strong component to autism, however there is limited research to confirm all of the specific genes are linked to autism. This genetic influence is supported by results from a study that showed almost 20% of younger siblings of a child with autism, will also be diagnosed with ASD.⁸

Gene mutations such as DUP15q and FMR1 have been shown to result in symptoms similar to those observed in those with autism- developmental delay, motor delay and impacts on social communication. However, the FMR1 mutation that leads to FXS is said to be ASD’s most common known monogenic cause.⁹

Signs of ASD

These will vary greatly between individuals, but some characteristic can include:

• Avoiding eye contact
• Repetitive speech or movements (e.g. flapping hands)
• Not doing as much pretend play as others their age
• Not talking to other children
• Liking a strict routine and getting upset when there are changes to this
• Keen interests in certain topics

It is often more difficult to identify autism in girls, compared to boys as girls may ‘mask’ their signs by trying to copy how others around them behave and play. Girls also appear to cope better with social situations and show fewer repetitive behaviours.¹⁰ All of these factors mean that many girls with autism are often left undiagnosed, therefore are not given the appropriate support.The consequence of this is that it leaves these individuals at a high risk of developing mental health conditions. This signifies the importance of raising more awareness about signs of autism so that children can be diagnosed as early as possible to ensure they are supported in the best way possible as they grow.

Diagnosis and intervention

Unlike FXS, autism diagnoses are based off on behavioural assessment which focuses on the DSM-5 criteria, since there are no confirmed genetic markers of ASD, yet.⁶ Globally, there are various different forms of behavioural therapies, medications and educational methods that have been used as interventions to help with difficulties that some individuals with autism may face For example, in England, the NHS’ main interventions are Behavioural, Speech, Language and Occupational therapies and doctors may prescribe any medications for associated medical issues (e.g. sleep difficulty, aggression, seizures, speech difficulty etc).¹⁰ Improving awareness within schools, will ensure that teachers are trained to give autistic students appropriate support or to identify any students that may potentially need to be referred for a diagnostic assessment.

Connection between Fragile X Syndrome and Autism Spectrum Disorder

It has been found that nearly 20% of females and 50% of males, with FXS, meet the diagnostic criteria for ASD. These statistics reinforce the importance of continued research into understanding the relationship between the two conditions: further genetic analysis in FXS could help improve detection and interventions for individuals affected by either disorder. 

As previously mentioned, FXS involves reduced levels of the protein FMRP. It has been found that FMRP regulates several proteins that are linked to ASD. This means that irregular quantities of FMRP leads to irregular wiring of the brain, leading to behavioural traits observed in ASD.¹¹ These similarities in neurobiological mechanisms in both FXS and ASD serve as explanations as to the shared symptoms between both conditions. These shared symptoms include:

• Large heads and rapid brain growth in early childhood¹¹
• Difficulty with social interactions
• Repetitive behaviours
• Sensory sensitivities
• Intellectual disability⁵

Despite the similarities, it is important for people to be aware of how to differentiate the two. These are some characteristics that differ between FXS and ASD:

• Individuals with ASD generally have greater levels of motor coordination
• Individuals with FXS generally have a higher interest in socialising, but anxiety or language delays can be limiting factors to this
• A greater frequency of individuals have an intellectual disability in FXS, than in ASD

Why do we care about a link between the two?

Understanding the links and differences between the two conditions is important as this can help with improving diagnosis. With improved genetic research, early detection can increase and this will allow for early interventions meaning individuals seeking interventions can have improved outcomes.

 The link will also help scientists when trying to understand the causes of some of the symptoms listed above: they can differentiate between when the individual shows these characteristics as a result of FXS or whether it is a result of ASD, or a combination of both. This accurate identification will also improve the delivery of appropriate care.

Another benefit for studying the link is that educational resources can be created that will focus on the specific, unique needs of individuals with FXS and autism. This will mean that teachers, caregivers and parents can give better support which can significantly help during the developing years of a child’s life.

Summary

Fragile X Syndrome and Autism Spectrum Disorder are two different conditions which have several overlapping symptoms. While ASD has various environmental and genetic causes, FXS has one known genetic cause. This means that there is a lot more potential for the development of targeted therapies that will focus on the target gene, in order to reverse symptoms. However, with ASD, it is not as simple and there are many ethical doubts raised about developing therapies in the first place.

Continued research and raising awareness of these conditions helps to increase public discussion. This is important as it will lead to improved services, a more inclusive society and an overall improvement in the quality of life of these individuals.