Introduction

Fragile X syndrome is a monogenetic disorder caused by a mutation in a single gene. Despite its single-gene origin, it is a complex disorder that has a wide range of symptoms. The symptoms usually begin around when the individual is 2 years old and are more likely to affect those assigned male at birth more severely due to being an X-linked disorder. Some common symptoms include autism, speech and language delay, and motor delay. There is also a high chance that individuals with fragile X syndrome will have epilepsy.¹ 

Epilepsy is a condition caused by an uneven balance between excitation and inhibition in cells called neurons. This imbalance can lead to overexcitation, which causes seizures. Hypersynchronisation of neuronal activity is another cause of epilepsy. This is when neuronal activity that should not be synchronous becomes synchronous, leading to overactivity of neurons and seizures. Approximately 10-20% of individuals with fragile X syndrome also have epilepsy.²

Causes of fragile X syndrome

Fragile X syndrome is a genetic disorder resulting from a mutation in the FMR1 gene. This gene helps produce FRMP protein, which is vital for neuronal binding and normal brain function. Everyone has a CCG repeat present in their FMR1 gene. However, the number of CCG repeats differs from person to person. The normal range for these repeats is between 5 to 44. However, an increased number of repeats can lead to silencing of the FMR1 gene. There is a correlation between CCG repeats and the effects they can have. For example, if a person has over 200 CCG repeats, it is a full mutation, and the patient would be diagnosed with Fragile X Syndrome. However, if the patient has 55-200 CCG repeats, they are referred to as premutation carriers. While the individual does not have Fragile X syndrome, being a premutation carrier increases their risk of passing on the condition to future offspring.³

Because fragile X syndrome occurs due to a mutation on the X chromosome, individuals assigned male at birth are usually more severely affected by fragile X syndrome. This is because they only have one X chromosome compared to those assigned as a female at birth. Therefore if they have a mutation on their X chromosome, they will not have any compensatory FMRP present. In contrast, individuals assigned female at birth have two X chromosomes, and it is more likely that there is some compensation for the loss and mutation. Therefore, it is less likely that they will be affected as severely if they have fragile X syndrome.³

Symptoms of fragile X syndrome

Fragile X syndrome is a complex disorder and has many symptoms. Some include:⁴

• Large ears
• Elongated face
• Macrocephaly (the individual’s head is bigger than standard)
• Macroorchidism (abnormally large testes after puberty)
• Hyperactivity
• Anxiety
• Socialisation difficulties
• Autism
• Hypotonia (decreased muscle tone)
• Poor eye contact
• Sleep disorders, e.g., sleep apnoea
• Motor delay (late crawling and/or walking)
• Speech and language delay
• Increased chance of aggression
• Epilepsy 

Epilepsy and fragile X syndrome

Hyperexcitability in fragile X syndrome, which is associated with epilepsy, can arise from several underlying causes, including:⁵

• Abnormal synapses (which are how neurons connect and communicate with each other)
• Impairment in how the neuron works and/or the synaptic functions change, causing an uneven balance of excitation and inhibition
• Disruption in ion channel function or a change in the number of ion channels, causing the cells to be more excited without any stimulation

If a seizure is suspected, an electroencephalogram (EEG) will be performed. This involves a doctor attaching small sensors to the head to allow recording of the brain activity. It is important to note that after a seizure occurs, there can be a slowing of brain activity, meaning an EEG performed shortly after seizure activity may not catch the seizure itself. In this case, individuals may be asked to return 2 weeks after a seizure for an EEG then. An EEG may not be diagnostic, but it helps determine whether a seizure has occurred or not.¹

Approximately 25% of fragile X syndrome patients have been diagnosed with partial (focal) seizures, and approximately 31% of seizures reported in fragile X syndrome patients are generalised seizures. The rest are unknown.¹

Epilepsy is common in fragile X syndrome patients, but not every person with fragile X syndrome has epilepsy. However, those who have both epilepsy and fragile X syndrome are more likely to have severe symptoms of fragile X syndrome. This includes severe intellectual disability, sleep apnoea, autism and hyperactivity.¹

Treatment of seizures in fragile X syndrome patients does not differ from regular treatment of epilepsy. However, knowing what type of epilepsy a patient has aids in finding the correct medication. It does sometimes take a couple of different medications to find the best one for each individual as epilepsy is highly complex.¹

Seizure types

Focal onset seizure

When someone is diagnosed with a focal onset seizure, it means that the seizure begins in one area of the brain and then may spread to other areas in the brain. These seizures are more subtle in the sense that the affected individual may look like they are daydreaming. When a patient is focal aware, it means that the person is aware of what is happening around them but may not be able to talk or respond. When someone has focal impaired awareness, it means that the patient may appear confused, vague or disorientated.⁶

Generalised onset seizure

Both sides of the brain are affected right from the start of the seizure. The patient experiencing the seizure may lose consciousness when the seizure begins. Generalised onset seizures can be classified into several types:⁶

• Generalised motor seizure – once the seizure begins, the muscles stiffen and jerk
• Generalised non-motor seizure – there are subtle changes in awareness, staring and potentially automatic or repeated movement, such as lip smacking
• Absence – there is a sudden loss of awareness and responses; this can present like daydreaming
• Tonic-clonic – the body stiffens (which is called the tonic phase), and then the limbs jerk rhythmically (which is called the clonic phase)
• Myoclonic – presents as sudden single jerks of muscle or a group of muscles (the jerking lasts approximately 1-2 seconds)
• Atonic – brief seizures that cause a sudden loss of muscle tone, that the patient commonly falls to the ground
• Clonic – this is an uncommon subtype, but it causes jerking in various parts of the body

Unknown onset seizure

This is a subtype in which it can be either focal or generalised. However, it cannot be diagnosed with the information presented to the specialist. Over time or with further testing, the diagnosis may change to either classification.⁶

Summary

Overall, there is a high degree of overlap between epilepsy and fragile X syndrome. Although there is no treatment for fragile X syndrome, there are treatments for epilepsy. If you suspect your child has epilepsy or fragile X syndrome, it is important to contact a specialist. Do not get discouraged if the anti-epileptic medication does not work the first time, as it may take time to personalise the medicine based on the individual’s history and epilepsy type.