Group: Fragile X Syndrome Issues & Topics

Health experts frequently remind the general public about the mental and physical benefits of a good night’s sleep. However, surveys and research over the past years confirm that many children with Fragile X syndrome (FXS) experience problems with sleep and that these problems can last for many years.

These sleep problems or “sleep disturbances” can make caring for a child with FXS even more challenging, as parents and other caregivers deal with their own need for sleep. Fortunately, as professionals have better understood these sleep problems, interventions have been developed that can lessen their severity. These interventions include the use of medication, which is prescribed and monitored by doctors, and various other interventions that involve behavioral therapists and other non-medical specialists.

Parents can hope that their child’s sleep quality will improve over time. Some of that improvement will occur as a result of the typical techniques that all parents utilize (bedtime routines, nightlights, comfort and security items), but in the case of FXS, specialist intervention may be necessary.

Alternate Version
We also have a more technical version of our sleep recommendations, in which the authors provide detailed descriptions of sleep disturbances, analysis of current and past research related to those with FXS and other neurodevelopmental disorders (NDDs), and recommended interventions. Parents and other care providers may want to share both of these documents with their child’s doctor and others involved in day-to-day care.

It has been well-established that children with neurodevelopmental disorders such as FXS have higher rates of sleep disturbances than those in the general population.[1] Common sleep problems among children with FXS include difficulties with falling asleep, reduced sleep quality, shorter sleep duration, frequent nighttime awakenings, resistance at bedtime, and daytime sleepiness.[2] These sleep problems can coexist and persist across the lifespan.

According to parental reports, which included parents of 1,295 children with FXS, approximately one-third of them currently face sleep issues, and, among those, over 80% are dealing with at least two sleep problems simultaneously.[3] The most common difficulties reported in this study were trouble falling asleep and waking up frequently at night. Additionally, nearly half of the boys and a significant portion of the girls received at least one medication to aid their sleep. Children with more severe health or behavioral challenges were more likely to experience ongoing sleep problems, as in NDDs in general.[4] In another study, caregivers provided information on the sleep patterns of a group of 90 children with FXS using the Children’s Sleep Habits Questionnaire, along with a 14-day sleep diary.[5] The results showed that nearly half of the participants had sleep issues that suggested the need for further evaluation and referral.[6]

The most recent and most extensive analysis of sleep problems data, from the FORWARD research project (a CDC-funded multi-year effort to better understand how FXS presents itself over a person’s lifetime), examined the frequency, severity, and impact of sleep disorders among a group of young individuals with FXS.[7] The researchers found that many individuals with FXS experienced problems, with six of the seven surveyed having sleep difficulties. The seventh, sleep apnea, was found to be less prevalent. The six surveyed common sleep difficulties involved either sleep duration (difficulties falling asleep, frequent night-time awakenings) or sleep quality (morning tiredness, teeth grinding, bed wetting, restlessness).

While initial publications have indicated a lack of differences between males and females, the FORWARD survey found that, except for snoring, sleep problems affected predominantly young males.[8] In addition to sex and age, autistic symptoms are also a risk factor for sleep problems in FXS.[7] The 2017 FORWARD study of autism in FXS found that children and adolescents with FXS and autism had a higher frequency of sleep difficulties than those without ASD.[9]

Several publications have shown that, in terms of severity, sleep problems in children with FXS tend to be mild to moderate.[7] Nonetheless, the large FORWARD survey demonstrated that their impact is substantial, as demonstrated by the frequent use of medications for sleep (nearly half of individuals, especially males) and the strong association with behavioral problems, particularly irritability and aggression.[7] These findings suggest that a shorter night sleep was associated with increased daytime problem behaviors and greater parental stress.[10]

Sleep Apnea in Fragile X Syndrome

Obstructive sleep apnea (OSA) is a sleep disorder characterized by repeated episodes of partial or complete blockage of the upper airway during sleep.[11] OSA can be associated with various neurodevelopmental disorders.[12] The blockages can cause breathing to stop for short periods, leading to disrupted sleep patterns and a decrease in oxygen levels in the blood. While some signs and symptoms of sleep apnea can be similar in both children and adults, certain features are more commonly observed in children: loud and persistent snoring, breathing pauses, restless sleep, mouth breathing, sleeping in unusual positions, and more.

It is important to note that not all children with OSA will display all of these characteristics. Additionally, some children may not snore loudly, making identifying the condition more challenging. If parents or caregivers notice these signs or suspect their child may have OSA, it is crucial to consult a healthcare professional for proper evaluation and diagnosis.[13] Specifically, the recent FORWARD study found that, according to parental reports, approximately 8% of children with FXS had a history of OSA.[14] However, clinicians reported a lower prevalence of OSA, with only 3.4% of individuals affected. Notably, these figures for OSA frequency differ significantly from the 30% of children reported to have loud snoring.

Studies have revealed a strong link between sleep apnea, intense snoring, and an association between OSA and morning tiredness or frequent night-time awakenings. In other words, loud snoring, when severe, and usually in teenage boys, indicates a high risk for OSA.[7] These findings have important implications for the management of children with FXS, as OSA may be underdiagnosed, particularly in patients with more challenging behaviors. It’s worth considering that individuals with less severe snoring symptoms may still have OSA, especially if it presents as gasping rather than snoring.

In line with advances in the field of pediatric sleep disorders, the diagnosis of sleep problems in individuals with NDDs has evolved from informal reports by caregivers to the use of standardized instruments.[14]

For detailed descriptions of the tools used to evaluate sleep disturbances, which you can print and share with your doctor or other care team members, we have a more technical alternate version of our sleep recommendations, in which the authors provide detailed descriptions of sleep disturbances, analysis of current and past research related to those with FXS and other neurodevelopmental disorders (NDDs), and recommended interventions. Parents and other care providers may want to share both of these documents with their child’s doctor and others involved in day-to-day care.

Sleep problems in individuals with FXS can be a significant problem for caregivers. Sleep problems requiring treatment occur more frequently in adolescents and young adults with FXS and autism than in their counterparts without autism. In contrast, sleep problems requiring treatment occur with equal frequency in children with FXS with and without co-occurring autism.[15] A recent FORWARD investigation showed that sleep difficulties are associated with behavioral problems in individuals with FXS. Indeed, the presence of any of the sleep problems was more frequently associated with the occurrence of irritability and aggression. All sleep problems, except morning tiredness, were also associated with hyperactivity.[7] Self-injurious behavior in males with FXS has also been associated with a number of co-occurring conditions, including sleep problems.[16]

There is some data from other populations that behavior can improve with treatment of a sleep disorder. In a study using an extended-release preparation of melatonin, increases in sleep duration in children with autism were associated with improvements in behavior.[17] One study showed that treating obstructive sleep apnea in typically developing children improved behavior.[18]

The recommendations for treatments for sleep problems in children with FXS presented here are primarily based on treatment for sleep disorders in autism or NDDs in general.[19]

Non-Pharmacological Treatment

The initial approach to addressing sleep difficulties involves applying behavioral techniques (sleep hygiene). These include establishing regular sleep times, following consistent bedtime rituals, and using calming methods for both going to bed and waking up in the middle of the night.[20] Nonetheless, these techniques might not always be enough, and in some cases, using medication alongside these strategies could be necessary.

Pharmacological Treatment

If behavioral strategies alone are not effective, medications are suggested. Always consult with your child’s doctor before undertaking any treatment involving medication. Never use medications prescribed for a different individual.

See the section on sleep in Medications for Individuals with Fragile X Syndrome for more details about the pros and cons of each medication, dosages, and timing.

• Melatonin: Melatonin is the first-choice drug for sleep issues because it has the largest body of evidence. It is generally a safe option, although drowsiness, dizziness, headaches, and increased enuresis have been reported. Clinical trials have demonstrated that melatonin is effective for sleep-onset insomnia, increasing overall sleep time, but does not decrease nocturnal awakenings (maintenance insomnia).[21]
• Clonidine: If melatonin is ineffective, the most commonly used alternative is clonidine. It is available in multiple formulations, including extended-release and transdermal patches. It is worth noting that over time, effectiveness may diminish, potentially necessitating higher doses to achieve the same outcome. Clonidine appears to be effective for night waking, sleep latency, and sleep duration, and, because of its behavioral effects, it should be considered for children who also present with behavioral symptoms. Clonidine is, in general, well tolerated; its side effects include daytime drowsiness. If needed to be discontinued because of adverse effects or lack of effectiveness, clonidine should be reduced slowly over 2 to 7 days.[22]
• Trazodone: The antidepressant Trazodone can also be used at bedtime. Although typically well tolerated, trazodone might make individuals feel tired.[22]
• Other Drugs: Diphenhydramine and hydroxyzine are suggested for short-term use. Please note that some individuals may become hyperactive on diphenhydramine. In addition, hydroxyzine can be used for sleep and anxiety throughout the day. The recommended dose for these medications depends on age and weight. If all medications mentioned do not work, the antidepressant mirtazapine could be considered.[23] Side effects include increased appetite and body weight. Other alternative drugs include gabapentin, atypical antipsychotics (risperidone, quetiapine), and hypnotics (clonazepam, zolpidem, temazepam, suvorexant).[22]

Complementary and Alternative Interventions

These include massage therapy, aromatherapy, and weighted blankets. The few studies investigating these treatments do not support their usefulness, although the latter are well tolerated.[24]

Data from the FORWARD project and the literature support the notion that, as in other NDDs, sleep problems are frequent and impactful in FXS. These findings emphasize the need for early diagnosis and tailored interventions in groups who are particularly at high risk, namely young children, males, and those with severe autistic behavior. Accurate diagnosis of sleep problems in FXS requires incorporating specialized tools, such as standardized questionnaires. For those concerned about sleep apnea, a referral to a center performing a sleep apnea test, called a polysomnogram (PSG), is encouraged. This may be done in a sleep disorder center or even at home.

Note: As previously noted, a more technical, descriptive, and detailed version of this treatment recommendation is available. It was also written by medical experts within (and reviewed by) the National Fragile X Foundation’s Fragile X Clinical & Research Consortium.

Supporting individuals with FXS with their speech and language development is something that should be considered across the lifespan. Many of the strategies (e.g., shared book reading, expansion of phrases) are ones that can be used regardless of age and are useful across a wide range of communication abilities. Caregivers and professionals should not hesitate to “borrow” from other ages to find appropriate assessment and intervention tools. The most important consideration is what the individual needs at that time, and choices should be focused on what is developmentally appropriate.

Another common theme is that a variety of factors impact communicative ability. These can include the setting in which communication occurs, the sensory regulation of the individual at that moment, the demands of the specific task, and so on. To be successful, it is crucial that all parties communicate, including teachers, therapists, caregivers, employers, residential workers, and family members. Supporting interaction and communication among the previously mentioned collaborators will ensure the highest possible communication outcomes.

FXS is a genetic condition that can cause learning disabilities, developmental delays, and social and behavioral issues. Significant anxiety is also very common. Although FXS occurs in both genders, males are more frequently and typically more severely affected than females. FXS is the most common cause of inherited intellectual and developmental disability and the most common, known single-gene cause of autism spectrum disorder (ASD).

FXS is caused by a DNA expansion in the FMR1 gene, which is located on the X chromosome. The FMR1 gene includes a repeated DNA code commonly referred to as “CGG repeats,” as it is composed of DNA elements called cytosine-guanine-guanine (CGG). Most everyone has the FMR1 gene as well as these CGG repeats.

Typically there are up to 45 CGG repeats, with people in the general population commonly having around 30 CGG repeats. Some people have a small expansion in the gene, with a range of 45–54 CGG repeats, which is also known as an “intermediate” or “gray zone” expansion. Individuals with larger expansions may have a premutation (55–200 CGG repeats) or a full mutation (more than 200 CGG repeats). Most people with FMR1 full mutations show symptoms of FXS.

When the FMR1 gene has >200 CGG repeats (full mutation), a process called methylation occurs that turns the gene off so it cannot make its protein product, FMRP, and thus results in decreased or absent FMRP; it is FMRP that is needed for typical brain development and functioning. Symptoms of FXS are typically caused by the absence of FMRP due to complete methylation of the FMR1 gene when there is a full mutation present.

Mosaicism is a term describing two or more genetic results in the same individual and mosaicism may result in variability in symptoms. In Fragile X syndrome, there are two types of mosaicism:

1. Size Mosaicism: The most common type of mosaicism in Fragile X syndrome, indicating one or more different CGG repeat numbers in the same individual, such that some CGG repeats are in the normal or premutation range and others CGG repeats are in the full mutation range.
2. Methylation Mosaicism: This indicates a pattern where some cells have a methylated FMR1 gene, which is therefore turned off (no FMRP being produced) while other cells in the same individual have an unmethylated FMR1 gene, which is still able to make FMRP. This pattern may also be called partially methylated when present.

Size Mosaicism

Because of the instability of the CGG repeat when passed down from one generation to the next generation, an individual can have both cells that have CGG repeats in the typical, intermediate, or premutation range, while the remaining cells have CGG repeats in the full mutation range. This situation is termed size mosaicism. Since FMRP is typically produced when there is a typical, intermediate, or premutation CGG repeat size, FMRP levels in individuals with size mosaicism may be higher than in individuals with only a full mutation CGG repeat. Size mosaicism may contribute to variable symptoms in these individuals.

Methylation Mosaicism

The process of FMR1 silencing through gene methylation may not occur equally in all cells. This situation is the basis for a second type of FMR1 mosaicism — methylation mosaicism — in which those with the full mutation may produce FMRP in a variable proportion of cells.

Both size mosaicism and methylation mosaicism can be present, but regardless of mosaicism status, individuals with an FMR1 full mutation will almost always show a reduction in typical FMRP level, with wide variability in symptoms.

Also see: Size and Methylation Mosaicism in Males with Fragile X Syndrome
— Expert Review of Molecular Diagnostics

As a group, people with mosaicism tend to be higher functioning with fewer symptoms. However, this cannot be predicted on an individual basis. The degree of size or methylation mosaicism detected in blood does not necessarily reflect the pattern of mosaicism in the brain or other body tissues.

A recent report from our multi-year, multi-clinic, CDC-funded FORWARD study showed that methylation mosaicism is associated with better cognitive functioning and adaptive behavior (less significant developmental delay) and less social impairment relative to the fully methylated full mutation. In contrast, the presence of size mosaicism was not significantly associated with better cognitive and behavioral outcomes than full mutation.

More research needs to be done, but knowing more about how FXS differs in people with and without size and methylation mosaicism may eventually help guide expectations and treatment of individuals with FXS. For now, the general education and therapy recommendations made for individuals with a full mutation of FXS apply to those with mosaicism, but consideration should be given to the specific needs and functioning of the individual.

What is a Seizure?

A seizure is a single event characterized by an abrupt change in behavior (e.g., staring without response, dropping to the ground, or twitching a part or all of the body). What you don’t see is that the behavior is accompanied by a burst of electrical discharges that comes from neurons in the brain, i.e., the behavior appears in association with the burst and then goes away when the burst is over. A seizure occurs either as primary excess electrical excitability in an otherwise normal brain or secondary to another disorder. In Fragile X syndrome (FXS) the excess electrical excitability is most likely related to the effects of the genetic change in the Fragile X gene (FMR1) and the resultant loss or reduction of the Fragile X protein (FMRP) on activity in neurons.

Other causes of seizures have to be considered in a person with Fragile X syndrome as there could be another diagnosis in addition to the FMR1 gene mutation. These causes include:

• An acute response to a new condition (such as trauma, infection, stroke, toxin/drug, tumor, metabolic problem)
• A delayed effect due to a recent disease (trauma, infection, surgery)
• A permanent brain “scar” from an old disease (stroke, prenatal or perinatal insult, tumor, infection)

A seizure refers to the event that occurred. A person is said to have epilepsy when they have had recurrent (at least two) seizures.

Seizures are classified according to the International League Against Epilepsy (ILAE) Classification of the Epilepsies.

Focal Seizures (aka Partial Seizures)

Focal onset seizures are seizures starting on one side or in one area of the brain. These are divided into focal aware seizures, in which the person is awake but having a localized seizure manifestation (like an arm twitching), and focal seizures with impaired awareness, in which there is an alteration of consciousness (also commonly referred to as complex partial seizures, or CPS). A focal seizure can spread to the entire brain and “generalize,” becoming a focal to bilateral seizure. Focal seizures may signify a problem in a specific area of the brain or may occur as part of a genetic syndrome without a specific area of the brain being abnormal.

Generalized Seizures

Generalized seizures involve both sides of the brain all at once. These include generalized motor seizures, which can be:

• Tonic-clonic: Stiffening followed by jerking
• Tonic: Stiffening
• Clonic: Jerking
• Myoclonic: Single or clusters of jerks
• Atonic: Sudden loss of tone — head drops, falls
• Absence or generalized non-motor seizures: Staring, eye blinking

Generalized tonic-clonic (GTC) seizures (known in the past as “grand mal”) are the most well-known seizure type and occur instantly, sometimes associated with a loud cry at the onset. Typically, the eyes open and roll up, and there may be noisy breathing, jaw clenching, oral secretions pooling in the mouth, stiffening and jerking throughout the body, incontinence, and drowsiness after the seizure is over.

Status Epilepticus Seizures

Status epilepticus is a single or repeated seizure lasting more than 30 minutes. This may be associated with poor breathing effort (shallow breathing), increased blood pressure, pulse, and temperature.

Febrile Seizures

Febrile seizures are a specific kind of short, generalized seizure occurring only with fever in children aged 6 months to 5 years. A range of 2%-5% of typical children have these, so they are very common in the population and they go away by age 6. As this type of seizure is so common, there will of course be individuals with Fragile X syndrome who have febrile seizures, but it is not thought these are increased in Fragile X syndrome.

In the evaluation of seizures, it is important to collect a detailed moment-by-moment history of the event, including:

• Activity
• Body position
• Progression
• Duration
• Loss of sphincter tone, resulting in urination or a bowel movement
• Tongue biting
• Visual, auditory, or olfactory auras

This will help determine if the event was likely an epileptic seizure versus a non-epileptic spell that might include things like:

• Shuddering
• Breath-holding
• Benign nocturnal myoclonus (twitching when falling asleep)
• Night terrors
• Migraine
• Panic attack
• Fainting
• Hyperventilation
• Heart arrhythmia

Initial seizures are usually evaluated with a laboratory evaluation that might include glucose, electrolytes, and calcium, and if the seizure seems like a focal seizure, an MRI would be obtained. An elevated prolactin level can also verify a recent seizure. A spinal tap may be needed to rule out infection if there is fever or an extended change in responsiveness beyond the seizure. An EEG (electroencephalogram) is usually done two weeks after the seizure to look for abnormal discharges and determine their location and character.

Typically, patients would be referred to neurology to manage seizures although in uncomplicated cases the primary care physician may handle the problem. Referral to neurology should always be done when there is confusion over:

• Whether the person is definitely having seizures
• The cause of the seizures

Or if:

• There is poor response to single drug treatment
• The physician is uncomfortable with seizure treatment
• The family is anxious about management options
• The patient has a complex mix of problems — e.g., behavior, learning disability, seizures — that may involve a specialized approach

Use of EEG

The EEG is used in people with seizures to:

• Diagnose the type of epilepsy
• Determine if episodes are actually seizures
• Identify epilepsy syndromes
• Help guide treatment decisions

After a major seizure there may be slowing of the brain activity and suppression of seizure foci so because the EEG may miss seizure activity, it is better to get the EEG two weeks after a major seizure. Ambulatory EEG (an EEG that a person wears for one or more days at home, such as Neurotech and DigiTrace) is used to monitor spells that may or may not be seizures so that the correct diagnosis can be made.

It is important to recognize that while a routine EEG is indicated to help guide treatment for a person suspected of seizure disorder, it may not be diagnostic, which means one has to rely on clinical judgement. Many individuals with FXS and seizure disorder have an abnormal EEG characterized by focal spikes or sharp discharges, however, those with FXS who will never have seizures may also have this or other abnormal EEG patterns. Individuals with FXS and seizure disorder may show other abnormalities on an EEG, or no abnormalities at all.

Thus, the EEG is not a useful test for individuals with FXS who do not have clinical episodes concerning seizures, because it does not predict who will develop clinical seizures.

There have been multiple reports in medical journals describing seizures in FXS and those reports studying the larger groups have identified seizures in 4.4%-18% of individuals with FXS.[1, 2, 3, 4, 5, 6, 7] Many children with FXS also have abnormal EEGs without overt epileptic seizures.[3, 5, 7] When seizures do occur, both focal and generalized types of seizures are seen. Seizures are reported to be easily controlled in most cases and have been thought to resolve during childhood in the majority of individuals with FXS.[3, 6, 7]

Frequency of Seizures in Fragile X Syndrome

Recently, the largest and most definitive study yet published on seizures in FXS was completed using FORWARD (Fragile X online registry with accessible research database) a multisite observational study initiated in 2012 involving participants seen at Fragile X syndrome clinics in the Fragile X Clinic and Research Consortium.[8] The study analyzed data on seizures collected longitudinally every year for multiple years of time from 1,607 participants with FXS. In this study the overall chance of having at least one seizure was 12% overall in FXS, 13.7% in males and 6.2% in females.

Age of Onset and Resolution of Seizures in FXS

In the group with seizures, the average age of the first seizure was 6.4 years with the great majority (86.7% of males and 81.8% of females) having the first seizure before age 10 years (see Fig.1A).

• For males, 96% had the first seizure by age 15, meaning that only 4% of those with seizures (0.5% or 1 in 200 of all males with FXS) had a first seizure after age 15.
• For females with seizures, 18.2% (1% of all females with FXS) had their first seizure after age 15.

The age of the last seizure followed a similar age dependence to age of first seizure, with 70.9% of seizures in males and 63.6% of seizures in females resolving by age 10 (see Fig. 1B). Only 7.9% of males and 18.2% of females (1% or 1 in 100 of all males and females with FXS) still had seizures continuing after age 20.

New onset seizures occurred in participants in FORWARD at a rate of 0.013 new seizures per person, per year of follow up, meaning about a 1 in 100 chance of having a first seizure each year for those in follow-up. Seizures changed type, for instance, a person with generalized seizures began to have focal seizures in about 4.2% of males with FXS, and seizures each year of follow-up.

Figure 1A-B: Age of Onset and Resolution of Seizures in Fragile X Syndrome

Partial (focal) seizures were reported in 25% and generalized seizures in 31% of those with seizures, with febrile seizures in 8% and the remainder of seizures being of unknown type (see Fig. 2).[8] Males and females did not show a different distribution of seizure types.

Figure 2: Seizure Types in Fragile X Syndrome

Association of Seizures with Other Fragile X Syndrome Characteristics

As compared to individuals with FXS without seizures in FORWARD, those with seizures were more likely to have more severe intellectual disability (see Fig. 3A), current sleep apnea, delayed acquisition of expressive language, autism spectrum disorder (see Fig. 3B), hyperactivity, irritability, and stereotyped movements.[8] The association with ASD confirmed findings from several prior studies suggesting an association of seizures with ASD in FXS.[9, 10, 11] For those with FXS and epilepsy, about half (52%) had seizures for more than three years. This group was found to have greater cognitive and language impairment, but not behavioral disruptions, compared with those with seizures for less than three years.

Figure 3A-B: Association Between Intellectual Disability, Autism Spectrum Disorder, and Seizures in Fragile X Syndrome

In summary, based on the FORWARD data, 12% of people with FXS have seizures. Treatment and management of seizures in FXS are similar to seizure treatment in other conditions associated with seizures.

There is no FXS-specific medication or approach to treating seizures, but the approach is to try to use the medications expected to have the least side effects first and those not requiring blood monitoring. In general, seizures are easily controlled in FXS and most patients grow out of their seizures before their 20s although, infrequently, seizures can be a more challenging problem.

My patient isn’t having any seizure-like symptoms, but his family would like me to do an EEG anyway. Is this necessary?

The EEG is generally used to provide data to support or detract from a clinical suspicion. As discussed above, however, many nonepileptic individuals with FXS have striking abnormalities on EEG, while some individuals with seizures and FXS may have mild or no abnormalities on this study. Because of this the EEG is not helpful in evaluating individuals with FXS and no clinical symptoms of seizures. If your patient is having a significant unexplained change in sleep habits, decline in communication skills, or dramatic increase in aggression, it may be appropriate to order an EEG even though these symptoms are not typically epileptic.

My patient’s teacher is reporting that she “stares into space” frequently and does not respond when her name is called. The teacher has to touch the child’s shoulder to get her attention. The staring lasts for several minutes and does not seem to be associated with any focal motor symptoms. The parents, who have never seen these spells at home, know about the association between Fragile X syndrome and seizures and are concerned.

Although staring and inattentive episodes are universal in students, they are more common in children with ADHD and intellectual disabilities. They may be more likely in less stimulating environments or when the child is overwhelmed or fatigued. The parents’ description of these episodes is not highly concerning for seizure, as the child becomes alert when they are touched. In addition, the symptoms seem dependent on environment, whereas seizures tend to occur across environments.

Seizures and Epilepsy in Childhood: A Guide 
A family-friendly book reviewing the medical and psychological issues related to seizures. By John M. Freeman, MD; Eileen P. G. Vining, MD; Diana J. Pillas (Johns Hopkins University Press).

Note and Disclaimer: The National Fragile X Foundation (NFXF) does not provide medical or legal advice or services. Rather, the NFXF provides general information about Fragile X as a service to the community. The information provided in this document is not an endorsement of any resource, therapeutic method, or service provider and does not replace the advice of medical, legal, or educational professionals. The NFXF has not validated and is not responsible for any information or services provided by third parties. Use independent judgment, request references, and seek the advice of or consult your physician when considering any information or treatment related to Fragile X.

The following information includes available data wherever possible, but much of the current approach to treatment relies on expert opinion. The core behaviors discussed below are commonly seen in FXS, and individuals with FXS may have one or more of the listed behaviors.

It is important to remember that individuals with FXS may:

• Be more sensitive to medication effects
• Respond to smaller doses than the general population
• Have side effects at dosing lower than expected to cause such effects. If side effects occur, the medication may need to be discontinued in consultation with the doctor.

General Recommendations for Adults: It is important to avoid adding new medications every time an adult has a crisis, and it’s important to make every attempt to avoid adults being overmedicated with high dosages and with many medications at once.

Dosing: An important general principle with all medication treatment in FXS is to start at low doses and raise the dose gradually and systematically until the desired benefit is achieved or until intolerable side effects occur.

• Adults are defined as 18 and older.
• Youth are defined as children and teenagers between the ages of 5 and 18.
• Some 3- to 5-year-olds may take medications under close supervision of their doctor.
• Where medication dosage is based on weight, it will be noted.

At all times, dosing level should be discussed with the individual’s doctor. Do not make changes to medications or supplements (increasing OR decreasing) without the guidance of the individual’s doctor.

If dosing levels are not provided for a medication listed below, it is because the medication is not recommended for use in individuals with FXS. In those instances, medications are only listed in case they are suggested by a doctor.

Medication Names: Medications appearing here are introduced using their generic name followed by the most common brand name (with a few exceptions) in parenthesis, for example: aripiprazole (Abilify). Otherwise, the generic name is used as many are available under multiple brand names.

Many individuals with Fragile X syndrome exhibit delays in development and can also have challenging behaviors, both of which can impact academic and daily functioning. Medications are at times helpful to facilitate the individual’s ability to attain optimal life skills and allow for better integration into educational, adult, and social environments.

Psychopharmacological (medication) treatment in FXS is recommended in appropriate individuals as a treatment to be used in conjunction with therapeutic services, including:

• Behavioral intervention
• Speech and language therapy
• Occupational therapy
• Individualized educational support

It is also important to set up the environment, to the extent possible, for success. Examples might include:

• Setting up a routine
• Using visual schedules
• Allowing time for transitions
• Minimizing sensory stimuli

There are several common symptoms and psychiatric conditions in individuals with Fragile X syndrome that are treated with the same medications used in the general population and in individuals with other developmental disabilities. These medications have been reported to be effective for individuals with Fragile X syndrome in retrospective clinical studies.

However, it’s important to note that there is limited formal research or clinical trial data to demonstrate the best approach to the use of medication specifically in the Fragile X syndrome population.

Agoraphobia is an anxiety disorder that can cause intense fear in situations where the person feels escape may be difficult or help hard to access. For some people with FXS, agoraphobia can cause the individual to not want to leave their house.

If agoraphobia leads to aggression when trying to get the individual with FXS to leave the house or their room, or results in them hurting themselves (or others) or breaking and throwing things, then medicines for anxiety (SSRIs) may help. If symptoms persist, medications for aggression are added, such as aripiprazole or risperidone.

For many agoraphobia challenges, behavioral supports can also be helpful.

People with Fragile X can take traditional asthma medicines, whether it is an albuterol inhaler, a steroid inhaler, or oral meds. It’s important to note that albuterol tends to make one’s pulse faster and may cause the user to become more hyper, but asthma should be treated similarly to how it is treated in typically developing individuals.

Sometimes, propranolol, which is a beta blocker, is used to treat anxiety. However, this should not be taken by people with asthma as it can cause bronchospasm.

Depression can be difficult to diagnose and treat in individuals with developmental issues. It is especially challenging to understand in individuals with communication challenges, but it can certainly happen, and it’s something to think about if the individual with FXS is having a pattern in their behavior that is changing. Signs of depression are:

• Not doing activities like they used to
• Changes in sleep
• Eating more or less
• Crying spells
• Acting differently in general, out of their norm

Depression is treated with SSRIs and SNRIs. See the Anxiety section.

Even with planning, preparing, using a visual schedule, and allowing plenty of time, individuals with FXS can have difficulty with changes and transitions. Such difficulties can include behavior challenges such as significant anxiety, agitation, aggression, and self-injurious behavior.

If either anxiety or agitation becomes interfering, refer to medication approaches for anxiety or aggression for guidance on possible medication management to address these situations.

Hyperarousal in individuals with FXS is hard to measure, but through the use of EEGs, it has been found that the brain at rest in individuals with FXS has increased high-frequency electrical activity. There are currently studies underway to evaluate this, but at this point, treatment recommendations include the use of relaxation and calming strategies, along with the use of SSRIs and SNRIs. See the Anxiety section.

Alpha-agonists have been used if SSRIs and SNRIs are activating.

See Non-Stimulant Medications in the ADHD section

See the ADHD section.

Some individuals like to stay in their rooms and will not come out when people come over to visit. Again, relaxation-related techniques and other therapeutic approaches are extremely helpful for caregivers and affected individuals, together and individually. The use of these techniques, in conjunction with anxiety medications, is often helpful.

See the Anxiety section.

Irritability is frequently seen in individuals with FXS, and the cause can be difficult to determine. Irritability is defined by the FDA as aggression, self-injurious behavior, and severe tantrums. Irritability also can represent oppositional interactions that may not adhere to the FDA use of this term.

SSRIs can be helpful in managing these irritable symptoms in higher functioning individuals with FXS if they appear to relate mostly to social anxiety, rigid behaviors, obsessions, or to some extent, perseverative behaviors. A go-very-slow approach is associated with the fewest side effects, especially in lower functioning individuals.

If SSRIs are not helpful, or irritable behavior does not seem specifically related to anxiety or perseverative behavior, antipsychotics such as aripiprazole or risperidone can work well thus targeting the FDA defined nature of irritability.

See the Anxiety and Aggression sections.

OCD is usually characterized by repetitive behavior and is one of the anxiety disorders. It can be treated with medications used for other anxiety disorders but often requires higher dosing than needed for other anxiety disorders.

Medications often used for OCD include the SSRI medications sertraline (Zoloft), escitalopram (Lexapro), and citalopram (Celexa). See the SSRI information in the Anxiety section.

Perseverative speech and actions, ritualistic behavior, constant chewing of clothing or other objects, hair-pulling, and a general love of routine and repetition are frequently seen in patients with FXS.

Although obsessive-compulsive behaviors may be mediated predominantly by the serotonin system, perseverative repetitive behaviors and stereotypies* may be more closely linked to dopamine systems.

*What are stereotypies?
Repetitive, ritualistic, purposeless movements, postures, or speech. For example, tapping feet or pacing back and forth.

Thus, either SSRI’s or antipsychotics (especially if associated with irritable behaviors) may be helpful for this category of behaviors. However, perseverative behaviors and stereotypies can be difficult to eliminate and there are no medications yet that target them well.

See the Anxiety and Aggression sections.

Individuals with FXS who experience seizures should be seen and treated by a neurologist who specializes in seizures. Seizures are generally quite treatable by FDA-approved agents, and they often go away over time.

Medications for seizures are listed in our treatment recommendation, Seizures in Fragile X Syndrome.

Many individuals with FXS engage in self-injurious behaviors, the most common of which is hand biting and finger chewing, though head banging is also seen. Behavioral assessment and treatment are the mainstays for these behaviors though sometimes medication is used as well.

It is usually treated similarly to treatments for aggression, with use of antipsychotic medications, unless it is felt to be due to anxiety.

Antipsychotics used may include:

• Aripiprazole (Abilify)
• Risperidone (Risperdal)
• Quetiapine (Seroquel)
• Ziprasidone (Geodon)

For more information, see the Aggression section.

In addition to behavioral and occupational therapies, anxiety medicines, for example, SSRIs, tend to help some individuals with sensory sensitivities. The SSRIs may reduce anxiety, and the individual with FXS may be less hypervigilant and hyperresponsive without being too sleepy. See the Anxiety section.

These medications should be used in conjunction with an occupational therapist (OT), the child’s school staff (for a school-aged child), and a behavioral psychologist.

Social anxiety is present to some extent in the vast majority of individuals with FXS. This can range from shyness to a clinical diagnosis of social anxiety disorder.

When evaluating social responsiveness, individuals with FXS are often motivated to be social, but become overwhelmed by the intensity of the social interaction and expectations, which causes a negative or avoidant reaction.

Some triggers for social anxiety include:

• Being put on the spot
• Forced eye contact
• Standing up in front of people
• Making phone calls
• Attending a party or large gathering
• Meeting new people

Fluoxetine (Prozac) may be used for girls with severe social anxiety and shyness. Also see the Anxiety and Selective Mutism sections

If a toddler is very anxious, and the anxiety is treated, improved communication may result.

If a toddler is exceptionally hyperactive and impulsive, or really anxious, or has a lot of sleep issues, it is recommended that those issues be treated aggressively because it will help them developmentally, especially in the communication area.

Sertraline (Zoloft): There is some published data on the use of sertraline (Zoloft), but it is not uniformly used with toddlers. The results of a randomized, double-blind, placebo-controlled trial of low-dose sertraline in young children with FXS provides helpful information.

When should medication be considered and at what age?

Medication can potentially be part of overall treatment, when combined with non-medication therapies, and should be considered when behavioral symptoms significantly interfere in the individual’s ability to participate in daily activities including, therapy, school, or family life, or are causing some kind of risk to the individual with Fragile X syndrome or to other people around them.

Caregivers should ask: What is the behavior? How is it causing a problem? Is it a tangible issue? If treated using medication, would it improve quality of life and open up opportunities?

In the Fragile X syndrome field, medication has been utilized with children who are in kindergarten, first, or second grade age and are either showing anxiety or the beginnings of ADHD symptoms. On rare occasions, medications have been utilized to treat severe anxiety and sometimes severe ADHD in preschool and toddler age children.

Lastly, it should be emphasized that every individual is different, and that medication should not be utilized in isolation of other interventions.

Can you use two medications for two different symptoms simultaneously? For example, anxiety and ADHD?

The short answer is yes. There are many individuals who may, for example, take an SSRI for anxiety and a stimulant for ADHD, and they do quite well.

The key is — what are you treating with each medicine and are you seeing benefit?

Do not start both these classes of medicines at the same time; do them one at a time to get a sense of what’s doing what, but they are totally compatible, potentially, together.

How long does it take before I can tell if the medicine is working?

With each medication class, there is a different time frame that is needed to see if it is going to have an effect.

• For an antipsychotic, effects should be seen in about a week
• For an SSRI or an SNRI, effects may not be seen for about a month
• For a stimulant, it only takes two or three day

Different medication classes take different amounts of time to evaluate at any one dose.

Families, and in some cases professionals, are often not clear about the relationship between Fragile X syndrome (FXS) and autism spectrum disorder (ASD). It is not uncommon for a child to initially be diagnosed with FXS and later to receive an additional diagnosis of ASD or vice versa.

This document attempts to bring clarity to how the ASD diagnosis and FXS can overlap, and where they do not. Understanding this distinction can be particularly helpful for genetic counseling and when deciding upon the most appropriate medical, therapeutic, educational, and behavioral interventions that will increase the potential for both short-term and long-term improvements. At the end of this document, readers will find general treatment recommendations based on the current expert consensus and evidence-based publications in the field of ASD in FXS.

ASD is a neurodevelopmental disorder characterized by social communication challenges and the presence of restricted and repetitive behaviors. ASD symptoms usually appear in early childhood and change over time and with development.

The diagnosis of ASD is based on observations and assessments of behavior by an experienced clinician, where clinical judgment is informed by the use of standardized diagnostic instruments and where there is a focus on core social communication and interaction and restricted and repetitive behavior symptoms.[38, 49] The gold standard for clinical diagnosis of ASD in FXS involves the use of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5; American Psychiatric Association, 2013) or the International Classification of Diseases, 11th Edition (ICD-11).

In earlier DSM-based guidelines (DSM-IV), ASD was represented by three different diagnoses: autistic disorder; Asperger syndrome; and pervasive developmental disorder, not otherwise specified (PDD-NOS). These three diagnoses were combined into the one diagnosis of ASD under the DSM-5. The term, “spectrum,” in ASD means that people can be affected in different ways, and symptoms can range from having mild to severe impacts on a person’s functioning.

The symptoms of ASD do not result solely from limited communication skills or intellectual disability (ID), though both may be present. Instead, ASD represents a difficulty in using communication and intellectual abilities for social interaction. ASD involves a number of behaviors, as described in the bullet points below.

Social communication and social interaction symptoms in ASD include challenges with:

• Social-emotional reciprocity — having a conversation, sharing interests and emotions
• Nonverbal communication used for social interaction — differences in use of eye contact, facial expressions, or gestures
• Developing and understanding social relationships — friendships, understanding rules for social behavior

Restricted, repetitive behaviors include:

• Stereotyped or repetitive motor movements — hand flapping, use of objects (e.g., spinning or lining up toys), and speech (using repetitive or unusual words or phrases)
• Insistence on sameness or ritualized patterns of behavior —  extreme distress at small changes, difficulties with transitions, needing to follow the same schedule or sequence of completing activities
• Unusual or overly intense interests — interest in an unusual object or topic, intense interest in a narrow area
• Hyper- or hypo-reactivity to sensory input — negative reactions to certain textures or sounds; excessive smelling, peering at, or touching of objects

When diagnosing ASD, the clinician should state whether it is associated with a known medical, genetic, or environmental factor. They should also specify whether ASD is with or without accompanying ID and with or without accompanying language delays.

ASD is a complex condition with a common set of behavioral symptoms, but with varied, yet not well understood, underlying risk factors and biological mechanisms. Although people with ASD share core features of social interaction challenges and restricted, repetitive behaviors, these symptoms can vary widely in form and severity. Further complicating the picture, many individuals with ASD have co-occurring conditions, such as language disorders, ID, or mental health diagnoses (e.g., ADHD, anxiety). Among the causes and risk factors noted by both the U.S. Centers for Disease Control (CDC) and the National Institutes of Health (NIH):

• Research has identified around 100 high-confidence risk genes, but many are yet to be discovered.[18, 41, 83].
• Children who have a sibling with ASD are at a higher risk of also having ASD.[66]
• Individuals with certain genetic or chromosomal conditions, such as FXS, can have a greater chance of having ASD.

It is expected that as genetic testing becomes more sensitive, the percentage of individuals with an identified genetic cause of ASD will increase further.[18] However, at this time, there is no medical test, such as a blood test or brain scan that can diagnose ASD.

FXS is the most common single gene disorder associated with ASD, accounting for about 1-6% of all cases of ASD.[60, 69] FXS is caused by an expansion of a CGG repeat sequence to >200 repeats (full mutation) in the promoter region of the FMR1 gene, which results in a loss of its encoded protein, the Fragile X Messenger Ribonucleoprotein (FMRP). [26]

FXS is diagnosed by a DNA blood test, unlike ASD, which is a purely behaviorally defined diagnosis. The behavioral characteristics of FXS, although quite variable, can include many features of ASD, such as difficulties with social interaction and communication (e.g., poor eye contact, problems with peer relationships, social withdrawal), repetitive movements (e.g., hand flapping), need for sameness, and self-injurious behavior (e.g., hand biting).[10, 25] Thus, careful discernment and a clinical evaluation are needed to understand whether ASD is present in an individual with FXS.

Many individuals diagnosed with FXS meet criteria for a diagnosis of ASD, with the estimated prevalence of ASD in FXS being approximately 50% for males and 20% for females. [44]

However, recent research indicates that, while a majority of males and females with FXS have restricted and repetitive behaviors common to ASD, far fewer meet criteria for the social communication and interaction problems associated with ASD. Receiving a diagnosis of FXS and ASD can be appropriate, but the relationship between FXS and ASD and the characteristics of ASD seen in FXS are still an evolving science and the diagnosis of ASD in FXS continues to be studied by clinicians and researchers working with people with FXS.

Many individuals diagnosed with FXS meet criteria for a diagnosis of ASD, with the estimated prevalence of ASD in FXS being approximately 50% for males and 20% for females.

Our current knowledge about ASD indicates that it is a developmental brain disorder, beginning shortly after birth or even earlier. Its most characteristic feature is the presence of abnormal patterns of neural “wiring” or connectivity. Because multiple genetic and environmental factors have been linked to ASD, there are probably multiple ways in which neural connectivity and other processes can be disrupted, leading to ASD [19,50].

There is evidence, based on studies of genes and proteins in neural cells, that FMRP plays a role in the processes that lead to ASD. FMRP, which is absent or deficient in FXS, normally turns off protein synthesis (the process of proteins being made) at the level of connections between neurons (dendrites). When certain receptors (such as mGluR, dopamine D2, and muscarinic cholinergic) are activated, this releases the FMRP brake and allows proteins to be made. In this way, FMRP regulates the levels of many proteins important at brain connections. Also, many proteins that have similar functions to FMRP, and also interact with FMRP, have been found to be associated with ASD.[14, 15] In addition, many of the proteins regulated by FMRP have been found to be associated with ASD.[3, 41] Thus, deficits in FMRP seem to be linked to abnormal wiring and related brain abnormalities that lead to behavioral symptoms of ASD.

It may be helpful to think of ASD as a “cloud” (see Figure 1), where multiple diverse genetic and other causes lead to atypical brain wiring that results in a final common diagnostic category. Some causes may stem from a single genetic change, some causes may require a number of factors to interact together (i.e., multifactorial), and some causes may be unknown. Although the causes can vary, the end result is the set of behaviors known as ASD.

Individuals with FXS who meet criteria for the current definition of ASD represent an area in the ASD “cloud” where an individual may meet for ASD criteria due to reduced social interactions with others, reduced interest in social interaction, and increased repetitive behaviors in addition to the common characteristics associated with FXS, such as social anxiety, intellectual disability, and sensory hyperreactivity. [27] However, not all individuals with FXS meet criteria for the diagnosis of ASD. FXS is not a kind of ASD; rather, it is a genetic disorder with its own set of symptoms, many of which overlap with behavioral symptoms seen in ASD. When enough overlapping symptoms are present and severe enough to impact functioning, the person with FXS could also meet criteria for a diagnosis of ASD. Some individuals with FXS may have enough ASD features to be near the ASD cloud, but not at the threshold needed for an ASD diagnosis, and those with FXS who are in the ASD cloud likely have genetic factors besides FMRP deficiency that contribute to the development of ASD.

FXS is not a kind of ASD; rather, it is a genetic disorder with its own set of symptoms, many of which overlap with behavioral symptoms seen in ASD.

Intellectual disability is an important variable in considering whether ASD is present within FXS. ID, a feature of FXS in most males, is common in ASD but is not necessary for a diagnosis of ASD, nor for FXS with ASD. However, severe ID is often difficult to differentiate from ASD, as it, too, includes challenges in social development and communication, and repetitive and self-stimulatory behaviors are often present.

The DSM-5 requires consideration of overall intellectual level in determining an ASD diagnosis. If a child’s social communication delays are in line with their overall developmental level, then a diagnosis of ASD is not warranted. In other words, social challenges must exceed those expected based on a person’s overall developmental level.

Figure 2 is a Venn diagram used to illustrate the relationship between ASD and FXS but it is not designed to be proportional.

Neurological and behavioral characteristics common to both FXS and ASD include:

• Social interaction problems, including being able to accurately read and respond to social situations
• Communication-language delays
  • in FXS involving a wide range of language and speech aspects
  • in ASD mainly involving non-verbal communication and language pragmatics (use of language in social situations)
• Poor eye contact (though this often improves in FXS as the person gets to the know the other person)
• Repetitive use of objects and repetitive movements
• Intellectual disability in most males and some females with FXS and a high proportion of those with ASD
• Unusual reactions to sensory input, including hyper-sensitivity (e.g., tactile defensiveness) and hypo-sensitivity (e.g., high tolerance for pain, seeking sensory input such as visual fascination with moving objects or lights), the latter more common in ASD
• An area of strength in visual memory
• Seizures in a higher proportion than the general population
• Motor coordination difficulties (e.g., challenges with handwriting, atypical walking patterns)
• Difficulties with attention, activity level, emotional-behavioral regulation and mood, often leading to additional diagnoses
• Other behavioral issues (e.g., aggression, noncompliance, self-injury)
• Sleep problems

While both ASD and FXS (without ASD) involve social challenges, clinicians working with individuals with FXS observe distinct differences in that lack of social initiations alone do not necessarily imply the absence of social awareness or social interest in individuals with FXS.

For most individuals with FXS, lack of social initiation often reflects language delays, intellectual disabilities, and general or social anxiety.

In contrast, lack of social initiation in ASD, including individuals with FXS who meet criteria for ASD, are defined based on reduced interest in social interaction or a failure to attend to social information that might promote social behavior.

A similar trend is found for eye contact. Although poor eye contact is characteristic of both FXS and ASD, the nature of eye contact may be substantially different.

Individuals with FXS typically avoid eye contact directly , and looking away from people may help in coping with emotional discomfort that is driven by underlying social anxiety. [10, 79, 28]

While social anxiety might also play a role in some individuals with ASD, including those with FXS who meet criteria for ASD, other individuals with ASD make little eye contact for other reasons, such as a lack of recognition that eye gaze is a source of social information or interaction. [32, 35]

Characteristics that have been found to differ between FXS and ASD include:

• Individuals with ASD typically have higher levels of motor coordination.
• Individuals with ASD are more likely to show higher expressive language skills relative to receptive language, while individuals with FXS tend to show higher receptive language skills relative to expressive [1]
• In general, interest in socializing is higher in FXS than ASD, though anxiety and language delays can be limiting factors [17, 62]
• Social awareness is typically better in FXS than ASD
• Motor imitation skills are typically better in FXS than ASD [51, 53]
• Sequential processing is typically harder for individuals with FXS than ASD [33]

Outlined above were descriptions of behaviors that are common and different between FXS and ASD. Compared to individuals with FXS who do not meet criteria for ASD, those who do meet ASD criteria present with more severe cognitive and behavioral problems that include:

• Less developed language skills, particularly receptive skills [1, 57]
• Often non-verbal or minimally verbal [57]
• Lower IQ scores [9, 11, 42, 62]
• Lower adaptive skills [9, 42]
• More severe overall behavioral problems, including attention problems, hyperactivity and impulsivity, anxiety (particularly after childhood), irritability, aggression, agitation, self-injury, hypersensitivity to stimuli, and obsessive-compulsive and perseverative behavior [9, 16, 44]
• Sleep problems, particularly after childhood [44]
• Seizures [44]

It is interesting to note that the above list contains characteristics that are not core features of ASD. Rather, they reflect common comorbidities and greater developmental impairment. It is important to note that many of these characteristics are seen in individuals with FXS with significant ID, who do not have ASD. Therefore, the diagnosis of ASD can be difficult to make in these individuals with FXS and significant ID. So, when making the ASD diagnosis in FXS, consideration must be given to the cognitive level of the individual to ensure that ASD symptoms (social communication challenges and repetitive behaviors) are more impaired than expected based on overall developmental level.

Future studies are needed to improve methods for diagnosis of ASD in those with ID. Using data from the FORWARD project (A CDC-funded, multi-year, natural history study involving multiple Fragile X clinics), revised questionnaires for the diagnosis of ASD that are more appropriate for FXS have been developed, and further work is needed to refine ASD diagnostic measures for use in individuals with FXS.[45]

From the educational, vocational, and adaptive functioning viewpoints, individuals with FXS with ASD face similar but more severe challenges than those with FXS without ASD. Individuals with FXS with ASD have a higher frequency of use of medications for behavioral management, as well as higher likelihood of having very delayed toilet training, seizures, and sleep problems [7, 16, 44].

Failure to accurately identify ASD in FXS has multiple implications including that developmental and neurobehavioral comorbidities associated with ASD in FXS may not be recognized, leading to failure to enact preventive strategies. An inadequate diagnosis may also prevent the implementation of interventions and educational strategies shown to have benefit in ASD, such as applied behavior analysis (ABA). More precise delineation of ASD behaviors exhibited by an individual with FXS could also assist in developing targeted interventions.[44] Therefore, accurate and early diagnosis and prompt referral of children with FXS and ASD to receive appropriate therapies and supports is essential to make an early and positive impact on outcomes.

Up to half of the people with FXS will also have a behavioral diagnosis of ASD, and it can be useful to get the dual diagnosis early as it may impact treatment and intervention. It is important to note that, while many people with FXS with ASD will have increased challenges, they may also have the positive attributes of those with FXS without ASD including having a good sense of humor, a desire to engage with others, and to be helpful. It is important to use those strengths to further their academic and life skills. Regardless of ASD status, evaluations and treatment plans work best when they are individualized to an individual’s specific needs and profile of strengths and weaknesses.

Toilet training, which can be challenging even in the general population, is characteristically an area of stress for families with a child affected by fragile X syndrome (FXS). While the majority of boys and girls with FXS will become toilet-trained, this is typically delayed anywhere from one to multiple years later than the general population.

An analysis of data from FORWARD (Fragile X Online Registry With Accessible Research Database), a natural history project collecting data from FXS patients at most of the FXCRC (Fragile X Clinical and Research Consortium) clinics, has recently provided new information on the age of toilet training in children with FXS, and factors that impact when children with FXS will toilet train.[3] This allows an understanding of which patients are most at-risk for very late toilet training and thus can guide training strategies in terms of when intensive toilet training techniques will need to be applied. For most males with FXS the various stages of toilet training will each likely take longer to master, and will require specific training geared to both global characteristics of FXS and the individual needs of each child.

Data from 633 individuals with FXS enrolled in FORWARD between 2012 and 2016 (77% male) were used to generate the curves (called survival curves) as shown in the figures farther down on this page (Figures 1 and 2 for bladder training and Figures 3 and 4 for bowel training).

The figures compare females (red/pink) and males (blue/green). These curves tell us for any given age (plotted along the bottom of the chart) what the chance a male or female with FXS will be toilet trained for urination (Figure 1) or bowel (Figure 3).

Overall, females train much earlier than males, and males train later with about half of males trained at age 5. There are some individuals (mainly males) with FXS who do not train at all or are trained very late (after age 10). Figure 2 and Figure 4 show the male and female curves like Figures 1 and 2 but divide the groups into those with a co-diagnosis of autism spectrum disorder (ASD) and those without ASD. Most of the males who train very late have a co-diagnosis of ASD. For males with FXS without ASD, about 65% are trained by age 5. Additional description is provided in the text with the Figures at the end of the document.

An analysis that included the 313 individuals with FXS over age 10, showed that 39 individuals (12.4%) were not toilet trained at age 10. All but 1 of these was male. This severe delay in toilet training was associated with low or nonverbal language abilities, lower IQ, presence of ASD, and severe behavior in areas of both irritability (being easily upset, over-reacting to things, tantrumming) and hyperactivity. Since many of these features can occur together, statistical models (multivariate and Cox proportional hazard models) were used to determine which factors are the main drivers of late toilet training. These analyses showed that lower language milestones, ASD comorbid diagnosis, and irritable behavior were the only independent predictors of severe delay in toileting. Of these, language and communication milestones were the biggest predictor of age of toilet training, such that for each higher language level of:

1. small number of words or less,
2. many single words and two-word phrases, and
3. phrases of 3 words and sentences,

the individuals with FXS were twice as likely to be toilet trained.

Addressing toilet training is essential for all children with FXS, especially males as a large percent will exhibit delayed toilet training, even if they do not have ASD or low language skills. Often the family will be struggling with numerous issues and just assume that delayed toilet training is expected. They may even be under the impression that acquisition of this skill is unrealistic. However, the converse is also true. Many families initiate toilet training based on the child’s chronological age and expected milestones, based on typically developing children. Initiating toilet training too early is often linked to extraneous factors, primarily related to childcare and preschool policies. Either situation requires guidance. Medical providers should therefore actively consider the developmental age of the child, and inquire about toileting skills for both bladder and bowel during night and day, and also about washing and wiping abilities. It is important to define the nature of the toileting issues, as there are different causes and treatments depending on whether the child never acquired toileting skills at all (primary encopresis and enuresis, respectively), or was toilet trained in the past and then lost control of bowel and/or bladder (secondary encopresis and enuresis, respectively).

Current treatment guidelines for toilet training in children with FXS are not intrinsically different from the general population, but must take into account the increased anxiety, sensory defensiveness, and in particular, the poor sequential learning skills of this population. It is also important to impress upon families that while eventual mastery can be expected, the time scale must be expanded. Each individual’s readiness must be carefully evaluated, as forcing the issue too early is likely to be highly counterproductive. Toilet training is actually a complicated behavior that involves elements of physiological, motor, and communicative readiness.

The first step in training is to make sure that the child is ready.

Readiness Signs

• Being dry for periods of at least two hours
• Recognition that a diaper is wet or soiled
• Indication of sensory awareness of having a full bladder or bowels
• Ability to communicate about wetness or toileting need
• Motor skills to get to the bathroom, pull pants down and sit on the toilet
• Ability and willingness to follow simple one-step directions
• Ability to sit in one spot for several minutes at a time.

Discussion Points with Parents

Though the following suggestions are divided by domain it does not mean that they should be implemented in isolation. This division illustrates the complex nature of toilet training and is designed to ease discussion with parents.

Physical

It is important to evaluate for any medical causes of toileting problems. As noted above, there are different medical causes for day and/or night as well as primary and secondary enuresis and/or encopresis. Any condition that can affect a child in the general population can also affect a child with FXS; it is therefore important to conduct a general pediatric evaluation for these conditions (the discussion of which is outside the scope of this guide but might include constipation, urinary tract infections, seizures, etc.).

• Discuss the consistency of the child’s stools to determine if additional fiber supplements should be added to his/her diet. The significant sensory issues associated with FXS can sometimes result in a very limited diet, thus affecting the consistency of the child’s stool. If that appears to be the case, then further strategies for dietary options may be considered with a pediatric dietician and/or a therapist (e.g. occupational, behavioral) with experience in helping to increase children’s willingness to explore other foods.
• Discuss the side effects medications may have on the child’s bowels. For example, some antibiotics cause diarrhea and guanfacine and antipsychotics like risperidone (Risperdal) and aripiprazole (Abilify) can cause constipation in some children.
• Encourage parents to track the child’s toileting schedule. It is generally easiest to start tracking bowel movements. Once a pattern has been established, they should begin placing the child on the toilet around the time she usually has a bowel movement. (Initially the parent rather than the child will be trained!)
• Once success has been achieved with bowel movements, parents can use the same process with urination. For many children, the opposite sequence will be more successful.
• Medication is not generally indicated, though the use of desmopressin to treat nighttime urinary incontinence for specific situations, e.g., trips, may be warranted.

Sensory

• Disposable diapers are so effective they may hinder the toilet training process because they do not allow the child to feel the wetness of the diaper. Many children with FXS are successful using cloth training pants so the child can tell when they are wet. Another way to accomplish this is to consider placing a non-absorbent cloth in the child’s diaper so they can be aware of feeling wet.
• Some children do not feel comfortable pooping outside of the diaper. If that is the case, place a diaper loosely around the child and allow her to poop while sitting on the toilet. Gradually place the diaper farther away from her bottom and closer to the bottom of the toilet. This type of behavior shaping allows the child to gradually feel safer while adapting to the toilet. Sometimes a hole can be cut into the diaper, so the child still feels the diaper around his/her waist and that helps the child feel more comfortable making a bowel movement.
• Many children with sensory issues have gravitational insecurity, meaning they do not feel comfortable when they are up off the ground. Encourage parents to place the toilet on the ground, or to use steps or a bench that are solid to add a feeling of security.
• Eliminate or at least reduce “exotic” smells as a way to limit sensory input in the bathroom. (If weather permits and noise from outside is minimal, an open window can help.)

Language

• Encourage the use of simple, concrete and consistent language when referring to body parts as well as the toileting act itself.
• If the child is non-verbal, apply whatever type of communication system is used in the other parts of his life. The speech therapist should be alerted to the toilet training experience so she or he can provide assistance in this area. There are many picture schedules and social stories available as visual aides to support toileting skills.
• Excessive language is not usually beneficial. Short, two-to-three-word sentences and directions are recommended.
• Since language development is often an issue, pair these words with signs. Research has shown the introduction of sign language often stimulates oral language.

Cognitive

Learning a new skill can be a slow process for children with FXS, but they do learn and make consistent progress. The key is to present the information in a way that is meaningful to the child. Individuals with FXS have strong imitation skills, and they learn by observing and copying.

Encourage parents to do the following:

• Read books to the child about toilet training and watch toilet training videos with them. Choose books that have limited language. Sitting and listening to an entire story is difficult.
• Allow the child to see family members or other children using the toilet, and use observational remarks such as, “He is going potty” to narrate what is happening. Remember to use short sentences.
• Practice toilet training with a doll, action figure or stuffed animal, e.g., “Sponge Bob goes potty.” This allows the child to have control over the situation and to practice the sequencing of the tasks without pressure. This type of activity is also helpful for decreasing anxiety.

Motor

• In order to account for fine motor delay, encourage parents to dress the child in clothes that she can manipulate easily. Elastic waistbands work the best.
• Due to low muscle tone, balance can be difficult for children with FXS. Have parents make sure that the child’s feet can touch the floor when sitting on the toilet. This will increase his stability and make him feel safe. When using the big toilet, place a block or an old phone book under his feet.
• Wiping also requires motor skills and coordination, and can be a challenge for some children. Occupational therapists may be able to provide some additional guidance and strategies if this is an area of challenge.

Psychological

Psychological factors are probably the most difficult of the entire process. Children with FXS often experience anxiety, but due to their limited language skills, we typically see only the ensuing avoidant behavior. This can leave parents feeling frustrated and confused. It is best to try to decrease the anxiety, rather than try to guess what is causing it. Anxiety can be decreased by presenting the child with information about the situation in a way that is easily understood. Practice and repetition will familiarize the child with the new situation and the items that go with it. Medications such as selective serotonin reuptake inhibitors (SSRIs) should be used to treat underlying anxieties that are affecting the child generally, and not specifically for toileting related issues.

• Provide a picture schedule.
• Spend time talking about the toilet, looking at it, touching it and sitting on it before it is time to actually use it.
• Do not initiate this process during known times of stress, i.e., right after a move, the arrival of a new baby, or other major changes.
• Involve the child in the selection and purchase of the training pants. This allows them to exert control in an appropriate manner. Involve them in the selection of the potty chair or toilet seat as well.
• Allow the child to decorate the toilet with stickers, etc.
• Ensure that the child can place their feet on the ground or stable platform; this has been found to be very helpful in diminishing associated fears.
• Modify the amount of time that the child sits on the toilet when first learning. Guides for typically developing children often recommend 10 minutes. Initially, this may be too long for children with FXS as many of them will have ADHD.
• Novelty will increase attention. Encourage the placement of some books next to the toilet. These books or toys should be engaging and should be kept in the bathroom, which will keep them “new” and engaging. Use whatever is engaging for the individual child.
• Pushing a child who is not developmentally ready for toilet training may slow or disrupt the process. If the parent is becoming too frustrated, encourage them to stop and try again in a month or so. There is nothing wrong with a parent taking time to regroup, and it may well benefit the child.
• Providers should work with parents to carry out a careful analysis of what is happening in order to separate antecedent behavioral elements from developmental and physiological factors. This will help in creating a developmentally appropriate plan for the individual child.
• Identified behavioral elements, if present, should be addressed with appropriate therapies.
• Cognitively, training with visual cues (e.g., video modeling, likely via cartoon, rather than showing an actual child on the toilet) is often very helpful.
• The preschool or school should work with the family, as far as possible, to use the same system for training.
• A behavioral reward system based on verbal praise should be helpful, as individuals with FXS have a strong drive to please.
• Regarding isolated nocturnal enuresis, consideration may be given to the “pad and bell” alarm systems. This is a popular method for treating nocturnal enuresis in the general population. If indicated, one of the less forceful variants (e.g., a pad and buzzer, rather than bell) may be a better option. Generally this should be undertaken only after careful consideration, since sleep disturbance can be a problem in FXS and will likely be exacerbated with this method. In addition the sensory stimulus of the bell may increase anxiety and potentially worsen general behavioral problems.

For children wit FXS with poor language function, co-diagnosis of ASD, or irritable behavior that puts them in a higher risk group for very delayed toilet training based on the FORWARD data, additional effort and different approaches may be required from early in training.

Since language is considered to be a central factor in toilet training, priming using language-heavy books or lengthy conversations should be not be done. Punishment procedures that involve language or extensive multistep processes of restitution, including cleaning up and putting the soiled clothes in the laundry, may cause too much frustration and, without effective language skills, may result in a lack of associating the punishment with the toileting accident; this would, in turn, eliminate any positive effect of the punishment, and as such is also ill-advised.

Scheduled sitting could be particularly effective because language could be diminished or virtually eliminated with the implementation of a picture schedule, a visual mechanism for marking time, and simple sign language for communicating success and completion. In addition, the use of video modeling or priming using picture books or social stories could be very effective.

Previous literature recommends starting with bowel training rather than bladder training; however, the data from FORWARD are not consistent with bowel training occurring first. Bladder training occurs before bowel training for many individuals with FXS, and based on the predictors identified from FORWARD, bladder training can be addressed first for children who seem predisposed to this. This suggests that the utilization of elimination schedules as a foundational component of any toilet training approach with individuals with FXS is essential. Elimination schedules identify the patterns of elimination, which can be used to inform a scheduled sitting approach in which individuals are placed on a toilet for set amounts of time and rewarded when they void their bladder or make a bowel movement. The schedule increases the likelihood of “catching” the child at the right time so that they void when placed on the toilet. Since bowel movements come less frequently and are easier to notice and track, the likelihood of success at “catching” the child at the right time is increased (this may have been the reason for the idea that bowel training occurred first). The key is to acquire accurate data for the individual child to inform the process, the order of training, and to allow for many opportunities to reinforce success.

For children at high risk for late training, it is important to consider accommodations and modifications to the environment that take into consideration the known behavioral phenotype of individuals with FXS. As previously discussed, modifying the bathroom environment by providing the child a stool to rest their feet on and an insert for the toilet might make some feel more stable. Decreasing the sensory stimuli such as lotions, potpourri, and candles might also be effective for those with sensory sensitivities.

Technological aides for detecting beginning urination could also be considered. It will be important for the quality of life for both the individual child and the family to set appropriate expectations and to introduce alternative toilet training strategies.

Information from the FORWARD data can inform toileting practices and expectations for children with FXS, ASD, or poor language skills. It will be important to focus on the foundational skills for daily living related to toilet training, such as teaching the child to remove clothes, to sit on the toilet for several minutes two to three times per day, and to flush the toilet and wash hands. This might be a more prudent and appropriate strategy for parents and teachers, rather than expecting traditional successful toilet training during the preschool and early elementary school years. This does not suggest that anyone has “given up” on independent toilet training, but rather acknowledges the significant challenges for some children and creates a more appropriate plan which will benefit both the child and their family. The expectation should be to employ consistent work toward toilet training across multiple years to achieve gradual progress — extra time or schedule-training will probably be most effective. Individuals who are schedule-trained can engage effectively in their communities with their peer groups and with the technology available can learn to use the toilet almost completely independently. Watches, phones, and iPads can be programmed with timers to tell an individual it is time to use the restroom. A schedule-training approach will require the parents to work with a behavioral specialist, trained educator, occupational therapist, or a psychologist to create an individual plan. Adjusting and resetting expectations about toilet training and toileting independence for the individual is key.

The focus should be on allowing the individual to live the most meaningful life in the long term and that often means setting a goal on reducing barriers to inclusion across the lifespan. It is important to note that initially this may be very difficult for parents and may trigger a grief cycle as it represents yet another loss. Acknowledging this will be crucial and counseling support may be advised.

What should I tell my patients about toilet training in FXS in general?

The child will become toilet trained but patience and consideration of readiness and developmental level are key. The child will (usually) not be toilet averse for oppositional reasons though there may be an anxiety or behavioral component in addition to standard physiologic considerations. It is important to carefully analyze the process and break down the different elements involved in order to move forward in a planned manner, emphasizing that speed of training is less important than consolidation and assimilation of skills.

How do I help families work effectively with the preschool or school around toileting?

It is important to note that issues around toileting are often related to licensing requirements rather than the personal preferences of the teachers. Classrooms are licensed for different types of activities. Changing diapers is one activity and the classroom will be licensed by the state’s Health and Human Service Department according to its ability to conduct this activity in a safe manner. This licensing includes physical structures such as child size toilets and diaper changing areas as well as training for those who will be involved in changing diapers.

Communication and education in working with the school is key. Toileting is another one of the elements of FXS that require the entire team to work together. The individualized education program (IEP) should incorporate toileting as one of its goals if this skill is not yet accomplished. This will ensure that the child is provided with the necessary opportunities to practice toileting, and will also provide the teacher with the necessary supports needed to accomplish this task in a way that meets licensing requirements. For individuals who are on Individualized Family Service Plans (IFSPs) or are attending preschool in independent settings, work with the director to understand the limitations and opportunities within their licensing and then work on a plan that will serve the child’s needs within these parameters. This can be accomplished in a variety a ways, again the key is communication and creativity.

In alphabetical order:

Adaptive Behavior Assessment

Administered by licensed or certified service providers

A determination of specific aspects of functioning that includes, but is not limited to: communication, activities of daily living (e.g., community use, home living, health and safety, leisure, self-care), self-direction, social, work, and motor skills. Information is gathered from parents, caregivers, teachers, and the individual, as appropriate.

Educational Assessment

Administered by special education or general education teachers; related service providers

An informal assessment that may include an observation of the child in classrooms, job sites, community settings, work study programs, and the greater school community. Interviews with parents, teachers, employers, job coaches, and private providers might also be included in the informal assessment. A review of the child’s academic history (e.g., work samples, school records, and school evaluations) can be part of this process. A formal administration of individual standardized tests of academic abilities and functioning may be provided by the school psychologist (see below) or trained special educator. A written or verbal report summarizing the findings with recommendations for programming strategies, further intervention, or for referral is shared by the teacher with the staffing team.

Functional Behavioral Assessment (FBA)

Administered by related service providers

A problem-solving evaluation, typically conducted by personnel trained in behavioral practices (e.g., behavioral specialist, school psychologist), designed to determine the underlying cause (function) of a specific behavior to determine the best approach for reducing or eliminating the undesired behavior(s).

Occupational Therapy (OT) Assessment

Administered by licensed occupational therapists

An assessment to help determine the need for skill development or compensatory tools and strategies (e.g., use of the computer and keyboarding skills) to assist with daily living functioning. This assessment may also determine what settings are optimal and what alterations can be made in the environment to achieve the best performance by the child. The PT evaluation can help plan an adaptive PE program.

Psychoeducational Evaluation

Administered by certified/licensed school psychologists, licensed psychologists

An evaluation process utilized to ascertain the underlying cognitive and academic processes that might influence the child’s educational performance. The evaluation must include more than cognitive testing (which may not be needed). For example, the school psychologist or a psychologist may conduct FBAs, administer achievement tests, analyze adaptive behavior scales, interpret behavioral assessments such as checklist for ADHD, autism spectrum disorders, and mood disorders (e.g., anxiety, depression), and initiate interviews with the parent, teacher, and student. They may review school, clinical, medical, and other private records. The evaluation must consider diversity factors. For example, as children with FXS are often better at simultaneous processing than sequential processing, instruments which assess both will provide helpful information regarding the student’s strengths and weaknesses. Social-emotional checklists are completed by teachers and parents or caregivers who have knowledge of the child’s skills in various environments. Formal educational testing, which is a part of the psychoeducational evaluation, is typically recommended every three years; however, the educational team may decide to waive further psychoeducational testing if they feel such assessments are not required.

Speech-Language Assessment

Administered by licensed speech & language pathologists

An assessment typically focused on all domains of language (e.g., phonology, syntax, semantics, pragmatics, and receptive and expressive language), as well as oral motor skills and hearing. Some areas may need further assessment and might involve more in-depth testing. For example, speech intelligibility may include an assessment of individual sounds, phonological processes, and measures of prosody (e.g., intonation, stress pattern, loudness variations, pausing, and rhythm).

Vocational Assessment

Administered by special education teachers; related service providers

A determination, in collaboration with the student, whereby appropriate placement and training for adult work can be arranged that aligns the student’s aspirations with their capabilities. Vocational assessments should includein vivoexposure to a variety of work environments, job coaching, and natural supports. When there is a social component, it usually increases engagement and motivation.

In all of the figures, age is shown on the horizontal line at the bottom of the graph. This is plotted against the proportion of individuals toilet trained at a given age (e.g., 0.6 would mean 6 of 10 or 60% of individuals are trained).

Figure 1: Bladder Training: Survival Curves by Gender

Figure 2: Bladder Training: Survival Curves by Autism/Gender Combination

The purple line shows the time when females with FXS without ASD achieve bladder toilet training. By 5 years of age, almost 100% of females achieve training. ASD status in females does not make much of a difference in achieving bladder toilet training.

The red line shows the time when females with ASD achieve bladder toilet training. By 5 years of age, almost 70% of females with ASD achieve training -females with FXS and ASD lag slightly behind females with FXS without ASD, but the lag is not substantial. There is not enough data on females to give a good idea beyond this age, but we encourage those who have not achieved training to have further evaluation for alternative approaches and new strategies.

The green line shows the time when males with FXS without ASD achieve bladder toilet training. By 5 years of age, about 50% of males achieve training. By age 10, about 90% of males achieve training. At age 4, the time to achievement starts to diverge for males, with those without ASD achieving at a much higher rate earlier than males with ASD.

The blue line shows the time when males with FXS and ASD achieve bladder toilet training. By 5 years of age, only about 35% of these males achieve training. By age 10, about 60% of males achieve training and there is some success beyond that age, with about 70% at age 15.

NOTE: An assessment for ASD for males over 6 with bladder toilet training challenges may be helpful, because if the child has ASD, it may be helpful to modify strategies in order to achieve toileting success.

Figure 3: Bowel Training: Survival Curves by Gender

The red line shows the time when females achieve bowel toilet training. By 6 years of age, almost all (95%) females achieve training – this is about 2 years beyond typically developing children.

The blue line shows the time when males achieve bowel toilet training. By 6 years of age, only about 50% of males achieve training. By age 10, about 70% of males achieve training with a plateau of success until age 15 (80%), and beyond that age with some males that are still having difficulty.

NOTE: These lines include people with and without ASD.

Figure 4: Bowel Training: Survival Curves by Autism/Gender Combination

The purple line shows the time when females with FXS without ASD achieve bowel toilet training. By 6 years of age, almost 100% of females achieve training. ASD status in females does not make much of a difference in time to achieving bowel toilet training.

The red line shows the time when females with FXS with a diagnosis of ASD achieve bowel toilet training. By 6 years of age, almost 75% of females with ASD achieve training -females with FXS and ASD lag behind females without ASD, but the lag is not substantial. There is not enough data on females to give a good idea beyond this age, but we encourage those who have not achieved training to have further evaluation for alternative approaches and new strategies.

The green line shows the time when males with FXS alone achieve bowel toilet training. By 6 years of age, about 70% of males achieve training. By age 10, about 90% of males achieve training. At age 6, the time to achievement starts to diverge substantially for males, with those without ASD achieving at a much higher rate earlier than males with ASD.

The blue line shows the time when males with FXS and ASD achieve bowel toilet training. By 6 years of age, only about 35% of males achieve training. By age 10, about 55% of males achieve training and there is some success beyond that age, with about 70% at age 15.

NOTE: An assessment for ASD for males over 6 with bladder toilet training challenges may be helpful, because if the child has ASD, it may be helpful to modify strategies in order to achieve toileting success.

Fragile X syndrome (FXS) is a genetic condition that causes developmental disabilities in both males and females. Though FXS occurs in both genders, males are more frequently affected than females, and often with more severity. FXS is the most common cause of inherited intellectual disability and the most common-known single gene cause of autism spectrum disorder (ASD) that accounts for about 2-3 percent of all ASD cases. At this time, there is no medical test, such as a blood test or brain scan, which can diagnose ASD; rather it is diagnosed by interview and clinical observation. Anxiety, especially social phobia and specific phobias, as well as generalized anxiety, is very common in FXS and often disabling.

FXS is a genetic disorder caused by a full mutation in the FMR1 gene. Full mutations in FMR1 cause a deficit in the Fragile X protein, FMRP. This deficit in FMRP results in abnormal communication among brain cells, which in turn affects learning and behavior. In many, though not all cases, FXS causes a spectrum of behavioral conditions in affected individuals, which can be challenging to their families, peers, and teachers, and can limit their interactions and opportunities within the wider society. At this time, there is no cure for the condition; therefore, management of FXS is largely focused on treatment of the challenging behaviors.

Behavior management tools may include medications or other treatment modalities, but ideally involves the combined efforts of a transdisciplinary team that ideally includes a psychologist, a physician who can prescribe and manage medication treatment (often a psychiatrist, neurologist, or developmental pediatrician), therapist, speech language therapist and educators, behavior analyst all working together with the family, school and community providers.

Individuals with FXS often present with many endearing personality qualities and relative adaptive strengths in addition to challenging behaviors.  While there are commonalities in behavior challenges in FXS, the intensity, frequency, and duration vary greatly and are influenced by other factors, such as their environment and medical conditions. Behavior problems can worsen if they are reinforced in a variety of ways; a behavioral specialist can help to specify factors that may exacerbate behavioral problems. It is critical to address behavioral concerns with an individualized approach.

The most common behavioral challenges seen in FXS include behaviors associated with generalized anxiety, social interaction difficulties (this includes social anxiety, withdrawal, and social aloofness), attention deficit hyperactivity disorder (ADHD), self-injury, and aggression. Addressing these challenges needs to be done with consideration to the person’s level of intellectual functioning, speech-language abilities, and ASD symptoms, if applicable.

High states of arousal, or hyperarousal, a common feature of individuals with FXS, are thought to be biologically driven but triggered or increased by environmental and social stimulation.  Individuals experiencing overstimulation or hyperarousal may feel anxious or fearful. Some may become flushed, their ears and cheeks may become red, and their palms may begin to sweat. Their behavior may appear disorganized, and they may begin to engage in repetitive movements or speech. Some may become obstinate, refuse an activity or attempt to leave the stimulating environment. They may become unfocused, inattentive, impulsive, or aggressive. Avoidance or escape behaviors are more prominent in individuals with limited ability to communicate. Social withdrawal and phobias can evolve into full blown reclusion especially in adolescents and adults as the demands of schedules in later life do not necessitate going out of their homes on a regular schedule.

Many males, and some females with FXS, exhibit behavioral symptoms consistent with a diagnosis of ASD, a developmental disorder primarily characterized by a selective impairment in social interaction, stereotyped and repetitive behaviors, and communication deficits. Specifically, people with ASD have differences in how they understand and react to people and social situations, which result from differences in how their brains process socially-relevant information. Symptoms of ASD appear in early childhood. It is a lifelong disorder, though symptoms change over time. In some cases, the cause of ASD is known, such as FXS, a genetically-defined condition that can be diagnosed by a DNA blood test, unlike ASD that is a behaviorally-defined diagnosis. This does not mean that individuals with FXS have two separate, unrelated disorders; the FMR1 mutation is simply the underlying cause of their ASD symptoms.

Understanding the behavioral challenges and common triggers in FXS are the key to effective behavior management. Developmental differences, such as delayed language and sensory sensitivities, often contribute to behavioral challenges, especially in younger individuals. A loss of capacity for self-regulation, manifesting in aggressive outbursts or self-injurious behaviors is often observed in individuals with FXS, often based on a specific trigger, which may or may not be easy to identify. Difficulty handling transitions, new environments and changes in routine often present behavioral challenges, potentially including aggressive outbursts.

Initial Step — Comprehensive Evaluations

Addressing behavioral challenges in an individual with FXS should start with a comprehensive evaluation. A transdisciplinary team approach ideally includes: educators, school administrator, psychologist, psychiatrist or other physician if medication is being considered, behavior analyst, occupational therapist, speech-language pathologist and caregivers. If the child has previously had a comprehensive evaluation, the evaluation should be reviewed and updated. There should be documentation of relative strengths and weaknesses across all developmental domains. Comprehensive evaluations should be used whenever developing behavioral support plans, behavior intervention plans, educational plans, specially designed instruction, vocational plans, etc.

The following are important components of a transdisciplinary comprehensive evaluation.

Psychological and Adaptive Behavior Evaluation

A thorough psychological and adaptive behavior evaluation should be conducted and reviewed regularly. If school-aged, academic and achievement assessments are important aspects to include. Adults with FXS benefit from vocational and adaptive assessments as part of an annual service plan review. Input from family, independent providers, and school personnel should be solicited. This information is crucial to deciding if the goals and strategies are appropriate and realistic for the person with FXS.

ASD Evaluation

Many children with FXS should be formally evaluated for ASD. A diagnosis of autism is typically made by a specialist (psychologist, developmental pediatrician, neurologist, or psychiatrist). A comprehensive evaluation for ASD should include an in-depth parent interview and formal assessments of cognitive skills, adaptive skills, speech and language skills, social development, and behavioral differences.

Occupational Therapy Evaluation

An occupational therapy (OT) evaluation should be conducted to evaluate and create a plan to address fine motor skills, motor planning, sensory issues, self-regulation skills, adaptive functioning and daily life skills.

An OT evaluation can identify sensory sensitivities in a person with FXS and the profile of dysregulation that often is associated with these difficulties. Challenging behaviors can be the result of the ways the child acts to try to eliminate, avoid or cope with the aversive sensory input. Examples include taking off clothes, throwing oneself on the ground to avoid entering a loud space, or covering ears. Additionally, the child may seek or need more sensory input (leaning on or pushing into people or stuffing too much food in the mouth) as a way of coping or helping to deal with the challenges they are struggling to manage.

A child can be both sensory seeking and sensory avoidant, which can prove challenging for caregivers. The OT evaluation helps to describe the way the sensory or motor foundations in the child might be best addressed, through direct intervention or environmental and interactional changes in the world around them. Identifying daily strategies to address the sensory and motor challenges and to support the acquisition of self-regulation and coping skills is central to the OT’s role on the team and important for a comprehensive behavior intervention plan. Additionally, difficulties with coordination and skill development, and with fine motor skills and handwriting skills compounded by dislike for hand over hand instruction may be triggers for challenging behaviors. These elements should be included in the OT evaluation.

Speech-Language Evaluation

A comprehensive speech and language evaluation provides a great deal of information and can shed light on the function of challenging behaviors. Delayed speech and language development is noted in many boys with FXS. Oral motor difficulties may significantly impact sound production skills, making expressive language difficult to understand. Some individuals may be minimally verbal due to delayed or deficient oral motor planning skills. Difficulty with expressive speech and language or limited means of functional communication is a cause frustration for many boys with FXS.  Also, attentional deficits and severe autistic features are also associated with relatively greater impairment in receptive language. In a state of hyperarousal, language demand can increase the arousal further, compounding an already compromised situation. Language frustration often results in challenging behaviors including: crying, grabbing items, hand biting or aggression. Refusal to follow directions may not be oppositional behavior but rather due to receptive language deficits (inability to understand the directions), expressive language deficits (inability to refuse or respond to the direction) or delayed auditory processing. Some boys and men may say “NO” initially in response to any direction.  The transdisciplinary team should assess and parse out if this is a learned response to accommodate for poor auditory processing, poor receptive language skills or heightened state of arousal rather than noncompliance.

Physical Therapy Evaluation

A physical therapy (PT) evaluation should be completed to assess the level of joint laxity (looseness) and generalized mild hypotonia. Additionally, general gross motor skills are often included in the PT evaluation. These conditions are noted with varying degrees in most individuals with FXS. Mild hypotonia is often associated with fatigue following physical exercise. Fatigue may be a reason for refusal to continue an activity, particularly if it involves prolonged exertion.  Frustration with motor skills can lead to resistance and hesitant participation and the PT evaluation can assist the team in best ways to alleviate these challenges.

ADHD Evaluation

Evaluation for ADHD can provide an understanding of how inattentiveness or poor impulse control may contribute to behavioral issues, such as lack of focus and poor response to redirection. Destroying materials or swiping at stimuli may be symptomatic of poor impulse control. Hyperactivity may also affect the person’s ability to stay engaged long enough to finish an activity or comply with a demand. An evaluation of ADHD symptoms assists in planning activities/goals that are appropriate and in alignment with the person’s attention span (for example, time on task, waiting time).

Sleep Study

A sleep study should be conducted if persistent sleep issues are noted by caregivers or daytime drowsiness is noted.

Neurology Evaluation

Approximately 10%–12% of individuals with FXS have a co-occurring seizure disorder, with a higher prevalence in males (13%–15%) and in those with a diagnosis of ASD. If the person with FXS has a seizure disorder, an evaluation by a neurologist may provide additional information for planning and interventions. Some anti-convulsants used to treat seizures can aggravate behavior. It is important for the team to help the neurologist monitor behavior when medications are changing, so that adjustments can be made if behavior specifically worsens after medication changes. Likewise, some anti-convulsants have positive behavioral effects and thus careful weaning of medication for seizures is warranted.

Functional Behavioral Assessment

A functional behavioral assessment (FBA) should be conducted to develop a hypothesis of the function of the challenging behavior and the maintaining consequences.

To start, the team, often led by a behavior analyst or psychologist, should carefully describe the challenging behavior of concern in an observable and measurable way. This description provides consistency among the family and those working with the person with FXS so that data collection can be used to determine whether progress is being made once an intervention is started.

Steps in the FBA process include identification of the following: medical concerns, history of the behavior and treatment approaches, possible triggers (activities, people, places, specific demands, etc.), preferences and possible reinforcers, and consequences that will not maintain the challenging behavior. Outcomes of the FBA include strategies for positive behavior support plans, and behavior intervention plans including strategies to prevent the behavior from occurring (antecedent strategies) and strategies to teach alternative-replacement behaviors. Ongoing collection and analysis of data is recommended to test the hypothesis of the FBA and identify triggers, trends in behavior, and multiple functions and maintaining consequences of challenging behaviors.

The culmination of the multidisciplinary evaluation process is best utilized when the information is integrated into a plan that is consistently utilized across providers and environments and maintained with consistent communication and collaboration.  It is important to collect baseline and post intervention assessments. Regularly scheduled team meetings should be convened to review progress, update goals, strategies, reinforcers, and so on. in a continuous and concerted plan.

Central to an effective plan for addressing behavioral concerns is a transdisciplinary approach across home, school and community settings. Effective management of physical and medical issues such as seizures should be addressed prior to a behavior intervention plan. Additionally, the team should ensure that there are appropriate accommodations to address functional communication skills and that the educational, vocational, or community program is appropriate for the individual’s needs.

Behavior problems serve a purpose (or a function) and are often a form of communication. The functions of behavior are sometimes reduced to four basic categories:

1. to gain sensory input,
2. to receive attention from others,
3. to access preferred objects or materials, and
4. to escape or avoid something undesirable (e.g., activity, person, place, demand).

Thoughts and feelings are private behaviors but may contribute to observable behavior. For example, if a person with FXS is feeling anxious, observable behaviors may include: flushed face, red ears or increased hand flapping, verbalizing the same statement repeatedly (perseveration) or mouthing of clothing. These behaviors often occur just prior to elopement or dropping to the ground and may function as escape from uncomfortable feelings, loud noises, fearful settings or activities, etc.

The purpose or function of the behavior is generally appropriate (individual is thirsty and wants a drink). It is the behavior the person utilizes that is not acceptable (grabbing someone’s water). In this example, it is recommended to teach alternative appropriate behaviors. For example, functional communication training can be used to teach the appropriate way to request and access a desired item. Reinforcement for engaging in the appropriate strategy is access to the desired item as well as additional reinforcement such as social praise, although praise may not be effective for everyone with FXS.  It is also important to be mindful of the need for supports and instruction in appropriate ways to express frustration, fear or protest (e.g., crowded setting, change in schedule) rather than engaging in challenging behaviors.  Anxious individuals may become hyper-aroused causing already compromised communication skills to worsen and result in more significant behavioral challenges.

An FBA conducted by the transdisciplinary team who are familiar with FXS will contribute to a better understanding of the multiple functions and maintaining consequences of challenging behaviors seen in individuals with FXS.

Common triggers for challenging behaviors in children and adults with FXS include:

• Forced eye contact
• Unclear expectations
• Verbal instructions that are unclear, too rapidly spoken or not at developmental level
• Lack of consistency and routine
• Environmental noises, crowds, and close proximity to others
• Transition, even when from preferred to preferred activities
• Having to wait without clear understanding of the time requirement
• Heightened emotion or excitement

Traditional strategies for addressing behavioral issues in children with intellectual and neurodevelopmental disorders include the use of positive reinforcement for appropriate behavior, shaping, reward systems, time-out, loss of privileges, and ignoring negative behavior. Such strategies are widely used in educational and residential settings. These approaches are “consequence-based” in that they are implemented after a behavior has occurred. While useful in shaping, reinforcing, increasing, or maintaining positive behaviors, these approaches are less effective for decreasing inappropriate behaviors with individuals with FXS. Preventative or antecedent strategies facilitate the learning of new skills, rather than addressing inappropriate behaviors that have already occurred. A behavior plan that is “front-loaded” with antecedent strategies is recommended so that the person with FXS is supported and set up to engage in appropriate behaviors which will then be reinforced by positive consequences. (see figure below)

While no two individuals with FXS present with the same repertoire or severity of behavioral issues, there can be striking similarities. Knowledge of behavioral and learning characteristics associated with FXS provides a foundation to develop appropriate supports and interventions.

Evidence-based behavioral interventions grounded in Applied Behavior Analysis (ABA) are often effective. ABA is not a specific program but rather a behavioral framework from which specific therapeutic interventions (such as Lovaas therapy, verbal behavior, or discrete trial) have been developed. As such, there may be wide variability from one ABA program to another. It is important to keep in mind that systematic instruction, careful ongoing assessment, positive reinforcement, and attention to the ABC’s (antecedents, behaviors, and consequences) of behavior are essential aspects of any successful therapeutic program, regardless of whether or not it is designated as “ABA.”

Decisions about the appropriateness of ABA services for a child with FXS should be made after careful evaluation of the individual. Discrete trial training (DTT) and intensive table teaching (ITT) procedures may need to be less direct and may include another student to utilize peer modeling or turn taking. Staff working with these students should continue to glean ideas and potential strategies from well-established programs while keeping in mind the syndrome-specific characteristics associated with FXS.

The following general treatment guidelines may be useful to customize the environment and set the stage for success for the person with FXS.

Speech and Language

For many young males and some adolescents and adults with FXS, verbal speech and communication is not functional across settings.  Rapid rate of speech or poor intelligibility and anxiety interfere with effective communication.  Augmentative and Alternative communication systems (AAC) may be suggested for individuals with FXS.  AAC refers to all tools that are used to supplement or replace speech when it is not sufficient to meet the individual’s needs. AAC includes high-tech tools, such as tablet technology, as well as low-tech strategies, such as a picture communication and sign language.  Access to language may increase functional communication and reduce frustration which in turn may decrease challenging behaviors.

Effective strategies to support children and adults with FXS include:

• Clear, concise verbal instructions; always remember to reduce verbiage
• Consistent expectations, routine and structure
• Visual supports and strategies, such as an individual schedule
• Allow for possible delay of initial response to direction or instruction
• Ample personal space
• No demand for eye contact
• Limit known individual triggers, such as noises, crowds, specific environments
• Provide transition activities, such as job or transitional items
• Allow the child or adult closure before changing activities
• Consistent responses to challenging behaviors among caregivers and across settings
• Interrupt behavior chains; distract and engage in alternative behavior or venue

Crisis Intervention Plan

For school-aged children, a crisis intervention plan (CIP) should be included as part of the individualized education program (IEP). For adults with FXS, it is essential to create a plan or protocol to be utilized in the day program, work, or community settings. This should be developed and reviewed/updated annually. This plan will be critical to prepare staff to be proactive rather than reactive. The specific response to the crisis depends upon the individual situation. When there is a history of unsafe behaviors, it is crucial that the family and team develop a written crisis plan that focuses on safety. If crisis related behaviors are likely to occur across settings, separate crisis plans may be necessary.

This proactive crisis intervention plan should emphasize de-escalation interventions e.g., provide a quiet, safe, familiar place for the child/adult which removes the audience and possible triggers. The plan should delineate the behaviors that may be seen in a crisis as well as the different phases of escalation. It should include specific instructions of the interventions that will be implemented, who will be contacted with a list of current contact information. Contacts may include family members or a friend who would be helpful in a crisis, such as a psychologist or behavioral health provider who knows the child. It may also be necessary to include the local crisis line number, and walk-in centers or emergency rooms. In an emergency, as with anyone, you should call 911. If 911 should be called, emergency responders should be informed about the individual’s unique needs.

Interventions designed by a team who is knowledgeable of the behavioral, learning, medical, and physiological characteristics associated with FXS are usually helpful in reducing challenging behaviors. A proactive approach with appropriate supports and accommodations will likely foster positive outcomes and set up the child or adult with FXS to succeed in their home, school or community.