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Fragile X Syndrome

Shalene M. Denovan

Department of Psychology, Carleton University

NEUR 2202A: Neurodevelopment and Plasticity

Dr. Argel Aguilar-Valles

April 17th, 2023

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This paper aims to provide a comprehensive analysis of Fragile X Syndrome (FXS), a

prevalent genetic disorder that affects millions of individuals. First, the genetic mechanisms that

underlie FXS will be examined, focusing on the mutation in the FMR1 gene. Next, we will

explore how these genetic mechanisms affect developmental processes, leading to the cognitive

and behavioral deficits observed in individuals with FXS. Finally, potential interventions or

therapies for FXS will be discussed, with a focus on addressing various behavioral deficits.

FXS results from a mutation in the FMR1 gene located on the X chromosome, which

encodes the fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates

the translation of several neural proteins (Rais et al. 2018). The FMR1 gene is silenced when

there are more than 200 CGG repeats, leading to a lack of FMRP. As a results, several neural

proteins become overabundant, causing the cognitive and behavioral deficits observed in

individuals with FXS. The presence of extended CGG repeats in the FMR1 gene is often

inherited from parents carrying more than 50 repeats. Although an initial increase in FMR1

mRNA levels occurs with more repeats, protein levels eventually decline, resulting in the onset

of symptoms (Côté et al. 2021). By understanding the genetic mechanisms of FXS, we can gain

insight into how this disorder impacts developmental processes, which will be discussed next.

The absence of FMRP in individuals with FXS can cause an excess of protein synthesis

in the brain, which impairs developmental processes such as learning and memory (Côté et al.

2021). This disruption in protein synthesis also alters synaptic plasticity, resulting in an increased

number of dendritic spines in cortical neurons (Lee et al. 2022). The excess of several neural

proteins that would normally be in short supply can cause changes in synaptic function and

plasticity, contributing to the cognitive and behavioral deficits observed in individuals with FXS.

Furthermore, the lack of FMRP affects sensory processing, leading to hypersensitivity,

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hyposensitivity, and sensory-seeking behaviors (Rais et al. 2018). FMRP plays an essential role

for the development and function of sensory circuits in the brain, and its absence or deficiency

can cause major sensory processing problems in individuals with FXS (Rais et al. 2018). In sum,

the genetic mechanisms involved in FXS affect various developmental processes related to

synaptic function and plasticity. In the following section, a comprehensive examination of

interventions and therapies for FXS will be conducted, drawing from relevant literature sources.

Despite the absence of a known cure for FXS, there are various interventions and

therapies that aim to manage the symptoms and improve the quality of life of affected

individuals. Sensory integration therapy, pharmacological interventions, and behavioural

therapies, have shown promise in improving sensory processing, reducing anxiety, and

improving behavioral symptoms associated with FXS.

Sensory integration therapy (SIT) aims to regulate and integrate sensory information

from the environment to improve sensory processing. It typically involves engaging individuals

in sensory activities that are designed to be calming or alerting depending on their sensory needs

(Lang et al. 2012). A literature review by Méthot et al. (2001) examined the effectiveness of this

type of therapy on individuals with FXS. They found that SIT was effective in reducing sensory

hypersensitivity, improving social skills, and enhancing overall quality of life in individuals with

FXS. The studies reviewed by Méthot et al. (2001) employed various techniques, such as deep

pressure touch, massage, brushing, and weighted vests. The therapy sessions were conducted by

occupational therapists or trained educators who tailored the therapy to each individual’s sensory

needs. Overall, the findings suggest that SIT can be a valuable intervention for individuals with

FXS.
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Pharmacological interventions such as gamma-aminobutyric acid (GABA) agonists

medications that work to enhance the function of the inhibitory neurotransmitter, have also been

shown to be an effective treatment for FXS. Olmos-Serrano et al. (2011) used a mouse model of

FXS to investigate the potential of the GABA receptor agonist gaboxadol (THIP), as a

pharmacological intervention for specific behavioral deficits associated with the disorder. They

used a variety of behavioral tests to assess the effects of THIP on social interaction, anxiety-like

behaviors, and learning and memory deficits in mice. The results of the study showed that THIP

treatment improved social interaction and reduced anxiety-like behaviors in the mice with FXS.

Additionally, THIP treatment mice showed improved learning and memory deficits when

compared to the control group of mice who received saline solution (Olmos-Serrano et al. 2011).

These results suggest that GABA receptor agonists like THIP, may have potential as a

pharmacological intervention for treating specific behavioral deficits associated with FXS.

Aversion to eye contact is a common behavioral deficit among individuals with FXS and

has been a target in some applied behavior analyses. Hall et al. (2009) employed a behavioral

intervention called percentile reinforcement schedules (PRS) to increase eye contact duration in

six boys with FXS. PRS involve identifying the duration of the target behavior, establishing a

criterion for the desired duration, and providing reinforcement for durations that meet or exceed

the criterion. The results of the study showed that eye contact duration was increased in some

(4/6) of the participants using PRS. Overall, the study by Hall et al. (2009) suggests that applied

behavior analysis such as PRS may be an effective intervention for some behavioral deficits in

children with FXS.

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References

Côté V, Lalancette È, Knoth IS, Côté L, Agbogba K, Vannasing P, Major P, Barlaam F, Michaud

J, Lippé S (2021) Distinct patterns of repetition suppression in fragile X syndrome, down

syndrome, tuberous sclerosis complex and mutations in SYNGAP1. Brain

Research 1751:1-11.

Hall SS, Maynes NP, Reiss AL (2009) Using percentile schedules to increase eye contact in

children with Fragile X Syndrome. Journal of Applied Behavior Analysis 42:171–176.

Lang R, O’Reilly M, Healy O, Rispoli M, Lydon H, Streusand W, Davis T, Kang S, Sigafoos J,

Lancioni G, Didden R, Giesbers S (2012) Sensory integration therapy for autism

spectrum disorders: A systematic review. Research in Autism Spectrum Disorders

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Lee CH, Bartholomay KL, Marzelli MJ, Miller JG, Bruno JL, Lightbody AA, Reiss AL (2021)

Neuroanatomical profile of young females with fragile X syndrome: A voxel-based

morphometry analysis. Cerebral Cortex 32:2310–2320.

Méthot S, Berthiaume C, Aunos,M, Pidgeon C (2001) Le syndrome du X fragile: État des

connaissances. [Fragile X syndrome: A review of the literature] Revue Francophone De

La Déficience Intellectuelle 12:181-194.

Olmos-Serrano JL, Corbin JG, Burns MP (2011) The GABA receptor agonist THIP ameliorates

specific behavioral deficits in the mouse model of Fragile X Syndrome. Developmental

Neuroscience 33:395–403.
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Rais M, Binder DK, Razak KA, Ethell IM (2018) Sensory processing phenotypes in Fragile X

syndrome. American Society for Neurochemistry 10:1-9.