Overview
Fragile X Syndrome (FXS) is a genetic condition caused by the full mutation of the FMR1 gene. FXS is the most common genetic cause of intellectual disability (ID) and includes signs and symptoms such as behavioural and learning difficulties, and physical changes. Despite occurring in both people assigned female at birth (AFAB) and people assigned male at birth (AMAB), it is more common and severe in the latter, due to its X-linked inheritance.
People with FXS can also exhibit co-occurring physical and behavioural conditions (comorbidities) that may be difficult to manage. The most prevalent comorbidities in FXS are Autism Spectrum Disorder (ASD), Attention Deficit and Hyperactivity Disorder (ADHD), and anxiety.1 While these conditions can have multiple causes, most of which are still undetermined, it is believed that when they co-occur with FXS, it is due to the altered brain activity resulting from the full mutation of the FMR1. This in turn leads to altered behaviour and learning patterns that correspond to the symptomatic criteria.2
Autism spectrum disorder (ASD)
Autism Spectrum Disorder (ASD) is an umbrella term that has been used since 2013 to substitute previously used subtypes of autism, including Asperger’s syndrome, and pervasive developmental disorder not otherwise specified (PDD-NOS).
ASD is characterised by difficulties in socialisation and communication, sensory issues, and restricted and repetitive behaviours, interests, and routines. The severity and impact of these symptoms vary greatly between individuals with ASD, and some might need more support than others. Although there’s no definitive cause of autism, it is known that there is a strong genetic component, with a heritability of 80-90% and a 10-20% chance of reoccurrence in a sibling.3
ASD and FXS
While the genetic and environmental factors that contribute to ASD are not fully elucidated, it is known that approximately 15% of people with ASD present some type of genetic disorder, among which FXS is the most common. Indeed, about 1 to 6% of people with ASD also have FXS. ASD prevalence in FXS varies according to gender, with approximately 50% of people AMAB and 20 % of people AFAB with FXS also being diagnosed with ASD.4
Many symptoms and signs of FXS overlap with ASD, including:4
- Intellectual disability (ID)
- Issues with social interaction
- Issues with communication and language
- Repeated movements, such as hand flapping
- Repetitive use of objects, such as arranging toys in a line, or putting toys in and out of baskets
- Seizures
- Sleep issues
- Difficulties with motor coordination
- Additional behavioural diagnoses, such as obsessive-compulsive disorder (OCD) and ADHD
- Self-injury and aggression
- Sensorial hyper- or hypo-sensitivity
Notably, people with FXS + ASD have different symptoms than people with non-syndromic ASD, including less social and communication difficulties, more severe symptoms related to restricted and repetitive interests and behaviours, and more intense comorbidities, such as anxiety and ADHD.5
People with FXS + ASD may also face considerably more challenges compared to people with FXS alone, including:6,7
- More frequent seizures (20.7 % of people with FXS + ASD vs. 7.6 % in FXS alone)
- Continued sleep problems later in childhood, and more behavioural issues, including aggressiveness, and delayed toilet training
- Greater use of pharmacological behaviour interventions, such as alpha-agonists and antipsychotics
- Less-developed reading and listening skills
- Lower IQ scores
- More severe speech and language issues (often non-verbal or minimally verbal)
- More frequently lacking in verbal communication
Management strategies
Due to the overlapping symptoms of FXS and ASD, a diagnosis of comorbid ASD can be difficult. Nevertheless, the early identification of ASD in people with FXS is fundamental to eliciting adequate management strategies in a timely matter. While there is no specific medication for the core symptoms of ASD, many therapeutical strategies are available which can be adapted to people with FXS + ASD, and are currently underutilised.8 These include:
- Applied behavioural analysis (ABA)
- Occupational therapy
- Speech and language therapy
- Educational adaptations
- Cognitive Behaviour Therapy (CBT)
Attention-deficit/hyperactivity disorder (ADHD)
ADHD is a behavioural disorder affecting approximately 2.5% of adults and 8.4% of children and is characterised by hyperactivity, impulsiveness, and a lack of attention. People diagnosed with ADHD can be classified into three presentations:
- Predominantly inattentive, presenting symptoms like difficulty in paying close attention for prolonged periods of time, inability to focus, forgetfulness, easily distracted, and organisational difficulties
- Hyperactive/impulsive, presenting symptoms such as excessive movement not compatible with the setting, fidgeting, inability to stay seated or still, excessive talkative, and difficulty in waiting their turn
- A combination of both
There is no specific cause known for ADHD, however, there seems to be a genetic component, as well as several other environmental factors, such as stress and exposure to toxins during pregnancy, being born premature, and low weight at birth.
ADHD and FXS
ADHD symptoms account for the most common co-occurring conditions in FXS, with approximately 80% of people with FXS also exhibiting ADHD. Generally, people with AMAB with FXS display the hyperactive/impulsive presentation of ADHD more frequently, while typically AFAB exhibits the inattentive subtype.10
ADHD symptoms account for some of the most challenging psycho-educational aspects that a person with FXS faces which, together with ID, can lead to difficulties in adapting to school environments and more frequent use of psychiatric treatment when compared to children with ID and without ADHD. Therefore, early detection and intervention are essential to reduce the long-term impacts on education, socialisation, and mental health of patients with FXS + ADHD.11
Management strategies
Patients with FXS + ADHD often benefit from a combination of behavioural interventions and medication.
Among the behavioural interventions and therapies that can be performed both at home and in the classroom are:
- Occupational therapy techniques, such as brushing, deep pressure, and calming to alleviate over-stimulation and hypersensitivity
- Adaptations at school to promote attention, such as sitting in a quieter area close to a good role model, and away from distractions (i.e. windows)
- Make accommodations to include moving, such as seat breaks, offer variety in seating (i.e. bean bags, pilates ball, rocking chairs), and allow activities to be performed while standing
Behavioural interventions can also be adapted to the strengths of people with FXS, which include good imitation abilities. Thus, demonstrating an action, or placing the child close to a good role model, can greatly improve the assimilation of desirable behaviours. Overall, positive and redirective behavioural management is the most effective.
Medications can also be used to control the symptoms of ADHD, and patients with FXS + ADHD have been shown to respond well to traditional ADHD-pharmacological therapies. These include:
- Central nervous system stimulants, such as methylphenidate
- Amphetamines and amphetamine salts, such as dexamfetamine and lisdexamfetamine
- Alpha-2 agonists, such as guanfacine
- Selective Norepinephrine Reuptake Inhibitors (SNRIs), such as atomoxetine
Anxiety disorders
Anxiety disorders are the most common type of mental health disorder, and approximately 30% of adults will be affected at some point in their lives. While feelings of anxiety, fear, and worry are a normal part of the human experience, anxiety disorders are characterised by an exacerbation of these feelings that is not proportional with the context and/or not age-appropriate, and that might interfere with daily activities. Persistent thoughts of worry and fear can be accompanied by physical symptoms, such as sweating, heart palpitations, and feeling choked.
There are several types of anxiety disorder, including generalised anxiety disorder, panic disorder, social anxiety, specific phobia, agoraphobia, separation anxiety, obsessive-compulsive disorder (OCD), and selective mutism, among many others.
Anxiety disorders and FXS
Anxiety disorders are frequent in people with FXS, affecting as many as 86% of people with AMAB and 56% of people with AFAB with FXS. Generally, anxiety symptoms in people with FXS include manifestations of fear, social withdrawal, avoidance, reduced eye contact, increased arguing, tantrums, and panic.12,13
According to a study from 2011, the most prevalent anxiety disorders co-occurring with FXS are:14
- Social anxiety disorder (58%)
- Specific phobia (60%)
- Selective mutism (25%)
- Generalised anxiety disorder (24%)
- Obsessive-compulsive disorder (24%)
In children with FXS, anxiety disorders often manifest as a response to overstimulation, hypersensitivity, transition from one activity to the next, or a change in routine. In addition, structural modifications in the brain’s amygdala found in FXS could also be related to the occurrence of anxiety.13 Chronic anxiety can lead to the development of maladaptive behaviours, including aggressiveness, self-injury, screaming, trying to flee, and temper tantrums, which can cause physical and psychological distress to both patients and carers.
Management strategies
As with other co-occurring behavioural conditions in FXS, patients with FXS + anxiety would most benefit from a combination of non-pharmacological interventions and medication.
Possible non-pharmacological strategies are:13,15
- Establish a routine with increased structure and predictability, supported by visual cues such as visual schedules, checklists, pictures, etc
- Use of concise, clear, and simple language during anxiety crises
- Implement calming routines that may hinder the escalation of anxiety attacks caused by overstimulation, i.e. counting to 10, breathing techniques, calming activities that interrupt rumination of anxiogenic thoughts
- Occupational therapy
- Cognitive behavioural therapy (CBT)
Possible pharmacological routes are:
- Selective serotonin reuptake inhibitors (SSRIs), including sertraline, escitalopram, and citalopram
- SNRIs, such as venlafaxine, duloxetine, and desvenlafaxine
- Serotonin receptor antagonists and reuptake inhibitors (SARIs), like trazodone
- Norepinephrine and dopamine reuptake inhibitors (NDRIs), such as bupropion
- Anxiolytics, such as buspirone
Summary
FXS is a genetic condition caused by the full mutation of the FMR1 gene. This mutation causes a myriad of behavioural and physical alterations and may result in a higher incidence of certain conditions, called co-occurrent conditions or comorbidities.
Some of the most common comorbidities in FXS are ASD, ADHD, and anxiety disorders. The signs of these disorders, as well as the FXS itself, often overlap and affect each other, resulting in more severe symptoms and difficulties in diagnosis.
Management strategies involve a combination of behavioural interventions and medication. The first includes occupational therapy, ABA, and CBT, as well as adaptation and accommodations tailored to each individual. The latter involves medication traditionally prescribed for the treatment of non-syndromic individuals adapted for use in FXS patients. A holistic approach involving behavioural interventions, medication, and cooperation between parents, teachers, and carers, tailored to each person, can greatly improve the life quality of patients with FXS and co-occurring conditions.
References
- Bailey DB, Raspa M, Olmsted M, Holiday DB. Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A. 2008; 146A(16):2060–9.
- Finucane B. National Fragile X Foundation [Internet]. Making Sense of Multiple Diagnoses | NFXF; [cited 2024 Apr 26]. Available from: https://fragilex.org/understanding-fragile-x/fxs-symptoms-vs-causes/.
- The psychiatric management of autism in adults (CR228). www.rcpsych.ac.uk [Internet]. [cited 2024 Apr 26]. Available from: https://www.rcpsych.ac.uk/improving-care/campaigning-for-better-mental-health-policy/college-reports/2020-college-reports/cr228.
- Petraska D. National Fragile X Foundation [Internet]. Understanding Autism Spectrum Disorder in Fragile X Syndrome | NFXF; [cited 2024 Apr 26]. Available from: https://fragilex.org/professional-resources/treatment-recommendations/understanding-asd-fxs/.
- Abbeduto L, McDuffie A, Thurman AJ. The fragile X syndrome–autism comorbidity: what do we really know? Front Genet [Internet]. 2014 [cited 2024 Apr 26]; 5. Available from: https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2014.00355/full.
- Kaufmann WE, Kidd SA, Andrews HF, Budimirovic DB, Esler A, Haas-Givler B, et al. Autism Spectrum Disorder in Fragile X Syndrome: Cooccurring Conditions and Current Treatment. Pediatrics [Internet]. 2017 [cited 2024 Apr 26]; 139(Supplement_3):S194–206. Available from: https://publications.aap.org/pediatrics/article/139/Supplement_3/S194/34155/Autism-Spectrum-Disorder-in-Fragile-X-Syndrome.
- Abbeduto L, Brady N, Kover ST. Language development and fragile X syndrome: Profiles, syndrome‐specificity, and within‐syndrome differences. Ment Retard Dev Disabil Res Rev [Internet]. 2007 [cited 2024 Apr 26]; 13(1):36–46. Available from: https://onlinelibrary.wiley.com/doi/10.1002/mrdd.20142.
- Kidd SA, Berry-Kravis E, Choo TH, Chen C, Esler A, Hoffmann A, et al. Improving the Diagnosis of Autism Spectrum Disorder in Fragile X Syndrome by Adapting the Social Communication Questionnaire and the Social Responsiveness Scale-2. J Autism Dev Disord [Internet]. 2020 [cited 2024 Apr 26]; 50(9):3276–95. Available from: https://doi.org/10.1007/s10803-019-04148-0.
- Bogart K. National Fragile X Foundation [Internet]. Behavorial Challenges in Fragile X Syndrome | NFXF; [cited 2024 Apr 26]. Available from: https://fragilex.org/professional-resources/treatment-recommendations/behavioral-challenges-in-fragile-x-syndrome/.
- Sullivan K, Hatton D, Hammer J, Sideris J, Hooper S, Ornstein P, et al. ADHD symptoms in children with FXS. American J of Med Genetics Pt A [Internet]. 2006 [cited 2024 Apr 26]; 140A(21):2275–88. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.31388.
- Tonnsen BL, Roberts JE. Chapter Two - Characterizing Emergent Anxiety Through the Lens of Fragile X. In: Hodapp RM, Fidler DJ, editors. International Review of Research in Developmental Disabilities [Internet]. Academic Press; 2016 [cited 2024 Apr 26]; bk. 51, p. 41–83. Available from: https://www.sciencedirect.com/science/article/pii/S2211609516300148.
- Epstein JH. National Fragile X Foundation [Internet]. 2018. Managing Anxiety … What Works And Why? | NFXF.; Available from: https://fragilex.org/fxs/behavior/managing-anxietywhat-works-and-why/.
- Cordeiro L, Ballinger E, Hagerman R, Hessl D. Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization. J Neurodevelop Disord [Internet]. 2011 [cited 2024 Apr 26]; 3(1):57–67. Available from: https://jneurodevdisorders.biomedcentral.com/articles/10.1007/s11689-010-9067-y.
- Davidson M, Sebastian SA, Benitez Y, Desai S, Quinonez J, Ruxmohan S, et al. Behavioral Problems in Fragile X Syndrome: A Review of Clinical Management. Cureus [Internet]. [cited 2024 Apr 26]; 14(2):e21840. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8896844/.