Fragile X Syndrome in Females

Fragile X syndrome (FXS) is a rare genetic disorder caused by the full mutation of the FMR1 gene. This gene encodes the fragile X RNA-binding protein, FMRP, needed for normal brain development. Changes to this gene can hinder the production of the FMRP, resulting in intellectual disability, developmental delays, behavioral and learning challenges, and various physical characteristics.¹ FXS is the most common cause of inherited intellectual disability worldwide.²

While males are more likely to be severely impacted by FXS than females, understanding the symptoms of the disorder and the way in which it impacts females is important to aid in early diagnosis.

Why are females less affected than males?

The location of the FMR1 gene on the X chromosome explains the considerable disparities in effects reported between females and males with FXS. Males possess a single X chromosome (XY). Because of this, if they inherit the fully mutated FMR1 gene from their mother, their sole X chromosome is affected. However, females have two X chromosomes (XX). Therefore, if they inherit an X chromosome with the FMR1 full mutation from their mother and an X chromosome without the mutation from their father, only one of their X chromosomes is potentially affected. Given that only one chromosome is impacted, some FMRP may still be produced. For most females, however, this may still be insufficient to restore FMRP function fully and may lead to FXS symptoms, though of a lesser severity than experienced by males.³

Signs of Fragile X Syndrome in Females

Females inheriting the FMR1 full mutation generally may not exhibit the full range of symptoms or severity of symptoms of males.

Many females with FXS present with one or more of the following diagnoses:³

Generalized anxiety disorder (GAD)
Social anxiety disorder (SAD)
Math learning disability (LD)
Intellectual disability (ID)
Autism spectrum disorder (ASD)
Attention deficit hyperactivity disorder (ADHD)

A national parent survey by the CDC found that 46% of males and 16% of females with FXS have been diagnosed with or treated for Autism Spectrum Disorder (ASD). Approximately 84% of males and 67% of females have been diagnosed with or treated for problems with attention.⁴

Although physical features such as flat feet, loose joints, low muscle tone, long face, prominent forehead, and large head are more apparent in males with FXS, especially during post-puberty, females with FXS generally exhibit milder versions of facial characteristics and connective tissue problems.¹

The behavioral characteristics observed in males can also be observed in females, albeit in a lesser form. These may include:¹

Sensory processing challenges
Hand flapping or hand-biting
Poor eye contact
Increased risk for aggression
Sleep disorders

Cognitive deficits in people with FXS range from learning disabilities to more severe intellectual disabilities. Almost one-third of females with FXS have no to very mild learning disabilities, a third have mild intellectual disabilities, and the rest have moderate to significant intellectual disabilities.¹ Around 25% of females with FXS have an intelligence quotient (IQ) below 70, and another 25% have an IQ between 70 and 85 (borderline range). In contrast, one-third to one-half of females have normal cognitive functions. However, even in females with FXS who have normal IQs, learning disabilities, executive function deficits, and attention span deficiencies can develop.⁵

Because most females with FXS have normal or borderline IQs, they are more likely than males with FXS to acquire greater levels of schooling, hold employment, and live independently. However, math difficulties are especially widespread, making money management challenging even for individuals with higher levels of independence. Further, mental health and psychiatric issues such as social anxiety, depression, self-injury, excessive shyness, withdrawal, poor eye contact, and phobias are common. Some of these emotional and behavioral issues can be debilitating, lowering levels of independence and quality of life.⁵

Parents usually start to notice the symptoms between the ages of three and four in girls, whereas awareness of symptoms usually occurs around age three in boys.⁶ A small proportion of females with FXS may not show any of the apparent behavioral, cognitive, or physical signs of the disorder. These females are often identified through genetic diagnosis after another family member has been diagnosed with the condition.¹

Common Symptoms of FMR1-Related Disorders in Females

Three Fragile X-associated disorders are known to be caused by mutations in the FMR1 gene. The full mutation of the FMR1 gene (more than 200 CGG repeats) is referred to as FXS as discussed above. The remaining two disorders are due to a premutation of the FMR1 gene (between 55 and 200 CGG repeats).⁷

Fragile X-associated Primary Ovarian Insufficiency (FXPOI) is a disorder characterized by the reduced functioning of the ovaries. Approximately 20% of females who carry a fragile X premutation develop FXPOI throughout their reproductive years, compared to approximately 1% of the overall population who may develop primary ovarian insufficiency. FXPOI is a cause of infertility and early menopause among adult females. About one third of females with FXPOI stop having menstrual cycles by age 29. Common symptoms of FXPOI include absent or irregular menstrual cycles, sub-fertility or infertility, hot flashes, and on the more severe end of spectrum, premature ovarian failure (POF), which is marked by cessation of menstration before age 40.⁸ They also have a higher risk of having children with FXS.⁹

Fragile X-associated Tremor/Ataxia syndrome (FXTAS) is an adult-onset neurogenerative disorder that progresses at varying rates in different individuals. FXTAS affects only a small population of females, and their symptoms also tend to be less severe. Among premutation carriers, about 40% of males over 50 develop FXTAS, while only eight to 16% of female carriers over 40 develop the condition.¹⁰

The clinical and MRI manifestations of FXTAS are subdivided into minor and significant manifestations. The diagnosis is then classified as definite, probable, or possible FXTAS. The criteria were designed using symptoms in males as their primary foundation. As we learn more about FXTAS in females, the diagnostic criteria for females may change, as their symptoms are typically milder. The nature and intensity of FXTAS symptoms vary from person to person. Some will experience several symptoms that increase swiftly, while others will experience fewer symptoms that remain mild for many years.¹⁰

The most common symptoms of FXTAS in females include some degree of tremors and ataxia (impaired balance or coordination). Though psychiatric and mood disorders are less prevelant than in males with FXTAS, females with FXTAS are also at higher risk to experience anxiety and depression in general.⁹Additional symptoms experienced by females include fibromyalgia, generalized muscle pain, thyroid disorders, and seizure disorders.^{10 11}

Daily Living Challenges Faced by Females with Fragile X Syndrome

Females with FXS may show a high frequency of avoidant behavior, attention deficits, mood disorders, and learning disabilities. They may also be more withdrawn and depressed than females their age, making them more vulnerable to social anxiety and avoidance.⁹ Severity of withdrawal, depression, and social avoidance seem to worsen as girls with FXS enter puberty. This trend for increasing symptoms of depression and anxiety appears to occur despite a higher proportion of females receiving medication for anxiety; suggesting their symptoms may not be alleviated by traditional treatments. Researchers suggest that understanding and managing emotions and working to reduce social withdrawal could serve as key targets for intervention in the school-age years with the goal of preventing worsening symptoms and, in turn, facilitating long-term independence and quality of life.¹²

The following are examples of daily challenges faced by females with FXS.

Extreme Shyness

Females with FXS have higher levels shyness, and they tend to isolate socially, have poor eye contact, and show diﬃculties in establishing an adequate rapport with others.¹³ Extreme shyness may be a major issue for females with FXS. It is not unusual to see young girls with FXS huddled close to their parents, crying when asked to participate in activities, refusing to be separated from their guardians, and speaking in low tones or becoming silent in public. They may need desensitization through repeated exposure to group activities before they are comfortable to join. As these girls mature, their shyness frequently manifests as significant social anxiety.⁹

Self-Injury and Bullying

Self-injury is one of several aberrant behaviors that can manifest from anxiety. Self-injury occurs among females with FXS, albeit it is typically less blatant than in males. For example, what starts as picking a scab can lead to scars if it’s not stopped. In extreme cases, they may be unable to resist the urge. They may start to feel self-conscious about it and attempt to hide their arms in long sleeves or cover the scabs with bandages.⁹

There is also evidence that females with FXS, like other females with intellectual disability experience bullying or social exclusion at school.^{9 13} Females with FXS have shown an increased lack of social support and isolation by classmates. Diﬃculties in social communication and interaction could lead to diﬃculties in interpreting social signals and correctly identifying situations of bullying, which would mean a lowered awareness of the situation. This fact could place females with FXS in vulnerable situations given that when faced with a situation of bullying they would not be able to correctly identify the signals nor adequately manage and resolve the situation. Researchers suggest placing on emphasis on helping females with FXS develop their social skills and improving social communication to help reduce the risk of bullying.¹³

Attention and Speech

Attention deficits can make social relationships more difficult for females with FXS. For example, distractedness or forgetting essential information from a conversation may negatively impact social interactions. Females with FXS frequently use repeative pharses in conversation. As they become more emotional, they may repeat key phrases or repeatedly emphasize a specific aspect of the conservation, causing the listeners to lose interest and dismiss the speaker’s ideas.⁹

Academic Struggles

Females with FXS may lack the confidence they need to thrive academically because of the challenges they confront. Math is just one area that may be challenging for females with FXS. One explanation for difficulties with math by to a reduce capacity to process mathematical statements when presented verbally.¹⁴ Additionally, deficits in attention may have a negative effect on academic achievement.^{3 9} Attention deficits may have a cumulative and widespread effect on a student’s success in school. In many cases, the deficiencies are not recognized or diagnosed until much later in life, delaying any chance of early intervention.⁹

Executive Functioning

Another trait commonly linked to FXS in females is impaired executive functioning (the capacity to plan and carry out an activity).^{9 14} Not following through on tasks becomes problematic, making it hard to finish assignments and fulfill commitments. This could lead teachers and administrators to label such females as unmotivated or lazy.9

Unfamiliar Tasks or Activities

Females with FXS often have trouble when exposed to new or unfamiliar situations or activities. Having a regular schedule is comforting since it allows for predictability and security. However, dependence on a routine can lead to the development of intricate rituals and the veneration of obsessive behaviors. Females with FXS have been shown to rely on routine to maintain their composure.⁹

Personal Organization

The desire for consistency does not manifest in their skill for personal organization. A common symptom of FXS in females is a lack of cleanliness and order in their living spaces, vehicles, and other personal space. This is largely attributable to problems with their ability to focus and make and execute on decisions. Females with FXS have difficulty getting rid of unnecessary possessions because they enjoy collecting and storing memories like concerts and football ticket stubs.⁹ Higher levels of social anxiety also impacts the their ability to organize things.¹⁴

Relationships and Dating

Relationships constitute a challenge throughout the lifespan of females with FXS. Their acute shyness and incapacity to articulate emotions make relationships difficult. They may also gravitate towards males with ulterior motives because the males are more attentive and initially offer emotional support. This can result in the manipulation and exploitation of females with FXS. On the other hand, some females with FXS fear dating, getting married, and having children.⁹

Genetic Testing for Fragile X-Associated Disorders

Fragile X syndrome can only be diagnosed through genetic testing. A blood test can check for FXS by analyzing the patient’s DNA.¹⁵ A healthcare provider or genetic counselor may order the test.
When identifying fragile X-associated disorders, two major testing methods are utilized:¹⁶

Polymerase chain reaction (PCR) – The extent of the repetitive part of the FMR1 gene, including the rate of CGG repeats in the normal, intermediate, premutation, and full mutation ranges, can be determined using this method.
Southern blot analysis – For full mutations, laboratories often perform a Southern blot analysis to determine whether the gene has been methylated or has undergone a chemical alteration that prevents it from producing its usual protein, FMRP.

Due to the intricacies of FXS, families dealing with fragile X-associated disorders may wish to consult with a genetic counselor or geneticist, their health care provider, or a fragile X clinic to discuss what a positive result means for the affected person and their loved ones.

References

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Eunice Kennedy Shriver National Institute of Child Health and Human Development. What are the symptoms of Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS)? Retrieved Oct 17, 2022, from https://www.nichd.nih.gov/health/topics/fxtas/conditioninfo/symptoms#
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