What Is Fragile X Syndrome?

Fragile X Syndrome (FXS) is a rare genetic condition that causes intellectual disability, anxiety disorders, behavioral and learning challenges, and various physical characteristics. The impairment can range from learning disabilities to more severe cognitive or intellectual disabilities. FXS is the known leading cause of inherited intellectual disability and the leading single-gene cause of autism spectrum disorder (ASD). Patients with FXS may exhibit autism-like symptoms, including anxiety, social impairment, social avoidance (seeking isolation from others, not wanting to be with other children, and avoiding all types of new social engagements), and restricted/repetitive behaviors.¹ Currently, no known cures or approved drug therapies are indicated for treating FXS or its symptoms. Special services, such as speech, physical and occupational therapies, along with symptomatic treatments for anxiety and irritability, are employed to lessen the burden of illness.

Fragile X syndrome is caused by a mutation of a DNA segment known as the CGG triplet repeat in the FMR1 gene. This DNA region is often replicated between five and 40 times in unaffected individuals. However, the CGG region is replicated more than 200 times in those afflicted with FXS. Due to the excessively enlarged CGG region in patients with FXS, the FMR1 gene becomes methylated and is rendered inactive and unable to produce FMRP, the fragile X RNA-binding protein. The significant reduction or absence of this protein causes Fragile X syndrome symptoms. While some individuals with FXS produce low levels of FMRP, approximately 60% of patients have complete methylation of the FMR1 gene, leading to the absence of FMRP. Although both genders are affected by FXS, males, who only have a single X chromosome (XY), are more likely to be severely impacted and develop FXS symptoms because their single X chromosome is mutated. In females, who have two X chromosomes (XX), the unaffected X chromosome can mitigate the consequences of the afflicted X chromosome. Because the gene for FXS is situated on the X chromosome, there are fewer females with the disorder, and females with FXS often have milder symptoms than males. ^{2 3}

Three Main Types of Fragile X-Associated Disorders

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).⁴

Premutation FMR1-related disorders include:

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) – is a neurodegenerative condition with “adult-onset” that typically affects males over 50.⁶ About 40% of males and 16% of females who are premutation carriers develop FXTAS.⁷ FXTAS affects the neurologic system and progresses at various rates in different people. The most common symptoms of FXTAS in males include tremors, gait ataxias, Parkinsonism, cognitive deficits, neuropathy, mood disorders, and low blood pressure.⁶ Females can experience the same neurological symptoms as males, but the severity is nearly always less. Although most women exhibit some degree of tremor or ataxia, women with FXTAS are also more likely to experience anxiety and depression in general.⁶ Additional symptoms experienced by females include fibromyalgia, generalized muscle pain, thyroid disorders, and seizure disorders.⁶

Fragile X-Associated Primary Ovarian Insufficiency (FXPOI) – is a condition in which a fragile X premutation carrier’s ovaries do not function at full capacity. Regarding the number and quality of accessible eggs, the ovaries of women with FXPOI may resemble those of older women. Approximately 20% of women who carry a fragile X premutation develop FXPOI throughout their reproductive years, compared to approximately 1% of the overall population. Approximately 3% of women with FXPOI will experience menstrual cycle irregularities in their teens or twenties, and 1% will stop menstruating before 18. The most common symptoms of FXPOI include absent or irregular cycles, sub-fertility or infertility, hot flashes, and premature ovarian failure (POF), which is the cessation of menstruation before the age of 40. In the spectrum of FXPOI symptoms, premature ovarian failure represents the most severe symptom.⁸

Symptoms & Signs of Fragile X Syndrome

Individuals with Fragile X syndrome may not have identical symptoms and signs of the condition but may share certain characteristics.

Infants and younger children with FXS may not exhibit the physical characteristics of the condition. However, when boys reach puberty, they may begin to exhibit physical features that are indicative of Fragile X syndrome.

Physical characteristics may include:⁹

Narrow face
Large head
Large and protruding ears
Prominent forehead and chin
Soft skin
Flat feet
Low muscle tone
Double-jointed fingers
Flexible or loose joints (joint laxity)
High arched palate
Large testicles (post-puberty)

Behavioral characteristics may include:⁹

Sensory processing challenges (sensitive to certain fabrics or clothing, loud noises, crowds, food textures, and social interactions)
Hand-flapping and hand-biting
Poor eye contact
ADHD (attention-deficit/hyperactive disorder)
Anxiety
Autism spectrum disorder
Increased risk for aggression
Sleep disorders

The behavioral characteristics observed in males can also be observed in females. However, the disorder’s behavioral, physical, and connective tissue manifestations are typically milder in females.⁹

Medical issues may include:⁹

Ear infections (often due to poor connective tissue)
Strabismus (crossed eyes)
Seizures

The cognitive impairments in FXS range from mild developmental delays to severe intellectual disabilities. While most males with FXS may have a severe intellectual disability or mental impairment, most females will have normal IQs or moderate intellectual or learning difficulties.⁹

A small percentage of females with the full mutation of the FMR1 gene that causes FXS will exhibit no intellectual, behavioral, or physical symptoms. Often, these females are only diagnosed after another family member has been diagnosed. ⁹

FXS does not alter life expectancy because there are typically no life-threatening health complications connected with the disorder.⁹

Genetic Testing

Genetic testing frequently identifies the underlying cause of children’s developmental delays, autism spectrum disorder, or intellectual disability. The first genetic test for diagnosing FXS utilized a microscopic examination of the X chromosome. In the 1970s, it was found that the X chromosome of some males with a hereditary intellectual disability appeared “fragile,” as if the end had broken off.¹⁰ This is where the term “fragile X” originated. This test was reasonably accurate in identifying males with Fragile X syndrome, but it was ineffective in identifying females with Fragile X syndrome or premutation carriers with certainty.¹⁰

In the 1990s, genetic testing technologies progressed, and the FMR1 gene was identified. Since then, extremely precise fragile X DNA testing has become available to identify individuals with any form of FMR1 gene repeat expansion.¹⁰

When identifying Fragile X-associated disorders, two major testing methods are utilized:¹⁰

Polymerase chain reaction (PCR) – This method can determine the size of the repetitive portion of the FMR1 gene, including the amount of CGG repeats in the normal, intermediate, premutation, and full mutation ranges.
Southern blot analysis – For complete mutations, laboratories typically do a Southern blot analysis to check whether the gene is methylated (chemical modification that prohibits it from making its usual protein, FMRP).

Typically, laboratories report the number of CGG repeats in the FMR1 gene. If observed, they also describe the methylation status and the presence of mosaicism for complete mutations. Mosaicism is the presence of different-size CGG repeats or when the methylation status of some of the parts of the chromosome (alleles) may vary. Due to the availability of fragile X testing through various facilities, the format of lab reports varies.¹⁰

Due to the intricacies of FXS, families dealing with Fragile X-associated disorders may 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.

Who Should Consider Testing for Fragile X?

There are many situations in which genetic testing for FXS should be considered:¹⁰

Symptoms of FXS, Fragile X-associated tremor/ataxia syndrome (FXTAS), or Fragile X-associated primary ovarian insufficiency (FXPOI) are present.
A family history of FXS, FXTAS, intellectual or learning impairments, autism spectrum disorder of unknown cause, or infertility.
Any male or female with intellectual disability, developmental delay, speech and language delay, autism spectrum disorder, cognitive decline, or unknown source of learning problems.
Any female with infertility with increased levels of FSH (follicle-stimulating hormone), premature ovarian failure, primary ovarian insufficiency, or irregular menstruation.
Any adult over 50 with FXTAS symptoms, such as tremors, ataxia, memory loss, cognitive decline, or personality change, particularly when accompanied by a positive family history of fragile X.
Any preconception or pregnant woman interested in or requesting carrier testing for fragile X.

Do I Need a Doctor’s Order to Get Tested for Fragile X?

All major genetic testing laboratories require an order from a healthcare professional. This is a critical safeguard to ensuring that test subjects receive appropriate notification, education, follow-up, and medical support regarding the significance of their test results¹⁰.

References

Salcedo-Arellano MJ, Cabal-Herrera AM, Punatar RH, Clark CJ, Romney CA, Hagerman RJ. Overlapping Molecular Pathways Leading to Autism Spectrum Disorders, Fragile X Syndrome, and Targeted Treatments. Neurotherapeutics. 2021;18(1):265-283. doi:10.1007/s13311-020-00968-6
Stone WL, Basit H, Los E. Fragile X Syndrome. June 29, 2022.
Sitzmann AF, Hagelstrom RT, Tassone F, Hagerman RJ, Butler MG. Rare FMR1 gene mutations causing fragile X syndrome: A review. 2017 Nov 27. doi:10.1002/ajmg.a.38504.
Akash R, Shergill J, Salcedo-Arellano M, Saldarriaga W, Duan X, Hagerman R. Fragile X syndrome and fragile X-associated disorders. 2017 Dec 8. doi: 10.12688/f1000research.11885.1.
National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. Data and Statistics on Fragile X Syndrome. Retrieved Oct 17, 2022, from https://www.cdc.gov/ncbddd/fxs/data.html
National Fragile X Foundation, Fragile X–Associated Tremor/Ataxia Syndrome | FXTAS. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/tremor-ataxia-syndrome-fxtas/
Cabal-Herrera AM, Tassanakijpanich N, Salcedo-Arellano MJ, Hagerman RJ. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications. Int J Mol Sci. 2020 Jun 20;21(12):4391. doi: 10.3390/ijms21124391.

National Fragile X Foundation, Fragile X-Associated Primary Ovarian Insufficiency| FXPOI. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/fxpoi-primary-ovarian-insufficiency/
National Fragile X Foundation, Fragile X 101. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/fragile-x-101/
National Fragile X Foundation, Genetic Testing for Fragile X Syndrome and Associated Disorders. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/fragile-x-101/testing-diagnosis/