Rare Disease Highlight: Fragile X Syndrome

Fragile X Syndrome (FXS) is a dominant genetic disorder that causes a range of symptoms from intellectual disability, developmental delays, and motor dysfunction, to abnormalities in the testes and ovaries (known as gonadal abnormalities) (Garber et al., 2008). While FXS is a rare disease affecting approximately 54,000 people in the US, it is the most common cause of inherited intellectual disability, second in prevalence only to Down syndrome (Coffee et al., 2009; Crawford et al., 1999; Saldarriaga et al., 2014). The cause of FXS is an abnormal expansion of a trinucleotide repeat in the Fragile X Mental Retardation 1 gene (FMR1). Nucleotides are the basic units that compose deoxyribonucleic acid (DNA). A trinucleotide repeat refers to the presence of three nucleotides consecutively repeated within a specific region of the DNA. Typically, the trinucleotide of cytosine-guanine-guanine (CGG) in the FMR1 gene is composed of less than 45 repeats. However, in FXS, the CGG trinucleotide repeats more than 200 times, which is known as a full mutation of FMR1 (Garber et al., 2008). This mutation impairs FMR1’s ability to produce the Fragile X Mental Retardation Protein (FMRP), essential for normal brain development (D’Incal et al., 2022).

The symptoms of FXS vary depending on several characteristics, including how many trinucleotide repeats are present, sex, and magnitude of FMRP deficit (Hagerman et al., 2009; McConkie-Rosell et al., 2005; Merenstein et al., 1996). The FMR1 gene is located on the sex chromosome known as X chromosome. Biologically, females have two X chromosomes while males have only one. Therefore, FXS is more common in males while females present milder symptoms (Verdura et al., 2021). The main symptoms of FXS are (Ciaccio et al., 2017; Lachiewicz et al., 2000; McConkie-Rosell et al., 2005):

  • Intellectual disability
  • Facial deformities, including long narrow face, large head (macrocephaly), and prominent ears and/or jaw
  • Psychomotor dysfunction, including delay in crawling and walking, low muscle tone, poor coordination and balance, spine deformity, and flat feet
  • Social dysfunction, including increased aggressiveness, anxiety, and depression, autism, and sleeping difficulties
  • Organization problems (attention deficit hyperactivity disorder [ADHD])
  • Functional deficits, including lack of hygiene and grooming, and inability to perform household tasks and maintain weight
  • Seizures
  • Heart disease
  • Misalignment of the eyes (strabismus)
  • Recurrent inflammation in the middle ear (otitis media)
  • Gastrointestinal dysfunction

The lifespan of FXS patients is generally unaffected by the disease. However, patients live with significant morbidities such as intellectual disability, functional deficits, social dysfunction, neuropsychological problems, and physical disabilities (Bailey et al., 2009). These morbidities significantly decrease FXS patients’ quality of life since they limit patients’ independence and ability to function without assistance. FXS patients with significant intellectual disability have difficulty learning new tasks, feeding themselves, keeping an organized and/or clean environment, bathing, and dressing. They also have challenges maintaining a satisfactory social life due to their behavioral and social abnormalities. Furthermore, FXS patients display motor dysfunction, restricting daily movement. As a result of the intellectual, social, behavioral, and motor challenges, FXS patients typically require a full-time caregiver and are dependent on others for survival (Ciaccio et al., 2017; Lachiewicz et al., 2000; McConkie-Rosell et al., 2005). Despite the serious nature of FXS, there are no approved curative therapies to date. Treatment of FXS patients focus on symptom management and includes non-pharmacological therapies such as speech and language, behavioral, and physical therapy, as well as pharmacological therapies. The most common drugs used for these patients are stimulants to improve attention deficit and hyperactivity, serotonin reuptake inhibitors to relieve anxiety, and antipsychotics to reduce irritability and aggression (Ciaccio et al., 2017).

FXS has a profound impact in patients’ life and the serious nature of the disease and the lack of effective treatments highlight the unmet medical need for this patient population. Thus, the development of novel pharmacological agents that can improve the quality of life of FXS patients is essential.


Bailey, D. B., Jr., Raspa, M., Bishop, E., & Holiday, D. (2009). No change in the age of diagnosis for fragile x syndrome: findings from a national parent survey. Pediatrics, 124(2), 527-533. doi:10.1542/peds.2008-2992

Ciaccio, C., Fontana, L., Milani, D., Tabano, S., Miozzo, M., & Esposito, S. (2017). Fragile X syndrome: a review of clinical and molecular diagnoses. Italian Journal of Pediatrics, 43(1), 39. doi:10.1186/s13052-017-0355-y

Coffee, B., Keith, K., Albizua, I., Malone, T., Mowrey, J., Sherman, S. L., & Warren, S. T. (2009). Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet, 85(4), 503-514. doi:10.1016/j.ajhg.2009.09.007

Crawford, D. C., Meadows, K. L., Newman, J. L., Taft, L. F., Pettay, D. L., Gold, L. B., Hersey, S. J., Hinkle, E. F., Stanfield, M. L., Holmgreen, P., Yeargin-Allsopp, M., Boyle, C., & Sherman, S. L. (1999). Prevalence and phenotype consequence of FRAXA and FRAXE alleles in a large, ethnically diverse, special education-needs population. Am J Hum Genet, 64(2), 495-507. doi:10.1086/302260

D’Incal, C., Broos, J., Torfs, T., Kooy, R. F., & Vanden Berghe, W. (2022). Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network. Cells, 11(8). doi:10.3390/cells11081325

Garber, K. B., Visootsak, J., & Warren, S. T. (2008). Fragile X syndrome. European Journal of Human Genetics, 16(6), 666-672. doi:10.1038/ejhg.2008.61

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Lachiewicz, A. M., Dawson, D. V., & Spiridigliozzi, G. A. (2000). Physical characteristics of young boys with fragile X syndrome: reasons for difficulties in making a diagnosis in young males. Am J Med Genet, 92(4), 229-236. doi:10.1002/(sici)1096-8628(20000605)92:4<229::aid-ajmg1>3.0.co;2-k

McConkie-Rosell, A., Finucane, B., Cronister, A., Abrams, L., Bennett, R. L., & Pettersen, B. J. (2005). Genetic counseling for fragile x syndrome: updated recommendations of the national society of genetic counselors. J Genet Couns, 14(4), 249-270. doi:10.1007/s10897-005-4802-x

Merenstein, S. A., Sobesky, W. E., Taylor, A. K., Riddle, J. E., Tran, H. X., & Hagerman, R. J. (1996). Molecular-clinical correlations in males with an expanded FMR1 mutation. Am J Med Genet, 64(2), 388-394. doi:10.1002/(sici)1096-8628(19960809)64:2<388::Aid-ajmg31>3.0.Co;2-9

Saldarriaga, W., Tassone, F., González-Teshima, L. Y., Forero-Forero, J. V., Ayala-Zapata, S., & Hagerman, R. (2014). Fragile X syndrome. Colomb Med (Cali), 45(4), 190-198.

Verdura, E., Pérez-Cano, L., Sabido-Vera, R., Guney, E., Hyvelin, J.-M., Durham, L., & Gomez-Mancilla, B. (2021). Heterogeneity in Fragile X Syndrome Highlights the Need for Precision Medicine-Based Treatments. Frontiers in Psychiatry, 12. doi:10.3389/fpsyt.2021.722378

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