By: Catherine Joachin
What is Fragile X Syndrome?
Fragile X syndrome (FXS) is the leading form of inherited intellectual disability (Mount Sinai, 2021). It is a hereditary disorder caused by alterations in the FMR1 gene, which produces the fragile X intellectual disabilities protein (FMRP), an important contributor to brain development (CDC, 2022). FMR1 mutations do not always lead to the development of an FMRP protein deficit. Protective factors against FXS and FMRP shortage include a smaller mutation size, the presence of cells unaffected by the mutation, and being female (Cleveland Clinic, 2021). The X chromosome carries the recessive gene, meaning that having an affected X chromosome has more of an impact on males than females (Mount Sinai, 2021).
Symptoms
Fragile X syndrome is commonly associated with varying levels of cognitive impairment, behavioral difficulties, anxiety, and autism spectrum disorders. It can affect intelligence, behavior, mental health, and anatomy (Cleveland Clinic, 2021). Symptoms may include:
• Learning disabilities
• Delays in communication (including nonverbal), cognition, social and motor development
• Intellectual disability
• Poor language processing
Anxiety, depression, and hyperactivity (attention-deficit/hyperactivity disorder) are also common in children with Fragile X syndrome (Cleveland Clinic, 2021). In boys especially, behavioral issues can translate into an inability to maintain eye contact, trouble paying attention, hand flapping, hand biting, trouble staying still, and poor impulse control (National Human Genome Research Institute, 2016). Symptoms usually become more apparent with age and can differ in severity with a bias towards males (Cleveland Clinic, 2021).
Physical characteristics of FXS include a long and narrow face, a large forehead, large ears, an elongated jaw, flexible or double-jointed fingers, and flat feet (Mount Sinai, 2021). In addition to these traits, males with FXS can develop enlarged testicles after puberty (Cleveland Clinic, 2021).
A small subset of individuals with fragile X syndrome also present uncommon symptoms. They can exhibit abnormal levels of aggressiveness or irritability, engage in self-harming behaviors, and experience sleep problems, obesity, and even seizures (Cleveland Clinic, 2021).
Fragile X syndrome and Epilepsy
10 to 20% of individuals affected by FXS report experiencing epilepsy, however, seizures are usually outgrown in childhood (Bonanni et al., 2017). According to EEG findings from patients with FXS and epilepsy, the epileptic phenotype shares similarities with benign childhood epilepsy disorder, suggesting that an FMRP deficiency enables the epileptogenic mechanisms that trigger seizures. (Berry-Kavis, 2002; Bonanni et al., 2017). This would indicate that susceptibility to seizures is inherited from the mother’s genetic baggage and highlights possible links between epilepsy and X chromosome genes (Musumeci et al., 1991).
Diagnosis and Treatment
To evaluate if a child has FXS, diagnosis requires blood testing or DNA extraction from amniotic fluid or other tissues.
Fragile X syndrome occurs in approximately 1 out of 4,000 births for males and in 1 out of 8,000 births for females (Stone et al., 2023). The condition cannot be cured; however pharmacotherapy can alleviate mood symptoms and behavior problems (Cleveland Clinic, 2021). There are various medications that target specific symptoms of the disorder. These can range from serotonin reuptake inhibitors (SSRIs) such as sertraline for individuals with aggressiveness and mood fluctuations; methylphenidate (Ritalin) or dextroamphetamine (Dexedrine, Adderall) for those with comorbid hyperactivity; and benzodiazepines for those with anxiety (Cleveland Clinic, 2021; Hagerman, n.d.). In conjunction with pharmaceutical treatment, therapeutic and early intervention services geared towards improving children’s development can be used to cope with speech, language, and behavioral difficulties (CDC, 2022). Individuals experiencing seizures alongside FXS have been reported to respond well to anticonvulsant treatment (Hagerman & Stafstrom, 2009; Stone et al., 2023).
Conclusion
Fragile X syndrome is a monogenetic disorder that affects brain development and can lead to seizures. While only a fraction of people with FXS have epilepsy, existing research calls attention to a potential relationship between fragile X intellectual disabilities protein and neuronal excitability that could shed light on genetic markers for epilepsy.
References
Berry-Kravis, E. (2002). Epilepsy in Fragile X syndrome. Developmental Medicine and Child Neurology, 44(11), 724–728. https://doi.org/10.1017/S0012162201002833
Bonanni, P., Casellato, S., Fabbro, F., & Negrin, S. (2017). Epilepsy in fragile-X-syndrome mimicking Panayiotopoulos syndrome: Description of three patients. American Journal of Medical Genetics. Part A, 173(10), 2753–2757. https://doi.org/10.1002/ajmg.a.38373
Centers for Disease Control and Prevention. (2022). What is Fragile X Syndrome? Centers for Disease Control and Prevention. Retrieved from https://www.cdc.gov/ncbddd/fxs/facts.html
Cleveland Clinic. (2021). Fragile X Syndrome: Diagnosis, Symptoms & Treatment. Cleveland Clinic. Retrieved from https://my.clevelandclinic.org/health/diseases/5476-fragile-x-syndrome
Hagerman, R. (n.d.). Medical Intervention in Fragile X Syndrome. Children’s Hospital of Pittsburgh. Retrieved from https://dam.upmc.com/-/media/chp/departments-and-services/brain/ documents/neurology-documents/fragile-x-center-documents/medications-in-fragile-x.pdf? rev=012b5729d8a645b78e952843e61d3bea&hash=D1C28FAFDD86A8F8EB93DC7F7A5B7E7 F
Hagerman, P. J., & Stafstrom, C. E. (2009). Origins of Epilepsy in Fragile X Syndrome. Epilepsy Currents, 9(4), 108–112. https://doi.org/10.1111/j.1535-7511.2009.01309.x
Mount Sinai. (2021). Fragile X syndrome. Mount Sinai. Retrieved from https:// www.mountsinai.org/health-library/diseases-conditions/fragile-x-syndrome
Musumeci, S. A., Ferri, R., Elia, M., Colognola, R. M., Bergonzi, P., & Tassinari, C. A. (1991). Epilepsy and Fragile X syndrome: A follow-up study. American Journal of Medical Genetics, 38(2-3), 511–513. https://doi.org/10.1002/ajmg.1320380276
National Human Genome Research Institute. (2016). About Fragile X Syndrome. Genome. Retrieved from https://www.genome.gov/Genetic-Disorders/Fragile-X-Syndrome
Stone, W. L., Basit, H., Shah, M., & Los, E. (2023). National Center for Biotechnology Information. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK459243/
