Fragile X Syndrome

About Fragile X Syndrome

Fragile X Syndrome (FXS) is a rare, serious, life-long genetic disorder caused by alterations in the Fragile X gene (FMR1). It is the leading single gene cause of intellectual disability. FXS affects about one in 2,500–4,000 males and about one in 7,000–8,000 females. Most boys and approximately 30 per cent of girls with FXS will have significant intellectual disability across their lifespan. As females have two X chromosomes, they tend to have milder symptoms compared to males.

A serious genetic condition

FXS is characterised by a range of developmental problems, including learning disabilities, behavioural issues including autism features, cognitive impairment, speech and language deficits, sleep problems, anxiety, and severe difficulties with regulating stress and emotions1. These core symptoms have a substantial impact on day-to-day functioning of patients and their carers.

Following diagnosis, which typically occurs around three to five years of age, a patient may require treatment to help alleviate the behavioural challenges they experience. Currently, medications prescribed experimentally (not formally approved by regulators) and behavioural interventions developed for other conditions are used to help improve some of the symptoms, with no FXS specific treatments available.

FXS is caused by a mutation to the FMR1 gene located on the X chromosome. This gene controls the production of the FMR protein (FRMP), which is required for the normal development of neural connections. A mutation of the FMR1 gene prevents normal development of neural networks in the brain, disrupts nervous system functions, and leads to the symptoms of FXS2.

 

The protein produced by the FMR1 gene, known as FMRP, is essential for normal brain development

Figure 1 FMRP acts as a protein production regulator, ensuring that the protein building blocks necessary for normal neural connections are produced in the right quantity. In people with FXS, there is no FMRP to regulate protein production. This results in unregulated, over production of protein building blocks and prevents normal development of neural networks in the brain. The malformed neural connections disrupt nervous system function and leads to the symptoms of FXS.
  1. Intellectual functioning and behavioural features associated with mosaicism in Fragile X Syndrome. Baker EK, Arpone M, Vera SA, Bretherton L, Ure A, Kraan CM, Bui M, Ling L, Francis D, Hunter MF, Elliott J, Rogers C, Field MJ, Cohen J, Maria LS, Faundes V, Curotto B, Morales P, Trigo C, Salas I, Alliende AM, Amor DJ, Godler DE. J Neurodev Disord. 2019 Dec 26;11(1):41. Doi: 10.1186/s11689-019-9288-7.
  2. Epigenetics of fragile X syndrome and fragile X-related disorders. Kraan CM, Godler DE, Amor DJ. Dev Med Child Neurol. 2019 Feb;61(2):121-127. Doi: 10.1111/dmcn.13985. Epub 2018 Aug 7. Review. PMID: 30084485

FXS is caused by a mutation to the FMR1 gene located on the X chromosome

Figure 2 At the start of this gene lies a DNA sequence, called the CGG triplet repeat (in yellow), that varies in length from one person to another. When this sequence of DNA falls within a range of length that would be considered ‘normal’ (<45 CGG repeats), there are normal levels mRNA and protein (FMRP) produced and neural development is normal. In some people, this sequence expands longer (55-199 CGG repeats) in what is known as a ‘premutation’. This causes more mRNA to be produced than normal which may result in RNA toxicity, and reduced levels of FMRP. When this sequence od DNA expands beyond a certain length (200 CGG repeats), the FMR1 gene is switched and no FMR1 mRNA or FMRP is produced. This is known as a ‘full mutation’ and results in FXS.

Fragile X Syndrome is a rare disease
- it is a serious life-long genetic disorder for patients living with the condition

Fragile X occurs in approximately one in 2,500–4,000 males and about one in 7,000–8,000 females

There are approximately 74,000 Fragile X patients in the United States. About 16,000 are under the age of 18 years

No treatment or cure for Fragile X Syndrome

There are currently no approved drugs to treat FXS.

The current standard of care for FXS includes speech and language therapy, special educational support, occupational therapy, and behavioural therapy. Care may also include the use of off-label pharmaceuticals such as stimulants, anti-depressants, anti-psychotics and anti-convulsants. Selective serotonin reuptake inhibitors (SSRIs) are effective approximately 50 per cent of the time in managing anxiety in FXS patients. However, FXS patients tend to be more sensitive to these drugs and side effects are common even at low doses. This reflects a substantial unmet medical need.

Currently, treatment options that focus specifically on the behavioural aspects of FXS are limited. Drugs registered for other indications and not approved for use in FXS are commonly used. However, these only minimise symptoms of the disorder.

High cortisol levels associated with Fragile X Syndrome

In children with FXS, raised cortisol levels are significantly associated with cognitive impairment and behaviour problems including social anxiety, hyperactivity, and social withdrawal3, 4. High levels of stress hormone may also impair neural circuits important for the regulation of these behaviours.

Figure 3 In a normally developed brain there is a balance between excitatory and inhibitory signals that ensures nerve cells respond appropriately to incoming signals. This balance is crucial for the brain's response to stress. In FXS, the lack of FMRP leads to the loss of inhibitory (GABA) signals and this causes the brain to misinterpret normal neural signals as stressful. The chronically overactive stress response leads to dysfunction of the HPA-axis, elevated cortisol, and this is thought to contribute to the debilitating symptoms of FXS including anxiety, behavioural issues, and cognitive impairment.
  1. Cortisol and social stressors in children with Fragile X: a pilot study. Wisbeck JM1, Huffman LC, Freund L, Gunnar MR, Davis EP, Reiss AL. J Dev Behav Pediatr. 2000 Aug;21(4):278-82.
  2. The neuroanatomy and neuroendocrinology of Fragile X Syndrome. Hessl D1, Rivera SM, Reiss AL. Ment Retard Dev Disabil Res Rev. 2004;10(1):17-24.

Xanamem as a potential treatment for Fragile X

Xanamem is an investigational oral medicine specifically designed to target and inhibit the production of excess cortisol in brain cells. Xanamem is being investigated as a potential new therapy to decrease elevated cortisol and alleviate associated symptoms in people with Fragile X Syndrome such as anxiety and improve cognitive performance.

Publications

Intellectual functioning and behavioural features associated with mosaicism in Fragile X Syndrome

Baker, E. K., Arpone, M., Vera, S. A., Bretherton, L., Ure, A., Kraan, C. M., Bui, M., Ling, L., Francis, D., Hunter, M. F., Elliott, J., Rogers, C., Field, M. J., Cohen, J., Santa Maria, L., Faundes, V., Curotto, B., Morales, P., Trigo, C., Salas, I., Alliende, A. M., Amor, D. J. & Godler, D. E. 2019. Journal of Neurodevelopmental Disorders, 11, 15.

 

Biobehavioral composite of social aspects of anxiety in young adults with Fragile X Syndrome contrasted to autism spectrum disorder

Roberts, J. E., Ezell, J. E., Fairchild, A. J., Klusek, J., Thurman, A. J., Mcduffie, A. & Abbeduto, L. 2018. American Journal of Medical Genetics Part B-Neuropsychiatric Genetics, 177, 665-675.

 

Cortisol profiles differentiated in adolescents and young adult males with Fragile X Syndrome versus autism spectrum disorder

Matherly, S. M., Klusek, J., Thurman, A. J., Mcduffie, A., Abbeduto, L. & Roberts, J. E. 2018. Developmental Psychobiology, 60, 78-89.

 

Fragile X Syndrome

Hagerman, R. J., Berry-Kravis, E., Hazlett, H. C., Bailey, D. B., Moine, H., Kooy, R. F., Tassone, F., Gantois, I., Sonenberg, N., Mandel, J. L. & Hagerman, P. J. 2017. Nature Reviews Disease Primers, 3, 19.

 

HPA axis function predicts development of working memory in boys with FXS

Scherr, J. F., Hahn, L. J., Hooper, S. R., Hatton, D. & Roberts, J. E. 2016. Brain and Cognition, 102, 80-90.

 

Cortisol and behavior in Fragile X Syndrome

Hessl, D., Glaser, B., Dyer-Friedman, J., Blasey, C., Hastie, T., Gunnar, M. & Reiss, A. L. 2002. Psychoneuroendocrinology, 27, 855-872.

 

Cortisol and social stressors in children with Fragile X: A pilot study

Wisbeck, J. M., Huffman, L. C., Freund, L., Gunnar, M. R., Davis, E. P. & Reiss, A. L. 2000. Journal of Developmental and Behavioral Pediatrics, 21, 278-282.

 


Back
to top