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Fragile X Syndrome Research Gains Momentum

By: Sai Srihaas Potu

Fragile X syndrome, also called Martin-Bell syndrome, is an inherited genetic disorder that can cause intellectual disabilities and behavioral problems. It is the most common cause of inherited intellectual disability, affecting an estimated 1.4 in 10,000 males and 0.9 in 10,000 females, according to the Centers for Disease Control and Prevention (CDC).


People who have fragile X syndrome have learning and developmental disabilities, which can vary from mild to severe. Fragile X is a chronic condition that can significantly impair a person’s ability to live independently. Genetic disorders, including fragile X syndrome, occur when a person inherits one or more mutated genes from their parents.


Genes contain segments of DNA that carry instructions for making proteins and molecules. People have 23 pairs of chromosomes, which contain between 20,000 and 25,000 genes in total. The first 22 pairs are called autosomes. Autosomes look relatively similar in most people. The last pair of chromosomes — either X or Y — determines a person’s gender. Males have one X and one Y chromosome, while females have two X chromosomes.


Fragile X syndrome occurs as a result of mutations in the FMR1 gene on the X chromosome. The FMR1 gene provides instructions for making the FMRP protein. FMRP plays a vital role in the development of synapses, which serve as communication junctions between nerve cells. FMRP also carries messenger RNA (mRNA) molecules that hold information for the production of proteins.


The specific mutation occurs in a portion of DNA on the FMR1 gene called the CGG triplet repeat region. Usually, the CGG DNA segment repeats between 5 and 40 times. However, people with fragile X syndrome have CGG segments that repeat more than 200 times. People who have expanded CGG segments do not always develop fragile X syndrome. Experts consider CGG repeats between 45 and 54 to be intermediate expansions. Individuals who have 55 to 200 repeats have a premutation, which can expand further into a full FMR1 mutation in future generations. An abnormally long, or expanded, CGG segment inactivates the FMR1 gene, which leads to the absence of the FMRP protein.


Recently, new studies have been conducted in order to find a different avenue that can help lead to a cure for fragile X. Researchers at the Hebrew University of Jerusalem have acquired, for the first time, the generation of neuronal cells from stem cells of fragile X patients. The discovery paves the way for research that will examine the restoration of normal gene expression in fragile X patients.


A potential way to help patients is to find compounds that will clear the abnormal methyl groups from the regulatory elements and reactivate normal gene expression. In their work, the Hebrew University researchers have identified a chemical compound that restored normal gene expression specifically in neuronal cells, the cell type most affected in patients with fragile X. They demonstrated, for the first time, the generation of brain neuronal cells from patients of fragile X syndrome in a dish culture. In doing so, they were able to find a substance that restored normal gene expression in patients’ cells.


In a previous study conducted in the Benvenisty laboratory, novel technology was used to induce pluripotent stem cells from skin cells of fragile X patients. Pluripotent stem cells have the amazing ability to differentiate into any human cell type in a dish culture.


In their latest study, the researchers harnessed this ability to turn the stem cells into neuronal brain cells. After generating the cells, they screened several chemical substances to find one that would restore FMR1 normal gene expression. They showed that the substance 5-azaC was able to clear the methyl groups from the regulatory elements of the gene, allowing for the efficient restoration of FMR1 expression in both stem and neuronal brain cells.


The substance 5-azaC has been known for many years to clear methyl groups from regulatory elements of genes and is an already established drug for other diseases. However, this is the first time that it has been shown to successfully clear the methylation in neurons or stem cells of fragile X patients. In addition, the researchers were able to show that gene expression is maintained even after 5-azaC withdrawal, so there is no need to administer it continuously. This raises hopes for the use of the compound as a potential drug for the benefit of fragile X patients.


The results of this study show that it is possible to restore gene expression in neuronal cells which paves the way for further study of its restoration in patients. However, there is still a substantial gap between the restoration of gene expression in cultured patients’ cells and restoring it in live patients.


Currently, there is no cure for fragile X syndrome, but treatment services can help teach people valuable language, learning, and social skills. Early intervention services help infants and young children with developmental delays build the following skills:

  • physical movements, such as crawling and walking

  • cognitive abilities and problem-solving

  • communication skills, such as listening and speaking

  • social skills, including playing with others

  • essential daily functions, such as getting dressed and eating

People who have a child with developmental disabilities can contact their pediatrician for more information about early interventions. Parents and caregivers can always speak with a pediatrician if they have concerns about their child’s development. A doctor may prescribe medication or recommend cognitive behavioral therapy to treat behavioral or mood disorders, such as attention deficit hyperactivity disorder (ADHD) or anxiety.


Fragile X syndrome is a genetic condition that can cause mild-to-severe intellectual and developmental disabilities that may inhibit a person’s ability to live independently. The study done by the Hebrew University researchers can pave the way for further analysis of the 5-azaC substance. As the days go by, researchers continue to conduct new studies in order to provide the public with more reliable treatment options and a plausible cure to get rid of fragile X once and for all.


References:

1. Bagni C, Tassone F, Neri G, Hagerman R. Fragile X syndrome: Causes, diagnosis, mechanisms, and therapeutics. Journal of Clinical Investigation. 2012.

2. Ori Bar-Nur, Inbal Caspi, Nissim Benvenisty. Molecular analysis of FMR1 reactivation in fragile-X induced pluripotent stem cells and their neuronal derivatives. Journal of Molecular Cell Biology. 2012.

3. Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell. 1991.

4. Pietrobono R, Tabolacci E, Zalfa F, Zito I, Terracciano A, Moscato U. Molecular dissection of the events leading to inactivation of the FMR1 gene. Human Molecular Genetics. 2005.

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