Fragile X Syndrome: What you need to know about this rare genetic condition

Flo Read, Research Assistant in the School of Biomedical Sciences, speaks to Dr Marine Krzisch about Fragile X syndrome, and how research at Leeds is supporting families with the condition.

What is Fragile X syndrome?

Fragile X Syndrome (FXS) is the most common cause of inherited learning disability, affecting 1 in 4,000 males and 1 in 6,000 females.

The condition is also frequently co-diagnosed with autism spectrum disorder (ASD) or attention deficit hyperactivity disorder (ADHD).

Fragile X can present itself in different ways, including learning disability, anxiety, difficulties with social communication and interactions, a short attention span, overactivity, and sensory difficulties.

However, individuals with FXS can also have a strong memory, a good sense of humour, and be engaged with family life.

How is it diagnosed and treated?

Diagnosis of FXS usually involves a blood test, which assesses the number of repeated genetic sequences within the FMR1 gene. If this number exceeds 200, they receive an FXS diagnosis.

However, diagnosis can be a challenge. Many doctors have never come across the disorder, despite it being the most common single gene cause of ASD. Females with FXS can also mask symptoms, making diagnosis even more difficult.

There is currently no cure for Fragile X Syndrome, and treatments focus on improving symptoms. Medicines can be used to reduce anxiety, ADHD, aggression and other mood-related symptoms.

However non-pharmacological approaches, including speech and language therapy, specialist occupational therapy, special educational support and other community social and health services can also have a part to play . However these are interventions that families can find hard to access when needed.

What causes Fragile X syndrome?

An important driver of Fragile X syndrome is mutation of a gene called FMR1. This mutation causes the gene to be silenced and stops a protein in the body called Fmrp being produced. Fmrp is crucial for neuronal development.

The FMR1 gene is located on the X chromosome. Males, who only have one X chromosome, are very likely to have presenting effects as a result (susceptible to FXS). Females, who have two X chromosomes, are more protected against the condition, often presenting with less severe symptoms, as they typically only have the FMR1 mutation on one X chromosome.

Some individuals can be carriers of FXS, meaning they carry a smaller number of repeated sequences in the FMR1 gene. This premutation can be passed down generations. Around 1 in 250 females and 1 in 800 males can be carriers.

Being an FXS carrier can also lead to Fragile X Premutation Associated Conditions (FXPAC). For example, Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS), causes shaking and balance problems later in life, and Fragile X-Associated Primary Ovarian Insufficiency (FXPOI) can cause early menopause in women.

Can you tell me more about your research into Fragile X syndrome?

With so little research and knowledge about how processes in the brain lead to Fragile X syndrome, more research is critically needed.  

Gene therapies and protein replacements may be a promising avenue to restore Fragile X gene function, but without fundamental understanding of how the brain controls and coordinates functions in the body, chances of medical advancements are low.  

That’s why my laboratory is currently undertaking research into FXS, with both the aim of increasing our understanding of the disease and ultimately to find a cure.

Our research into FXS primarily focuses on using stem cells derived from FXS patients to model the disorder.

This approach can differentiate these stem cells into brain cells in order to see how these cells behave in comparison to healthy control cells.

This builds on previous work during my post-doctoral training which observed neurons derived from Fragile X patients stem cells and how they developed compared to neurons where the FMR1 mutation was corrected.

We found abnormalities in the development process of these neurons, and they were hyperactive. We are now particularly interested in microglia, which are the immune cells of the brain and play a role in the development of neurons.

Human Fragile X neurons (red) and control neurons (green) transplanted into a mouse brain. In magenta is an immature neuron marker (doublecortin).

Are you working with any other researchers?

We are keen on collaborating with researchers and organisations interested in FXS. 

For example, last month, Pete Richardson, Managing Director of the Fragile X Society and Leeds alumn, gave a seminar about Fragile X Syndrome at the University of Leeds.

The Fragile X Society provides information and support to families affected by Fragile X Syndrome, including the opportunity to join their online community.

Pete, who has a daughter with a rare genetic learning disability, is passionate about supporting families and addressing common misconceptions surrounding the disorder.

If you’re a researcher exploring Fragile X syndrome, or microglia, please reach out Dr Krzisch by emailing M.Krzisch@leeds.ac.uk. You can also request to join the Fragile X Society Facebook group which brings together researchers and families affected by the condition. Alternatively you are welcome to contact Pete Richardson the Managing Director of the Fragile X Society via email pete@fragilex.org.uk.

If you’re affected by Fragile X syndrome, you can also find help and support on the Fragile X Society website.