Fragile X Syndrome

What is Fragile X Syndrome and What Causes It?

Fragile X Syndrome is a genetic disorder that can cause changes in a person’s ability to learn and causes alterations in behavior. It is caused by mutations in the FMR1 gene.

Symptoms involved in Fragile X syndrome include:[ref][ref]

autism spectrum disorder
intellectual disability
anxiety
hypersensitivity
ADHD
deficits in language
anxiety and social avoidance
aggression and outbursts
physical symptoms including protruding ears, hyperflexible fingers, flat feet

In addition to these primary symptoms, FXS can also be associated with other health issues, such as seizures, sleep disturbances, and connective tissue problems. The severity of symptoms can vary widely among individuals with FXS.[ref] Chronic pain, neuropathy, allodynia, and migraines are also common, especially in women with Fragile X.[ref]

While Fragile X is a genetic disorder with distinct features, a significant proportion of individuals with FXS (60% of males and 20% of females) also meet the criteria for autism spectrum disorder. There are some nuances as to whether it causes autism or just causes all the symptoms of autism.

Genetic Cause of Fragile X:

Fragile X syndrome is caused by large expansions of a CGG (cytosine, guanine, guanine) sequence in the FMR1 gene.

Normally, individuals have 15-45 repeats of the CGG section, but in people with fragile X, this expands to over 200 repeats of CGGs (full mutation).

This type of repeated section in Fragile X is not able to be determined from genetic data from 23andMe, AncestryDNA, or MyHeritage.

Some people may have a partial expansion with somewhere between 55 – 200 repeats of the CGG section. This actually causes different symptoms, such as ataxia or primary ovarian insufficiency, and may upregulate the FMR1 protein.

To know if you have Fragile X syndrome, you would need a DNA test that looks at the whole region of the Fragile X gene (either a whole genome sequencing or a specific test for Fragile X). Here’s more on what to talk with your doctor about for testing.

X-linked condition:

The FMR1 gene is located on the X chromosome, so males only have one copy of the gene. Females have two copies of the FMR1 gene and are less likely than males to have severe problems from the FMR1 gene changes, due to likely having a functioning copy.

Researchers have looked at whether women with one copy of the fragile X expansion are at a higher risk of being diagnosed with fibromyalgia. One copy of the mutation can lead to tremors and increased pain. One small study of five women with a copy of the Fragile X expansion showed that all of them had widespread pain in various areas of their bodies starting in their 30s or 40s. [ref][ref]

What Does FMRP Normally Do and What Goes Wrong?

FMR1 gene encodes an mRNA-binding protein, which regulates the translation of proteins involved in neuronal synapse maturation and function. In people with the full mutation, the lack of functioning FMR1 disrupts multiple signaling pathways, leading to enhanced neuronal excitability and reduced inhibitory signaling. In a sense – it leads to too much of the ‘on’ switch and not enough ‘off’ switch in regions of the brain.

Excessive Glutamate Signaling and GABAergic System Dysfunction

Glutamate Signaling: Overactivity in glutamate signaling is believed to be a key factor in FXS, affecting synaptic plasticity and neuronal circuit excitability.
GABAergic System: Reduced activity of this system contributes to the excitatory/inhibitory imbalance, impacting both FXS and autism spectrum disorder.

Treatments for Fragile X:

The treatments for Fragile X help with the symptoms, such as medications for ADHD and ways to help children with anxiety. CBD oil has been shown to help children and teens with fragile X. Metformin has also been shown in both animal and clinical trials to be promising for fragile X.[ref]