Read Full Text: Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back (Free to access)
Journal: Neurotherapeutics
Year Published: 2015
Ranked 26th on our 2015-2020 list of the 100 most influential OT-related articles
This week’s article allows you to “zoom out” and look at a genetic disorder, Fragile X syndrome (FXS), from a broad perspective.
I left the article feeling awed by all we’ve been able to learn about the disorder on a molecular, cellular, and systems level. And, I’m hopeful that we will see many more advances in the future.
At the same time, despite the optimistic outlook for the many treatments that might lie ahead, the article serves as a poignant reminder that occupational therapy—specifically, your individual clinical reasoning—is one of the best known treatment at this time.
Author’s note: We will be covering Fragile X Syndrome two weeks in a row, so watch for another article on this diagnosis next week!
What was the intent of this article?
If you love basic science, this article is for you!
The authors provided an overview of what we have learned about the fragile x protein—including the research that is currently being performed on mice.
From a basic science perspective, incredible progress is being made toward understanding the disease. However, there are currently no disease-altering treatments available.
So, for us as occupational therapy practitioners, the most helpful portion of this article comes from the descriptions of the manifestation of Fragile X, as well as the general recommendations given for therapy.
What is Fragile X syndrome (FXS)?
Fragile X syndrome is an inherited intellectual disability. Many people with Fragile X syndrome also meet the criteria for autism—in fact, FXS is the most common inherited cause of autism and intellectual disability.
Mutations of the gene associated with Fragile X syndrome tend to increase in size as the gene is passed down through generations, leading to the syndrome manifesting in more individuals in the family.
What causes Fragile X syndrome?
Fragile X syndrome is caused by a single gene mutating, and therefore becoming defective at making a protein called FMRP. (Reminder: the human genome has about 20,000-25,000 genes, so it is pretty remarkable that we are learning so much about this one specific gene!)
This gene is found on the X chromosome. Depending on the extent of the mutation, there can be either a partial or total loss of the FMRP protein. (This becomes important to remember when we discuss different presentations of FXS below.)
Why chromosomal sex matters when working with someone with FXS…
Those born female carry the XX chromosomal pattern (vs. the XY pattern found in those born male). This is why girls tend to be more mildly affected by FXS than boys; the second X chromosome is typically able to produce the FMRP protein and partially compensate for the mutated gene.
What does the FMRP protein do? (Hint: It impacts more than cognition.)
The FMRP protein is present in many tissues throughout the body—and we are still learning about its function.
In the brain, it is believed to help with synaptic plasticity, which in turn helps with learning and memory.
The protein is also found in the ovaries and testes, though we are still learning about its function there.
Physical manifestations of FXS for OTs to be aware of:
FXS is thought to be an underdiagnosed condition, so I think it is extremely important for occupational therapy practitioners to be aware of the physical patterns associated with it. We must be poised to speak with our interdisciplinary team if this diagnosis has not been ruled out for a patient on our caseload.
Individuals with FXS can present with:
- Macroorchidism (enlarged testes)
- Prominent ears
- Macrocephaly
- Prominent jaw and forehead
- Midfacial hypoplasia
- Loose connective tissues, leading to:
- Hyperextensible joints
- Flat feet
Co-occurring medical conditions:
Individuals with FXS have a normal life expectancy, and the condition itself does not worsen overtime. However individuals with FXS are at a higher than normal risk for:
- Seizures
- Strabismus
- Frequent middle ear infections
- Sleep apnea and other sleep disorders
As OTs, we can help our team watch for the co-occuring conditions and get the interdisciplinary team involved as needed.
Cognitive, behavioral, and language considerations for OTs to keep in mind:
Cognition
The majority of males will meet criteria for mild-severe intellectual disability. Only about 25% of females with FXS meet criteria for cognitive impairment.
There is a pattern of both females and males with FXS of struggling with:
- Visuospatial skills
- Working memory
- Processing of sequential information
- Attention
People with FXS have a pattern of cognitive strengths, as well! I’ll save those for the strengths section below 
Behavior
Common behavioral difficulties include:
- Attention (As many as 73% of males with FXS also have an ADHD diagnosis)
- Anxiety (As many as 86% of males with FXS are also diagnosed with an anxiety disorder)
- Aggression/self-injurious behaviors
- Hyperarousal (a strong reaction to sensory input)
Language
Language development is often globally delayed for those with FXS. Expressive language and pragmatic language (communication in social interactions) can be particularly difficult.
STRENGTHS of individuals with FXS:
In some ways, this article felt extremely dated because the language was so deficits-focused. But, a few strengths were highlighted!
For example, those with FXS tend to demonstrate long-term memory and simultaneous processing strengths.
And, as occupational therapy practitioners, it is extremely important to know that receptive language skills are typically stronger than expressive skills in this population—specifically keeping in mind that receptive vocabulary in particular is a major strength.
A note on the highly variant phenotype of FXS.
Remember phenotypes? These are observable characteristics in patients that we see as a result of how various genotypes interact with the environment.
And, because there is variance in what the gene mutation associated with FXS looks like (and probably a million other reasons we have yet to understand) there are highly variant phenotypes/presentations of FXS. So, even though we just talked extensively about common patterns, it is important to treat each individual as an individual.
Assessments that were mentioned:
The one commonly used assessment that was mentioned was the Vineland. Scores on this assessment tend to decline throughout childhood, not because the patients’ skills are declining, but because individuals develop at a slower pace than typically developing peers. Scores tend to stabilize in adulthood.
See the Vineland Adaptive Behavior Scale in our OT Assessment Search.
Treatment recommendations
The highly variant presentation of FXS has made treatment difficult to study, and even though there are many treatment avenues being explored, the recommended treatment at this time is your occupational therapy care (in conjunction with PT and SLP).
Here’s what the article says:
“OT, PT, and SLP should all be accessed at the maximum level allowed so as to maximize early growth.”
The article notes that techniques that have been validated for autism are often helpful for FXS, but must be modified based on what is known about the FXS phenotype.
The article also points out that individuals have been shown to display better behavioral and adaptive functioning when their environment and supportive programming matches their needs. Therefore, the authors recommend a highly individualized behavioral, therapeutic, and educational intervention plan for home, school, and work environments.
Takeaways for OT practitioners
1.) Across diagnoses, we seem to be on a pathway to precision medicine.
It seems whenever we look at research on a given diagnosis, there is a theme of trying to categorize different phenotypes of the diagnosis and find biomarkers for better tracking if treatments are working.
All of this is pointing to a what is becoming an increasingly likely future, where OTs are not only providing specific treatments for FXS, but adjusting them based on categories of phenotypes along with information gleaned from specific biomarkers.
We’re not there yet, but if you glance through the article (and other research on FXS), you’ll see that lots of effort is going into moving us toward more precise care.
2.) But, in the meantime part of the role we can play as OTs is just helping individuals get on the pathway to the right diagnosis.
While all of the research around FXS makes us hopeful for advances in care, one of the basic struggles we encounter is ensuring that an accurate diagnosis is made.
Especially due to the wide variance (especially among girls) in presentation, screening for FXS may not be in the forefront of physicians’ minds—especially when you consider that FXS occurs on a global scale.
Because OTs work with so many children with developmental delays, I think it is extremely important to be familiar with the typical presentation of FXS. That way, we can talk to the team if someone on our caseload has not been screened for FXS, yet presents with these patterns.
3.) For treatment: your clinical reasoning is what is needed.
This is yet another article where I left truly feeling the weight of why occupational therapy is so important. For individuals with FXS, there is no silver bullet; there aren’t even set answers when it comes to supportive therapy! So, providing these individuals the best care possible really comes down to you as a therapist working with your team, the family, and the individual. When you use your clinical reasoning skills to devise a treatment plan that incorporates a collaborative approach, these individuals truly can live life to its fullest.
(Possibly) Earn CEUs/PDUs for reading this article.
Many of you can receive continuing education credits for reading this article. Here’s a form to help you do it, along with information to help you understand who qualifies.
And, here’s the full APA citation you many need:
Gross, C., Hoffmann, A., Bassell, G. J., & Berry-Kravis, E. M. (2015). Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back. Neurotherapeutics, 12(3), 584-608. doi:10.1007/s13311-015-0355-9
