It's been 22 years since UC Davis MIND Institute Medical Director Randi Hagerman and her husband, researcher Paul Hagerman, discovered the neurodegenerative condition called FXTAS (fragile X-associated tremor ataxia syndrome). Hagerman, a pediatrician known for her enthusiasm for her work and patients, has been studying FXTAS ever since, seeking to develop treatments for it.
She was recently awarded her 24th consecutive year of funding from the National Institutes of Health for her fragile X-related work, a five-year, $3.2 million grant. The study has evolved over the years and is now focused on better understanding the characteristics, or phenotype, of FXTAS.
FXTAS causes tremors, balance problems, dementia and other neurological challenges. It gets worse over time and there are no approved treatments -; only therapies to manage symptoms.
The syndrome is caused by a "premutation" expansion of the FMR1 gene. It's genetically related to fragile X syndrome. Both are caused by different-sized changes in the FMR1 gene. Fragile X syndrome starts in early development, and includes intellectual disability, developmental challenges and often, autism. FXTAS begins in late adulthood. The premutation usually runs in families.
Hagerman is an endowed chair in fragile X research. In this Q&A, she shares details about her research, what she's focused on next and why she's hopeful about future treatments.
What is the goal of the FXTAS study?
We're trying to better understand FXTAS, which leads to tremor and balance problems as individuals age, particularly in their 60s. We're studying the progression of FXTAS, which is often misdiagnosed as Parkinson's and even Alzheimer's, as it can also be associated with cognitive decline.
About 1 in 200 females and 1 in 400 males have the premutation in the general population. We're trying to understand the different phenotypes, or presentations, between males and females. Males tend to develop FXTAS symptoms earlier and about half develop dementia. Females have a milder form, with less white matter disease in the brain according to our MRI studies. But females may also have autoimmune problems and more significant anxiety and depression.
Who is in the study?
We'll have a total of about 160 people after enrolling additional participants from more diverse backgrounds this year. Some participants have been part of the study for 10-15 years. That includes men and women who either have a FXTAS diagnosis or who have early signs of the condition but don't yet have FXTAS, ages 40 to 85. This includes mild tremor, neuropathy, memory challenges and balance problems but also emotional symptoms that may exacerbate these. We're looking at the illnesses or events that can be a sign FXTAS is starting.
When the study began in 1999, we were mainly focused on younger people with the premutation. We began focusing on FXTAS about 15 years ago. We are meeting with them about every two years so we can follow their progression and to see what therapies and treatments may help.
Might it be possible in the future to predict that someone will develop FXTAS?
It's possible. Better understanding the "pre-FXTAS" stage is very important. We are looking for biomarkers that could help with that goal. For instance, are there biomarkers that will tell us whether someone has white matter disease? And does the degree of white matter disease correlate with motor or mental health challenges? The interplay among these domains in the phenotype are important as we strive to help our patients.
What are some of the things you're measuring or testing?
We do a special MRI brain scan protocol that shows the degree of white matter disease in the brain. We measure brain volume in different parts of the brain, too. We also look at the degree of tremor and balance problems that they have and assess their gait. We have them walk while doing mental calculations because sometimes that causes more balance difficulties. We also measure reaction time and grip strength and assess for depression or anxiety. And we give them recommendations about what might help them, including exercise, nutrition or medications that their primary care doctor might consider.
What are the key takeaways from this study over the years?
One thing we've learned is that premutation challenges can be lifelong. Not necessarily FXTAS, which happens with aging, but there can be neurodevelopmental challenges, including autism, that can occur in a subset of premutation carriers. There are also psychiatric conditions like depression, anxiety, obsessive-compulsive behavior and chronic fatigue, which can occur in mid-adulthood. The premutation is also the most common single-gene cause of ovarian insufficiency, which causes infertility or early menopause. This is a condition we call fragile X-associated primary ovarian insufficiency, or FXPOI.
In fact, women are often tested by their gynecologist and then when we investigate the family tree, we find out their father or mother may have FXTAS. That's mainly how we find people with FXTAS -; either the grandparents of a child with fragile X syndrome or the parent of a woman with the premutation who has FXPOI.
Are there better treatments on the horizon for FXTAS?
I feel very positive about potential future treatments. For example, we recently did a study about sulforaphane, a sulfur-containing protein in broccoli, brussels sprouts and cauliflower. It turns on the Nrf2 gene, which controls the pathways to relieve oxidative stress in the neurons. This was helpful for some cognitive problems with FXTAS. We are also focused on exercise, which can help reduce inflammation and oxidative stress. But we need a better primary treatment for FXTAS. That's why we're excited about finding biomarkers in these studies that will lay the groundwork for treatment trials. I believe the next few years could bring about new treatments for FXTAS.
How far has the field of research come since you discovered FXTAS in 2001?
It is now an entity that has worldwide interest and hundreds of papers have been published about it by scientists around the world. But there are still clinicians that I meet who have not heard of FXTAS -; even neurologists.
I see patients from all over the world at the MIND Institute, but there are still providers elsewhere who confuse FXTAS with fragile X syndrome, though they are two very different conditions. We must keep building awareness. My MIND Institute colleagues and I recently hosted a conference on the FMR1 premutation in New Zealand which included researchers from all over the world who are studying this, and I am very hopeful for the future.
What drives you to continue this work?
I truly want to find better treatments for FXTAS and all fragile-X associated conditions. You can help a whole family through multiple generations once you make the diagnosis with one or two members in a family. Also, these conditions occur all over the world. I love to bring new treatments and awareness to other places. We do such great work at the MIND Institute, and I want to share that with people all over the world.
StitchR technology delivers large genes for muscular dystrophy treatment