Maude Brownlie, pictured with her husband, Sandy, traveled from Scotland to the UC Davis MIND Institute to receive treatment for FXTAS, a neurodegenerative condition.
Posted March 16, 2011
Maude Brownlie, who lives in Melrose, Scotland, wasn’t aware of her head tremors until her young granddaughter pointed it out. Over the next few years, the tremors worsened and spread, causing balance problems that resulted in several falls and phantom pains. She also began losing her words. A dynamic woman who adored being a grandmother, she became irritated, fatigued and depressed by her physical and cognitive decline.
Disheartened by the lack of information from her own physicians, Brownlie sought answers. Her daughter, whose sons had been diagnosed with fragile X syndrome, suggested she meet with the team at the MIND Institute at UC Davis Health System.
Randi Hagerman, medical director of the MIND Institute, discovered that Brownlie was a carrier of the premutation of fragile X. She diagnosed Brownlie with fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative condition that was causing her symptoms.
“I was very much against going and felt that it would be a complete waste of their time and our money,” she says. “How wrong I was!”
Fragile X is a family of genetic conditions that includes FXTAS, which Hagerman and her fellow researcher and husband, Paul, a molecular biology physician-scientist and director of the Neuro- Therapeutics Research Institute, discovered in 2001. It also includes fragile X syndrome (FXS), the most common cause of inherited intellectual disability and the most common known single-gene cause of autism, and fragile X-associated primary ovarian insufficiency (FXPOI), a problem with ovarian function that can lead to infertility and early menopause.
“My experience with the MIND Institute and UC Davis has had a hugely beneficial outcome. I am really enjoying ... my ‘new self.’”
— Maude Brownlie
Brownlie and her family had consulted with the right team. Researchers at the MIND Institute are at the epicenter of robust basic and translational science research into psychopharmacological treatments for FXS and FXTAS.
“This is a most exciting time for us,” says Randi Hagerman, also the co-founder of the world-renowned National Fragile X Foundation. “Our goal is to reverse the neurobiological, structural and hopefully cognitive and behavioral abnormalities of fragile X.”
One in 129 women is estimated to carry the fragile X premutation. Like Brownlie, women typically show no neurodevelopmental deficits in youth. One in 3,600 individuals has the full mutation, which results in fragile X syndrome. Approximately one-third of all children diagnosed with FXS have autism and another third have some features of autism spectrum disorder (ASD).
Randi Hagerman, medical director of the MIND Institute, with fellow researcher and husband, Paul Hagerman.
The treatments in trial for FXS are designed to address the core of the genetic problem: the absence or deficiency of a single protein, the fragile X mental retardation protein (FMRP).
FMRP is a “mother protein” that controls the translation of about 800 genetic messages, many of which are important for synaptic plasticity. With fragile X syndrome, this protein is eliminated or deficient, thus interfering with normal brain development and learning.
One affected system, for example, is the metabotropic glutamate receptor 5 system (mGluR5), an excitatory system that leads to the weakening of synaptic connections. In a regularly functioning system, FMRP works something like a gatekeeper to keep mGluR5 activity in check. In the absence of FMRP, the gate is left open, and enhanced activity leads to weak synaptic connections throughout the brain. This leads to anxiety, hyperactivity, impulsivity, a short attention span and social deficits that can include autism.
In a pilot study reported in the Journal of Medical Genetics, researchers at the MIND Institute and Rush University Medical Center, Chicago, found that an mGluR5 antagonist called fenobam helped to lower mGluR5 activity, which calmed behavior and reduced hyperactivity and anxiety in patients with FXS. The New York Times reported in April 2010 that another antagonist was successfully used in a European medical trial. The principal investigators of that study were trainees from the MIND Institute: Sebastien Jacquemont and Vincent Des Portes.
“This is a most exciting time for us. Our goal is to reverse the neurobiological, structural and hopefully cognitive and behavioral abnormalities of fragile X.”
— Randi Hagerman, medical director of the MIND Institute
The remarkable promise of mGluR5 antagonists is spurring further research. The MIND Institute has three additional clinical trials scheduled throughout 2010 and 2011.
Two pharmaceutical treatments that show particular promise for younger patients are arbaclofen and minocycline. A controlled trial of arbaclofen in children and adults with FXS was completed in April 2010, and preliminary positive results were presented at the 2010 International Meeting for Autism Research. A six-month double-blind controlled trial of minocycline, funded by the National Fragile X Foundation, began in February 2010 and studies children ranging in age from 3.5 years to 16 years.
Also under way is a study of memantine, a medication used to treat moderate to severe Alzheimer’s disease. The study is funded by the National Institutes of Health for people with the fragile X premutation who have FXTAS – like Brownlie. FXTAS is of special interest because it reveals a generational gap that the Hagermans uncovered.
"Closing in on targeted treatments for fragile X" first appeared in the 2010 UC Davis Health System annual report. Click to read more and find out how UC Davis is making far-reaching advances in health care to improve the lives of people in our own communities, across the nation and around the globe.
“Current research on FXS and autism has led to dramatic advances in understanding aging and even dementia,” Randi Hagerman explains. “We now know the premutation can cause problems in adult life, including depression, anxiety, mood instability, early cognitive decline, difficulties with ovarian failure and FXTAS. It’s all related.” Brownlie found relief with a treatment regimen of memantine and an antidepressant. When she returned to the MIND Institute for an annual evaluation, her tremors had been greatly reduced and her depression was gone.
“She was a completely changed woman,” Hagerman says.
“My experience with the MIND Institute and UC Davis has had a hugely beneficial outcome,” Brownlie says. “I am really enjoying ... my ‘new self.’ My energy levels, self-esteem and confidence are back to what they were five years ago. My aim now is to persuade the other FX carriers in my family to be assessed by the team at the MIND Institute. Or, just maybe, some interested professionals in the U.K. will come on board and extend the research so that treatment is available here.”
“Our team is on the cusp of finding effective drugs to mitigate fragile X syndrome’s devastating impact,” Hagerman says, “and we are leading the way to restoring quality of life for all generations of families affected by fragile X.”