Raise the Bar on FXTAS: Recognize It

Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset progressive neurological disorder, is found in carriers of a fragile X mental retardation 1 (FMR1) premutation (55 to 200 CGG repeats). Studies are showing that the disorder affects up to 1 in 3000 adult men older than 50 years and is less common in women.

Although FXTAS was first recognized and reported in 2001 by Randi J. Hagerman, MD, professor and director of the M.I.N.D. Institute at the University of California, Davis,¹ she said many physicians are still unaware of the condition. That's why she and other researchers from the M.I.N.D. Institute collaborated with the CDC to send informational postcards on FXTAS in February to all practicing neurologists and geriatric psychiatrists in the United States.

"There are some neurologists who read the journals and are right on top of this issue, but some patients have told me horror stories about physicians who have not heard of FXTAS and are unwilling to test their patients for the disorder," she said. "I knew of a family where the grandmother was being treated by neurologists at a local HMO in California.

"She began having symptoms of tremor and ataxia, then couldn't walk, and is now bedridden. Her daughter, who has a son with fragile X, asked the neurologist whether the issues could be related, and the neurologists would always answer 'no.'" That's when family members discovered information about FXTAS on the National Fragile X Foundation's Web site (www. fragilex.org/html/fxtas.htm). "They brought papers on FXTAS to the grandmother's neurologist who said 'I've never heard of fragile X syndrome or FXTAS.' This is astounding, because fragile X syndrome is the most common cause of autism or retardation," Hagerman said.

"Unfortunately, physicians in the autism field tend to ignore the fragile X component too. They often do not test families for this disorder. So, in general, there seems to be resistance to testing, even though it is so cheap," Hagerman said. She discovered FXTAS through her research on fragile X, which brought her into contact with many patients with the disorder and their families. By talking to these family members, she discovered that many grandfathers of children with fragile X seemed to have the same neurological symptoms. "We decided to look into this issue because I kept hearing the same story about a lot of the grandfathers," she said. "After seeing 6 of these grandfathers, we realized that they all had the same behavioral phenotype and tremor/ataxia."

But she had no idea how prevalent these symptoms were until she presented her hypothesis to the International Fragile X Foundation meeting in Los Angeles in 2000. "I presented the 6 cases to a roomful of families and asked whether any other people had seen these kinds of issues in the grandparents. About one third of the people in the room raised their hands, and I suddenly realized this could be a very common problem." This prompted Hagerman to report on FXTAS in 2001 with colleagues at the M.I.N.D. Institute.¹ Since that time, the team has collaborated with researchers from other institutions to learn more about FXTAS.

SIGNS AND SYMPTOMS
In many patients with FXTAS, the disorder is misdiagnosed as another neuropsychiatric or movement disorder, such as Parkinson disease (PD), essential tremor, ataxia, Alzheimer disease, normal pressure hydrocephalus, or stroke. According to Hagerman, genetic testing is important in all patients presenting with risk factors of FXTAS because many may not know they are FMR1 premutation carriers.

Hagerman suggests that testing should be performed in persons 50 years or older presenting with any of the following symptoms or combinations of symptoms: unexplained gait ataxia; dementia with action tremor; action tremor, dementia, or parkinsonism; family history of developmental delay or autism; or premature menopause.

MRI will show generalized atrophy, white matter changes, and distinctive T2 hyperintensities in the middle cerebellar peduncles (Figures 1 and 2), according to a study that also showed FXTAS symptom severity corresponds with the degree of MRI changes.¹ However, a small study led by Danuta Z. Loesch, MD, PhD, senior research fellow in the School of Psychological Science at La Trobe Universtity, Melbourne, Australia, showed that only 3 of 9 patients with fxtas studied had close correspondence between clinical features and MRI status.² Loesch and colleagues suggested that MRI changes precede manifestations for some patients with FXTAS.

Normally, there are approximately 5 to 44 CGG repeats on the front end of the FMR1 gene, while minor instability can be associated with 45 to 54 repeats from generation to generation. Carriers of a FMR1 premutation have 55 to 200 CGG repeats, and those with fragile X syndrome have more than 200 CGG repeats. The prevalence of the premutation in the general population is approximately 1 per 259 men and 1 per 810 women. The prevalence of fragile X causing mental retardation is approximately 1 per 4000 men and 1 per 6000 women.³

While most premutation carriers have a normal IQ, premature ovarian failure occurs in approximately 21% of women who are carriers, and FXTAS occurs in approximately 38% of older men who are carriers. Some carriers also have been shown to have lower FMR1 protein levels, in addition to features of fragile X syndrome, and all have elevated FMR1-mRNA. The full mutation of the FMR1 gene is clinically associated with features of fragile X syndrome, including prominent ears, long face, hyperextensible finger joints, and cognitive deficits, such as learning disabilities and mental retardation.⁴

Genetic testing for FXTAS is underused, although it is simple and inexpensive, according to Hagerman. The FMR1 DNA test is available at most clinical and molecular laboratories, and it may be called the "Fragile X" or "FXTAS" gene test. When results of a test are positive for the FMR1 premutation, physicians should talk to the patient about FXTAS and refer the patient and his family to a genetic counselor. Patients and their families may also want to contact the National Fragile X Foundation at 800-688-8765 (www.FragileX.org) for more information and a list of FXTAS experts.

TREATMENT
Although no specific treatments have been established for patients with FXTAS, there is anecdotal information that points toward the effectiveness of certain medications. In a recent study conducted by Deborah A. Hall, MD, assistant professor in the Department of Neurology at the University of Colorado Health Sciences Center at Denver, and colleagues, 56 patients with FXTAS completed a questionnaire to determine whether medications had been effective for neurological symptoms.⁵ All known patients with FXTAS who were seen at the University of Colorado, Rush University, and University of California, Davis, were included in the study.

Of these patients, the mean age was 69.1 years and 73% were men. Eleven patients had definite FXTAS; 70% were being treated for neurological symptoms. Of the remaining 45 patients with possible or probable FXTAS, 70% did not receive medications. There were no therapies that were found to be uniformly effective for intention tremor, ataxia, parkinsonism, memory loss, or anxiety.

The most commonly prescribed medications were for memory or anxiety. Cognitive decline was slowed in 2 of 6 patients taking venlafaxine (Effexor) and in 3 of 9 taking acetylcholinesterase inhibitors.

Of patients with anxiety, 2 of 6 improved with venlafaxine and 5 of 8 with benzodiazepines. Of those patients who were treated for intention tremor, 3 of 6 reported mild to moderate improvement with primidone, 3 of 8 had moderate improvement when treated with ß-blockers, 2 of 8 had moderate improvement with benzodiazepines, and 1of 8 improved with memantine (Namenda). Of those patients with parkinsonism, 2 of 8 improved with carbidopa/levodopa and 1 of 2 with pramipexole (Mirapex). No patients improved with treatment using bromocriptine or gabapentin (Neurontin), although the gabapentin helped with pain.

Hall and colleagues concluded that patients with possible or probable FXTAS are not usually treated for neurological motor signs, while those with definite FXTAS are more likely to receive medications, suggesting that those patients with milder FXTAS may not find their symptoms to be intrusive enough to warrant treatment with medication. They also showed that patients with FXTAS can derive improvement from medication for some of their symptoms. Similar results were reported in a recent study of patients with essential tremor, of whom only 6% were taking medication.⁶

Hagerman said that her studies and clinical experiences have shown that a variety of medications can be used for FXTAS. "Patients with anxiety and depression respond very well to selective serotonin reuptake inhibitors. But there are no controlled trials out; this is all anecdotal information," she said. "These patients have a lot of nerve pain, and some of it is associated with neuropathy. For some of the women, there may be a fibromyalgia-like component. We think that gabapentin helps with this nerve pain problem. The tremor can sometimes do well with other agents, such as primidone. Amantadine may be helpful for balance problems. And the more traditional PD treatments may be helpful, such as carbidopa/levodopa."

Some controlled trials are beginning to explore these treatments, but results from these studies will not be published for a few years, according to Hagerman. Recent reports have shown that some patients with FXTAS may have a testosterone deficiency. "We also think testosterone and thyroid should be routinely tested," Hagerman said.

It is crucial that physicians correctly diagnose FXTAS so the patients can receive the best interventions, Hagerman noted. "But the most important reason to identify those with FXTAS is for genetic counseling," she said. "Once you find someone with the genetic condition, there is a whole family tree that you have to think about. Men with the premutation will be carriers themselves. All of the daughters are carriers, because they inherit the gene from their father. And they are at very high risk of having a child with fragile X-having a 50/50 chance. So this is critically important. And when you do a family tree, there are usually many people affected by the full mutation or the premutation. That varies from psychiatric problems to gynecological problems."

In the past few years, more research has focused on fragile X, and molecular mechanisms of involvement have been identified, including RNA toxicity in premutation carriers. Phenotypes have also been broadened, said Hagerman. "There are a whole slew of proteins that we think cause dysregulation of function for the neurons, which causes the neuron to die more readily and leaves the neuron more vulnerable to oxidated stress," she said. "That understanding has led us to seek more funding looking at neuroprotective agents and agents to decrease this problem." Hagerman's team plans to conduct further research focusing on neuroprotective agents for patients with FXTAS and targeted treatments for children and adults with fragile X syndrome.

References:

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3. Hagerman PJ, Hagerman RJ. Fragile X-associated tremor/ataxia syndrome-an older face of the fragile X gene. Nat Clin Pract Neurol. 2007;3:107-112.
4. Grigsby J, Brega AG, Leehey MA, et al. Impairment of executive cognitive functioning in males with fragile X-associated tremor/ataxia syndrome. Mov Disord. In press.
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