Since its identification less than a decade ago, researchers have learned a good deal about Fragile X-associated tremor/ataxia syndrome (FXTAS). Not surprisingly, each advance has raised a set of new questions. Progress seems to come very slowly, but the issues are complex, and we have much to learn about FXTAS. Much of the research to date has been intended to determine the nature and progression of the disorder—the commonalities among affected carriers of the premutation, or what is often referred to as the phenotype. But equally important are those factors that differentiate one carrier from another, and that determine who will or will not develop the signs and symptoms associated with FXTAS.
What We Don’t Know
Photo by Akash Kurdekar
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We have a basic understanding of the ways in which cognitive functions—reasoning, memory, attention, and other intellectual abilities—are affected by FXTAS. A few years ago, we knew a lot more about how it affects men than women. FXTAS and Fragile X syndrome (FXS) are X-linked disorders, and inheritance works rather differently for males and females when the gene in which you are interested resides on the X chromsome. Consequently, female carriers of the premutation present what is sometimes a more confusing picture than do male carriers.
When FXTAS was first identified, we didn’t know whether women were even affected by the disorder. Females have two X chromosomes, and males have only one. If a woman carries the premutation, she is most likely to be heterogyzous—that is, one of her Xs has a CGG repeat length between 55 and 200, which is the premutation range, while the other has a more typical size (usually around 29 or 30, but generally between 6 and 40). It was thought that perhaps, as with Fragile X syndrome, women’s second (usually normal) X chromosome might protect them from FXTAS, or at least reduce its effects.
We now know that a substantial number of female carriers of the premutation are likely to develop Fragile X-associated premature ovarian insufficiency (FXPOI) or ovarian failure. They also appear to be more likely to develop inflammatory and autoimmune disorders such as hypothyroidism and firbomyalgia. And importantly, a significant number of women have been diagnosed with FXTAS.
We know that a smaller percentage of females than males is affected by this movement disorder, and it seems that the signs and symptoms may be less severe among females. However, there are important differences that we don’t yet understand in the ways the gene, FMR1, affects men and women. Neither do we know how endocrine and immunologic disorders are related to FXTAS: Are they part of it, or independent medical problems also related to the malfunctioning of FMR1?
We now think that not all male carriers of the premutation will develop FXTAS, and in fact it may be that fewer than half will eventually do so. Among women, the penetrance (the percentage of persons who will develop the genetic disorder) is unknown, but is significantly lower—maybe in the vicinity of 15-20 percent.
Why only a certain percentage of people with the premutation develop FXTAS is an interesting, unanswered question. The length of a person’s CGG repeat appears to play a role in the process, but the importance of this variable is unknown as well. Most individuals with FXTAS have between about 70 and 120 repeats, with a tendency toward greater impairment as the number increases. But what about those persons with CGG repeats in either the lower or upper end of the premutation range?
Not many people with 130 to 200 CGG repeats have been identified in studies of FXTAS, but the reason remains unclear. There may be fewer people with repeats in this range because the gene becomes unstable, and tends to expand to a full mutation. It also appears that the phenotype changes somewhat as the CGG repeat size gets into the less clearly defined zone between the full mutation and the premutation.
There also are indications that interruptions of the CGG expansion at different points, often by a different trinucleotide (AGG, for instance), may affect the expression of the gene. And it continues to be the case that most health care providers don’t know much, if anything, about FXTAS. In part for this reason, many carriers of both sexes simply don’t come to the attention of physicians or researchers. We also don’t yet know when the cognitive problems begin to develop in relation to the motor symptoms of tremor and ataxia, and we don’t know why cognitive deficits may be more severe in some persons than in others.
In all likelihood, other genes interact with the FMR1 gene to determine who will be affected, as well as determining the age of onset, rate of progression, and the nature and severity of signs and symptoms. These genes might be located on other chromosomes, or may even be found in the mitochondrial DNA that we inherit only from our mothers.
It is even possible that the influence of other genes may be associated with normal variants of other genes. At this point, however, we know little about the role, if any, played by other genes.
Likewise, we don’t know whether other developmental processes, or environmental factors, affect the expression of FXTAS. For example, although it hasn’t been rigorously studied, investigators at UC Davis are interested in the possibility that surgery under a general anesthetic may affect the progression of FXTAS.
What We Do Know
Despite the fact that there’s a lot to learn about FXTAS, we know quite a bit more than we did even just five years ago. What have we learned, and what does it mean?
First, we know that FXTAS affects specific aspects of cognitive functioning. In the early stages of the disorder, the problems may be so subtle that they are overlooked by family, friends, and providers. Sometimes the first thing the spouse of a person with FXTAS notices is a slight change in personality—usually nothing striking, often attributed to circumstances, and occasionally appearing to be an exaggeration of pre-existing personality traits. For example, an individual who often needs encouragement in order to get going on household tasks may require even more prodding.
The primary problems in FXTAS appear to involve what cognitive neuroscientists refer to as executive functioning. The basic executive function is the ability to regulate one’s own behavior, to engage in goal-directed, purposeful activity.
Executive functioning involves the ability to hold an intention in mind (e.g., planning a big holiday dinner for the family), to formulate a plan for attaining the goal (what to prepare, buying the groceries), to initiate the activity necessary for completing the task (light the oven, find the knife, make the marinade, slice the vegetables), to inhibit irrelevant or inappropriate behavior that might distract one from the goal (don’t eat all the good stuff while you’re making dessert), to monitor how well one is staying on task and making progress (is the turkey cooking too slowly?), to change one’s plans if necessary (turn up the oven), and to follow through to completion.
Executive functioning is essential when we are faced with novel or complex situations. Infants and young children have very limited executive function abilities, which usually develop over the course of adolescence and into young adulthood. This is why they are not especially good at controlling their own behavior, and need varying degrees of adult supervision. When executive functioning becomes impaired, the neural system for behavioral control begins to unravel. This sort of problem with the executive abilities is relatively common among older persons, but becomes especially prevalent among those with FXTAS.
Impaired executive functioning, sometimes referred to as a dysexecutive syndrome, may lead to problems with concentration, short-term memory, planning ahead, and getting organized. Essentially, what happens is that people can lose the ability to control their behavior. Behavioral problems associated with a dysexecutive syndrome include difficulty getting going (trouble with initiation), and impulsivity. In addition, affected individuals may show an impaired capacity for insight. That is, people with the disorder have difficulty monitoring themselves, and hence become unaware of the inappropriateness of their behavior. This impairment of insight is commonly observed as FXTAS advances.
Problems with memory may become apparent over time, but at least initially these are a result of the executive deficits. The problem seems to be that a person with FXTAS may have increasing difficulty retaining and recalling newly learned information. Also associated with these executive cognitive deficits is impairment of what is called prospective memory, or remembering to remember. Difficulty with prospective memory may lead a person to forget to stop at the store on the way home, to buy an anniversary gift, or to take medications at the right time.
The other kind of memory that tends to be affected in FXTAS is working or short-term memory. This is the ability to recall what has been going on for the past 20-30 seconds, and it includes our recall of the things we intend to do. For example, if you go into the kitchen to get something, but when you get out there you can’t recall what it was you were looking for, your working memory has failed you. If you read a paragraph, but by the time you reach the end you can’t recall the beginning, it’s a problem with working memory.
What often is referred to as “multi-tasking” requires a good working memory. For people with FXTAS, both reading comprehension (especially of complex material) and doing more than one thing at a time (like using the cell phone while driving) become increasingly difficult because there’s just too much information to keep in mind, and to keep one’s thought organized.
Language, basic reasoning skills, and abilities such as arithmetic and spelling are likely to remain intact in FXTAS, at least until advanced stages of the disorder. For this reason, the more subtle executive cognitive deficits frequently go unrecognized. Because cognitive impairment isn’t obvious, it is likely that the altered behavior commonly observed in FXTAS is attributed to selfishness, dependency, laziness, some other such negative personality trait, or possibly to accelerated aging.
What may be difficult for family, friends, and caregivers to grasp is that the problem is not so much that an individual won’t behave “properly,” but that he can’t do so. This change in executive functioning may require family members to provide a good deal of structure for the affected individual—something that may be difficult to do, especially when the person’s insight is impaired, and he is unable to see that he has any significant problems. In this situation, some individuals with FXTAS may chafe at being “told what to do” by a spouse or adult child.
This basic cognitive phenotype was established fairly early on in the study of FXTAS, and it has now been confirmed and studied in more depth. Although there are a lot of individual differences, both men and women with FXTAS seem to experience essentially similar problems with memory, thinking, and attention.
Emotional and behavioral problems are frequently associated with FXTAS, and in those cases it appears that women may be more affected than men. Anxiety, especially social anxiety, is quite common among them, as is depression. Many of these psychiatric problems are related to the dysexecutive syndrome described above. Some people simply develop problems in controlling their behavior, and in avoiding distractibility. They become impulsive, or fail to get going on things that need to be done. They may focus repetitively on certain thoughts or behaviors, something referred to as perseveration. Although the attempt to find medications that will improve cognition in FXTAS has been frustrating so far, it appears that the current crop of anti-depressant and anti-anxiety medications can provide some relief from the emotional symptoms. The behavior changes, however, have been more difficult to treat.
It is important to understand the nature of the cognitive problems observed in FXTAS. They may appear prior to the onset of tremor and ataxia, but they often are initially subtle, and it can take a while before the family begins to see what seems like a personality change. Not understanding what is happening, family members are likely to misinterpret the behavioral disorder as deliberate and under the person’s control. Family, friends, and caregivers may find it very difficult to cope with this kind of impairment. In fact, some research shows that when caregivers believe such impulsivity or lack of initiation is deliberate, the stress of dealing with the individual is much greater than if they know the person can’t help it.
Trials of medications that might correct the signs and symptoms of FXTAS have not produced any breakthroughs, but there is reason to be optimistic, and they continue. Although there is no consistently effective treatment for problems with executive functioning, certain medications (e.g., stimulants such as amphetamines or methylphenidate, or modafinil) may be helpful, especially when the symptoms are relatively mild.
As executive cognitive functioning grows more impaired, it usually becomes necessary for others to provide varying degrees of encouragement, structure, and supervision for the affected person, since their capacity for independent functioning is compromised. Somewhat similar problems may occur in Alzheimer disease (AD), but in AD, significant memory problems are among the earliest symptoms, and executive functioning is not ordinarily affected until later in its course.
Spouses find it particularly challenging when a person with FXTAS was previously very independent, or took a leading role in many aspects of the relationship. When a considerable amount of the caregiving role falls to the daughters of men with FXTAS—who themselves often are caring for one or more children with Fragile X syndrome—the burden may feel overwhelming.
Future research on cognition in FXTAS is aimed at addressing some of the unanswered questions discussed above, especially regarding how women are affected, and on finding means of facilitating improvement in cognition.
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The sources below served as background for much of the material in this article.
- Brega AG, Goodrich G, Bennett RE, Hessl D, Engle K, Leehey MA, Bounds LS, Paulich MJ, Hagerman RJ, Hagerman PJ, Cogswell JB, Tassone F, Reynolds A, Kooken R, Kenny M, Grigsby J: (2008) The primary cognitive deficit among males with Fragile X-associated tremor/ataxia syndrome (FXTAS) is a dysexecutive syndrome. Journal of Clinical and Experimental Neuropsychology, published online 15 February 2008, (URL: http://dx.doi.org/10.1080/13803390701819044).
- Grigsby J, Brega AG, Engle K, Leehey MA, Hagerman RJ, Tassone F, Hessl D, Hagerman PJ, Cogswell JB, Bennett RE, Cook K, Hall DA, Bounds LS, Paulich MJ, Reynolds A: (2008) Cognitive profile of Fragile X premutation carriers with and without Fragile X-associated tremor/ataxia syndrome. Neuropsychology, 22, 48-60.
- Moore CJ, Daly EM, Schmitz N, Tassone F, Tysoe C, Hagerman RJ et al: (2004) A neuropsychological investigation of male premutation carriers of Fragile X syndrome. Neuropsychologia, 42, 1934-1947.
Jim Grigsby, PhD
is a professor in the Department of Medicine, School of Medicine, at the University of Colorado, Denver.
Angela G. Brega, PhD
is an assistant professor in the Department of Medicine, School of Medicine, at the University of Colorado, Denver.