It has been nearly 15 years since Fragile X-associated tremor/ataxia syndrome (FXTAS) was first discovered and described. In that time, our understanding of the disease has increased rapidly. The reason the field has moved so quickly is due to the amount of gene testing done in families with Fragile X, which identifies premutation carriers at risk for the disease. In addition, many Fragile X syndrome researchers and clinicians took on FXTAS as a second Fragile X-associated Disorder to treat.
FXTAS was first recognized by Dr. Randi Hagerman who noticed that many of her Fragile X syndrome patients had grandfathers with tremor. She referred these men over to my colleague, Dr. Maureen Leehey, in the adult movement disorder clinic at the University of Colorado. Together, the two doctors with help from others, described this new disease. FXTAS affects FMR1 premutation carriers, with higher rates seen in men compared to women. This is likely due to X-inactivation, where women are a mosaic of premutation cells and of cells with a normal FMR1 gene.
Note, the prevalence of premutation carriers is approximately 1/151 women and 1/468 men in the general population. Though it is rare, it is now known that FXTAS can also occur in people with full mutations and those who have smaller expansions in the gene, called “gray zone” or “intermediate” size, defined variably as 41-54 or 45-54 repeats. Individuals with a gray zone expansion are more common in the general population, with rates that may be as high as two percent.
FXTAS is a neurological disorder, or disorder of the brain, that progressively worsens over time. The key features are tremor of the hands when doing an intentional movement and uncoordinated walking (ataxia). There are many other features, including stiffness of the limbs, slowness of movement, numbness of the feet, impotence, and hearing loss. In addition, people with FXTAS typically have problems with their thinking, organizational skills, memory and the ability to control oneself. Depression and anxiety are common and personality changes can occur. A gray zone carrier’s FXTAS symptoms appear to be milder than those of a premutation carrier’s, and may appear more like Parkinson’s disease than the tremor and ataxia described above.
Individuals with FXTAS usually have symptoms after the age of 55. As premutation carriers age, especially men, the likelihood of having symptoms rises. This likelihood reaches 75 percent by age 75 for premutation men. The progression of symptoms is gradual, with interference of daily activities by tremor and falls occurring around ten years after onset of the tremor. Dependence on a cane or walker occurs approximately 15 years into the disease. Some people with FXTAS show a step-wise progression with acute illnesses, major surgery, or other major life stressors and symptoms worsen more quickly.
The disease is believed to result from several problems occurring within the cells of the brain. One issue is with the formation of extra message from the gene, which allows cells to make Fragile X protein. Toxic proteins are also made as the gene forms an abnormal structure from the expanded repeat during the process of making normal Fragile X protein. Both the extra message and toxic protein products clump within the cells in the brain, especially in areas that serve movement and thinking. In addition, structures within each cell that create energy for the cell or mitochondria do not function properly, also contributing the toxicity in the brain. Other issues within the gene itself or surrounding genes may contribute, increasing the chance that a premutation carrier gets FXTAS. These other issues are still being defined by researchers.
Other Disorders Related to the Premutation
With the discovery of FXTAS, researchers turned their attention to other potential medical issues reported by premutation carriers, especially women. Although additional research is needed to fully understand the extent of medical issues in premutation carriers without FXTAS, it is increasingly clear that mild neurological signs, endocrine dysfunction, and rheumatologic disorders in premutation women warrant a closer look. Some of these issues may start earlier than age 55 and are not necessarily a precursor to FXTAS in older age.
It is very important that people with FXTAS get referred to adult neurologists and ideally movement disorder specialists, who have experience treating adults with movement disorders and cognitive issues. There are a variety of medications that can be used to treat the symptoms of the disease. Medications used for other tremor disorders can be effective as can medications used for ataxia and Parkinson’s disease. Mood and anxiety disorders are responsive to medications and quality of life can be greatly improved if they are treated. Non-medication therapies should be considered, with an emphasis on physical therapy. Prolonged rehabilitation should be anticipated if a large surgery or protracted illness occurs.
Research investigating medications for FXTAS is in its infancy. Although there are many basic scientists and clinical researchers working on premutation-related diseases, larger collaborative clinical trials have not been done. Funding for FXTAS- related work lags behind Fragile X syndrome by decades. Those of us in the FXTAS clinical and research community are enthusiastically plowing ahead, despite any barriers, and hope to have some medications proven to help patients in the next decade.