Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) This page contains tooltip text
Until fairly recently (late 1990's) carriers of premutation expansions (55 to 200 CGG repeats) of the fragile X gene were thought to be clinically normal. However, my wife, Dr. Randi Hagerman MD, a leading fragile X researcher and clinician, and our genetic associate, Louise Gane MS, began to notice a pattern of concern in the mothers of children with fragile X - about their own fathers (premutation carrier grandfathers of the children with fragile X syndrome). Beginning in their 50's or 60's, these men began to experience balance problems and falling (ataxia) and/or shakiness and tremors of the hands with activity, often preventing them from carrying out normal activities such as writing.
At about the same time, Dr. Flora Tassone in my laboratory discovered that premutation forms of the FMR1 gene were producing too much message (mRNA) - just the opposite of full mutation forms of the gene (> 200 CGG repeats), which generally become silenced. This result was first published in 2000. The combination of these molecular findings, and the identification of the balance and tremor problems in the adult carriers, led to the recognition of a new disorder, fragile X-associated tremor/ataxia syndrome (FXTAS).
Nearly one-half of men over 50 years of age, and a smaller number of women who are carriers of premutation forms of the FMR1 gene, identified through families of children diagnosed with fragile X syndrome, will develop symptoms of FXTAS. The syndrome involves not only ataxia and tremor, but is often associated with parkinsonism, memory loss, problems with incontinence, impotence, and a peripheral neuropathy (loss of sensation in the feet or hands). Women who are carriers appear to have increased problems with hypothyroidism and other immune-related problems, and often experience muscle pain.
The fact that FXTAS occurs almost exclusively among premutation carriers, where the FMRP levels are normal or only slightly reduced, and not among adults who are most affected by fragile X syndrome; and the fact that the gene is producing much higher than normal levels of its message (RNA), led us to propose an "RNA-toxic-gain-of-function" model as the basis for FXTAS.
More on the relationship between fragile X syndrome and FXTAS. We view fragile X syndrome and FXTAS as two faces of the same gene, and research on one disorder will inform us about the other. Thus, we hope that our research as a whole will help us to develop therapies for both fragile X syndrome and FXTAS. It is important to note, however, that the two disorders are caused by entirely separate mechanisms: fragile X syndrome is caused by the loss of FMRP, while FXTAS is caused by excess mRNA; thus, most children with fragile X syndrome are actually protected against developing FXTAS late in life.
At the present time, the major research focus of the Hagerman laboratory is the establishment of the underlying disease processes that give rise to FXTAS with the objective of developing targeted therapeutic agents to treat this disorder.
