Hagerman lab > For families > more

For Families

We are currently studying various disorders that are linked to the fragile X gene (FMR1), including:

The fragile X (FMR1) gene – The FMR1 gene produces a protein, FMRP, which helps to form the proper connections (synapses) between nerve cells in the brain. When the CGG-repeat region within the gene expands beyond about 200 repeats (“full mutation” range), the gene usually (but not always) becomes modified by the chemical addition of methyl groups to the DNA, causing the gene to reduce its activity or to completely turn off (through mechanisms that we don’t fully understand). When the gene shuts down, it no longer produces sufficient FMRP for normal brain development.


Fragile X syndrome is the leading inherited form of cognitive impairment (formerly referred to as mental impairment or retardation), affecting nearly one person in 3,000 worldwide. It is also the leading single gene associated with autism. Approximately 2-6% of cases of autism are associated with fragile X syndrome, and approximately one-third of all boys with fragile X syndrome meet diagnostic criteria for autism, with a larger number meeting criteria for autism spectrum disorders (ASD).

Often referred to as a form of "intellectual disability," fragile X syndrome is a much broader spectrum disorder that includes learning disabilities and emotional problems; behavioral difficulties; and relatively mild physical features including prominent ears, high-arched palette, hyperextensible joints, and macroorchidism.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that almost exclusively involves individuals who carry premutation forms of the fragile X gene. FXTAS generally begins in mid-late adulthood (with usual onset of 50 years or later) with progressive action tremor (tremor or shakiness with activity; e.g., pouring liquids, writing, other purposeful movements) and balance/walking difficulties (gait ataxia).

Nearly one-half of men over 50 years of age, and a smaller number of women who are premutation carriers, 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.

Until the late 1990's, carriers of premutation expansions of the gene were thought to be clinically normal. However, my wife, Dr. Randi Hagerman, a leading fragile X researcher and clinician, began to notice a pattern of concern from the mothers of children with fragile X about their own fathers (premutation carrier grandfathers of the children with fragile X syndrome). 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.

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 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.

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 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.


Reason for Hope

With rapid advances in research on fragile X syndrome and FXTAS, and parallel development of new research tools and new candidate drugs currently undergoing treatment trials, there is every reason to be optimistic about effective treatment for both disorders. In light of these new developments, we have shifted our entire research effort to development of effective treatments for both FXTAS and fragile X syndrome.

From the perspective of research in neurodevelopmental disorders, fragile X syndrome represents a portal of understanding to the underlying mechanisms that many developmental disorders have in common. In particular, since fragile X syndrome represents the largest known form of autism, understanding fragile X syndrome should shed additional light on the mechanisms giving rise to that pervasive and all-too-common behavioral disorder.

With respect to neurodegeneration research, the particular advantage of studying FXTAS, beyond the development of targeted treatments for this disorder, is that the trigger for the disease process in FXTAS (FMR1 mRNA) is known (unlike the case for either Alzheimer’s or Parkinson’s Disease), thus facilitating the development of accurate animal and cellular models that may have broader applicability for other neurodegenerative disorders.

Research Participation

The Hagerman team welcomes the participation of individuals and families with fragile X syndrome, FXTAS, or any other condition related to expansions of the fragile X gene. Such participation may involve the development of better clinical measures for these conditions, involvement in clinical trials, or contributions to more basic molecular research into the disease process. For the latter, participation may involve providing a blood sample or skin biopsy as part of thorough clinical evaluation. For more details regarding participation, please contact us.

Tissue Donations

The role of tissue donations in our FXTAS research
Nearly all of the major discoveries in FXTAS research, particularly those that relate to the molecular basis of the disorder, have been made possible through the donation of body tissues, both at the time of surgical procedures, as volunteer skin biopsies or umbilical cord, or as a donation upon the passing of a family member. These tissue donations allow us to study the specific causes of FXTAS that would not have been possible otherwise.

For example, from our work with brain cells, we have been able to identify over 30 proteins that may be related to FXTAS. We have also been able to isolate living neural stem cells from brain tissue, and keep those cells alive in culture to study the processes related to FXTAS in more detail. This research is critical to our understanding and eventual development of treatments for FXTAS.

For those women who are premutation carriers and are soon to be moms, we also place great value on umbilical cords (not cord blood), which would otherwise be discarded, so please contact us if you are interested in donating that tissue.

We regard all tissue donations to truly be a gift to fragile X research, and to those families who may benefit from such research.