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For Families
We are currently studying various disorders that are linked to the fragile X
gene (FMR1), including:
Fragile X syndrome, the leading inherited form of intellectual disability
Fragile X-associated tremor/ataxia syndrome (FXTAS), one of the more
common neurodegenerative disorders known to be caused by a single
gene (FMR1)
The developmental problems associated with the premutation, including
autism.
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 dont fully understand). When the gene shuts down, it
no longer produces sufficient FMRP for normal brain development.
Our laboratory is working to increase the production of FMRP from the
lowered levels of fragile X mRNA that still exist in the more than half of
all individuals who have full mutation forms of the gene.
Even for the increased levels of FMR1 mRNA that are found in the
premutation range, the expanded CGG repeat at least partially inhibits
FMRP production, due to a block in translation initiation (production of
FMRP) by the expanded CGG-repeat within the mRNA. We are currently
screening small molecules (and are developing additional strategies)
that are designed to disrupt the inhibitory structure formed by the CGG
repeat.
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
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 Alzheimers or Parkinsons 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.
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.