Source American Academy of
Neurology (AAN), Date: July 19, 2005
Newswise — Fragile
X-associated tremor/ataxia syndrome can be difficult to
diagnose and should have guidelines for diagnostic
testing, according to a study in the July 26 issue of
Neurology, the scientific journal of the American
Academy of Neurology. A second study found chemotherapy
aggravated symptoms in one woman’s case.
Fragile X syndrome is the
most common inherited cause of mental retardation. Fragile
X-associated tremor/ataxia syndrome (FXTAS) was recently
defined as a disorder that affects carriers of the Fragile
X gene, called FMR1. People with FXTAS carry the FMR1 gene
and develop symptoms later in life, usually starting in
their 60s and 70s. Ataxia is the inability to coordinate
voluntary muscle movements. Predominantly
occurring in males, FXTAS could affect as many as one in
3,000 men over age 50. Male carriers pass the gene to all
daughters but none of their sons. Female carriers have a
50 percent chance of passing the gene to each child.
A multi-center study found 56
people had received 98 prior diagnoses, including
parkinsonism and essential tremor, before FXTAS was
concluded. The researchers believe this was partly due to
the recent definition of FXTAS and a lack of familiarity
with the disorder. The information about previous
diagnoses encouraged them to develop guidelines for
diagnostic testing for FXTAS.
“Men age 50 and older who
develop unexplained ataxia should undergo testing to check
if they have the FMR1 gene,” said co-author Maureen A.
Leehey, MD, of the University of Colorado Health Sciences
Center in Denver. “Also men 50 and older who have tremor,
parkinsonism, or dementia, along with a family history of
developmental delay, autism, mental retardation, or
premature ovarian failure, should be tested for the gene.”
These guidelines are
reasonable but may change in the future as larger numbers
of patients are detected, according to an editorial
published in the same issue of Neurology.
“A family history of mental
retardation or tremor/ataxia syndromes should be sought in
such patients,” said editorial author Thomas Gasser, MD,
of the Hertie-Institute for Clinical Brain Research at
University of Tuebingen in Germany.
A second study in Ireland
examined a 70-year-old woman with mild ataxia and tremor
that became severe after receiving chemotherapy to treat
breast cancer. She had two sons with Fragile X syndrome.
The researchers concluded she had FXTAS after a genetic
test using DNA from a blood sample showed that she carried
the FMR1 gene. Her symptoms became mild again after
“About 1 in 259 women carry
the FMR1 gene, but FXTAS is rarely reported in women,”
said co-author John P. O’Dwyer, MRCPI, of St. Vincent’s
University Hospital in Dublin. “You might expect to see
FXTAS more often, but it may only become evident when
toxic effects from a procedure like chemotherapy push mild
symptoms to the forefront.”
A related “Patient Page” on
fragile X syndrome and FXTAS is also published with the
July 26 Neurology and will be available freely at
The study by Leehey et al was
supported by grants from the National Institute of
Neurological Disorders and Stroke, National Institute of
Child Health and Development, and American Academy of
Neurology. Deborah A. Hall, MD, one of the authors,
received the American Academy of Neurology Clinical
Research Training Fellowship in 2003 for work in FXTAS.
The American Academy of
Neurology, an association of nearly 19,000 neurologists
and neuroscience professionals, is dedicated to improving
patient care through education and research. A neurologist
is a doctor with specialized training in diagnosing,
treating and managing disorders of the brain and nervous
system such as Alzheimer’s disease, epilepsy, Parkinson’s
disease, multiple sclerosis, and stroke.
For more information about
the American Academy of Neurology, visit
Fragile X and
Company: Finding the
S. H. Subramony, MD, Christopher
Freidrich, MD and Janet Jankowiak, MD
The Patient Page - at
Fragile X syndrome (FXS) is a
common cause of inherited mental retardation in
boys. (More information about FXS can be found
on the next page.) It is caused by a defect in a gene
located on the X chromosome that is inherited
from the mother. The gene in the mother carries
a "premutation" which, when passed on to her
son, expands to a "full" mutation that produces the signs
of fragile X syndrome. The mother who carries the "premutation"
does not have mental retardation because she also
carries a normal X chromosome. She may have
inherited the premutation from her father. This
grandfather does not have mental retardation
either because the gene only carries a "premutation."
However, some of these grandfathers develop a
progressive tremor (shaking) and gait ataxia
(unsteadiness) later in life, known as fragile
X tremor-ataxia syndrome (FXTAS). Even more rarely, the
mother with the premutation may develop FXTAS.
This issue of Neurology
has two papers that further describe FXTAS, as
well as an editorial on the subject. One of the papers,
by Hall et al., is from the same group of researchers who originally
reported this syndrome in 2001. In the clinics where
the boys with FXS were treated, the mothers
indicated that their fathers (the boys’
maternal grandfathers) were having neurologic
problems. Sixty-two family members were found to have the
fragile X premutation by genetic testing.
"Definite" FXTAS was diagnosed if the patients
had a tremor with movement (intention tremor)
or ataxia when walking with either 1) a very typical
abnormality on brain MRI scan or 2) the disease
was confirmed on autopsy. Twenty of the 62 met
this criterion; all 20 were men. "Probable"
FXTAS was diagnosed when patients had tremor and ataxia
but no typical MRI change, or the patient had
the MRI change with a disorder that looked like
Parkinson disease (PD) or memory loss.
Forty-two of the 62 fit in this category; 35 were men
and seven were women. It was noted that these 62
patients had been diagnosed by other doctors
(mostly neurologists and family doctors) as
having some other disease such as PD (24%), essential
or alcohol-related tremor (20%), ataxia of various
causes (17%), dementia (13%) and stroke (10%).
Thus, in families with fragile X syndrome,
family members over age 50 who have been diagnosed
with these other neurologic conditions may need a
second look by a clinician who is more familiar
with FXTAS to exclude the diagnosis.
A second paper, by O’Dwyer et
al., describes a woman with the fragile X
premutation who developed severe ataxia when
given a usually non-toxic dose of chemotherapy (carbo-platin)
for a cancer. The authors thought the gene
abnormality made her unusually vulnerable to
damage to the nervous system. Of interest, her
symptoms returned to her baseline level of mild
ataxia, intention tremor and some problems with thinking
when chemotherapy was stopped. Kamm and Gasser,
who wrote an editorial on FXTAS, suggested that
environmental factors might contribute to the
severity of FXTAS.
Most of the information on
FXTAS has come from studying family members of
children with known fragile X syndrome. Other studies
have tried to see if the fragile X premutation is
present in a subset of people with some of the
other diagnoses that have been confused with
FXTAS. It was not found in any of 81 patients
diagnosed with essential tremor or 414 patients diagnosed
with PD. However, in two reports of patients
with "ataxia" of uncertain type, a small number
turned out to have the premutation.
So, where do we go from here?
Since it is estimated that as many as one in
3,000 men over age 50 may have FXTAS, larger
studies are needed to find out how many patients with
"ataxia" or tremor, previously undefined, have
the fragile X premutation. The basic scientists
need to examine if such premutations can indeed
cause similar nervous system problems in laboratory
animals. In the mean time, the guidelines
suggested by Hall and colleagues seem
reasonable. Although fragile X premutations may
explain only a very small fraction of the cases of ataxia,
finding the premutation will make a major
difference to the families with fragile X
syndrome. Genetic counseling will be needed regarding
the chances of fragile X mental retardation in their
is fragile X syndrome (FXS)?
Fragile X syndrome is the
most common inherited cause of mental
retardation in boys. Normally, women have two X
chromosomes, one that is passed on from their
mother and the other from their father. On the
other hand, men have one X chromosome and one Y
chromosome, the X from their mother and the Y from their
father. In fragile X syndrome, there is a
defect in a gene (FMR 1) located on one
of the mother’s X chromosomes (figure
1). The defective gene contains an abnormal
expansion of a chain of DNA "nucleotides" known
as the "CGG repeat." Normal X chromosomes have fewer than
54 CGG repeats. The mother who passes on a "fragile
X" has a gene that carries a "premutation" with
55 to 200 CGG repeats. She does not have mental
retardation because she also has a second X
chromosome that is normal. However, in her son, the
gene may expand to a "full" mutation with more than
200 CGG repeats. This results in FXS. Because
this disease is inherited through the mother it
is called an "X-linked" disease.
What is fragile X
tremor/ataxia syndrome (FXTAS)?
Some of the maternal
grandfathers of the boys with FXS carry the "premutation"
on their X chromosome and may develop a progressive
shaking and unsteadiness as they get older. "Ataxia"
refers to a problem with coordination and
balance. The "tremor" (shaking) and ataxia in
FXTAS are due to damage to a part of the brain
called the cerebellum and its connections. In even more
rare cases, mothers of boys with FXS who carry
the premutation can also develop FXTAS.
What are the symptoms and signs of FXTAS?
FXTAS generally comes on
slowly in men (and rarely women) over 50 years
old. Problems may include:
Tremor (shaking) that can
occur with activity or at rest.
Poor balance and
Poor hand coordination and
Slow movements, stiff
muscles, lack of facial expression and poor
balance that may look like Parkinson disease (PD).
occurs with standing due to a drop in blood pressure
and problems with erection that suggest
problems with the autonomic nervous system
(part of the nervous system that controls more
"automatic" functions such as heart rate, blood
pressure, and sweating).
Is FXTAS easy for doctors
FXTAS has only been
recognized in the last 5 years or so and many
doctors are not yet familiar with it. Also, there seems
to be a wide variety of symptoms and signs in
different patients and the disease progresses
at different rates. Many patients may be
given other diagnoses, such as PD, essential tremor,
stroke, dementia, or other more unusual neurologic
diseases. However, special studies such as an
MRI of the brain is helpful because it shows
some typical changes in an area close to the
cerebellum called the middle cerebellar peduncles. The
diagnosis is made by finding the premutation
in such a patient by DNA analysis.
Why is it important to
At this time, FXTAS cannot
be treated with any medication that will stop
it. However, discovering it brings "diagnostic" closure
to patients who may have been told that the cause
of their neurologic disease is "unknown."
Also, it is very important for families with
FXTAS to get genetic counseling because all the
daughters of men with FXTAS will carry the
gene defect. This means that these daughters
can have sons with mental retardation and the
daughter herself may go through early menopause and
rarely even develop FXTAS.
American Academy of
American Academy of Neurology
National Fragile X Foundation
Hall DA, Berry-Kravis E,
Jacquemont S, et al. Initial diagnoses given to persons
with the fragile X associated tremor/ataxia syndrome (FXTAS).
O’Dwyer JP, Clabby C, Crown
J, Barton DE, Hutchinson M. Fragile X–associated
tremor/ataxia syndrome presenting in a woman after
chemotherapy. Neurology 2005;65:331–332.[Free
Kamm C, Gasser T. The
variable phenotype of FXTAS: A common cause of
"idiopathic" disorders. Neurology 2005;65:190–191.[Free