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GENETIC SCREENING RECOMMENDED TO DETECT
NEW NEURODEGENERATIVE DISORDER IN MEN OVER AGE 50
Common and small mutation in the fragile
X gene, once thought to have no health effects in male carriers,
now linked to tremors, balance problems and memory deficits.
January 27, 2004
(SACRAMENTO, Calif.)
— A team of researchers,
led by physicians at the UC Davis M.I.N.D Institute, have discovered
a new, progressive neurological disorder that predominantly affects
men over age 50 and results in tremors, balance problems and dementia
that become increasingly more severe with age.
A significant but currently unknown number of adults
with these tremor and balance problems are being diagnosed with
Parkinson’s disease, senile dementia and Alzheimer’s
disease when their condition may be accurately and easily identified
with a standard DNA blood test ordered by their doctor. The discovery
is published in the Jan. 28 issue of the Journal
of the American Medical Association.
Known as fragile
X-associated tremor/ataxia syndrome, or FXTAS (pronounced
fax-tass), the disorder affects older men who are carriers of
a small mutation (premutation) in the same gene that causes fragile
X syndrome, the most common cause of inherited mental retardation.
Nearly 1 in 800 men in the general population carries this premutation
in the fragile X gene, and UC Davis research suggests that as
many as 30 percent of carriers—roughly 1 in 3,000 men—may
develop FXTAS later in life.
“FXTAS may be one of the most common causes
of tremor and balance problems in the adult population, yet it
is being misdiagnosed because neurologists who see adults with
movement disorders are not aware that they need to look for a
family history of fragile X in grandchildren or to check for the
presence of the premutation in the fragile X gene,” said
Randi Hagerman, medical director of the UC Davis M.I.N.D. Institute.
(M.I.N.D. stands for Medical Investigation of Neurodevelopmental
Disorders.)
Screening for the gene mutation in men who have
tremor and balance problems is important regardless of their family
history, especially when accompanied by other signs such as parkinsonism
(rigidity in movement), short-term memory loss and dementia. Family
genetic counseling can help those affected with FXTAS, as well
as future generations who may inherit fragile X syndrome. Research
studies also are under way to specifically determine which medications
are better suited to alleviate FXTAS-related problems, and whether
other therapies, such as surgery to disable nerve tracks, may
actually exacerbate balance problems.
Hagerman, a developmental and behavioral pediatrician
who has specialized in the diagnosis, research and treatment of
fragile X for more than 20 years, began looking for a connection
between children and their grandfathers because the mothers of
her fragile X patients were worried about their own fathers, who
were falling down, becoming forgetful and experiencing other neurological
problems. Hagerman, along with her husband Paul, a professor of biological chemistry at
UC Davis School of Medicine and principal investigator of
the study, led the team of researchers from UC Davis M.I.N.D.
Institute,
University of Colorado Health Sciences Center, and
RUSH-Presbyterian-St. Luke’s Medical Center.
The researchers looked at 192 individuals whose
families belong to the Northern or Southern California Fragile
X Associations. While only 17 percent of the men in their 50s
had FXTAS, the percentage of individuals with tremors and balance
problems increased with each decade of life, to 38 percent of
men in their 60s, 47 percent of men in their 70s, and 75 percent
of men in their 80s. The study also showed that the majority of
older males carriers of the premutation will develop at least
mild symptoms of FXTAS.
FXTAS is characterized by tremors, balance problems
and memory deficits that become increasingly severe with age.
Initial signs of the disorder may include difficulty writing,
using eating utensils, pouring water and walking. These initial
symptoms progress over years or even decades, until carrying out
many of the tasks of daily living and walking without assistance
becomes difficult or impossible. Other features include short-term
memory loss, anxiety, decreased sensation in the lower extremities
to touch and vibration, lower-limb muscle weakness and parkinsonism.
“FXTAS is an enigma,” said Hagerman,
who also holds the Tsakopoulos-Vismara Endowed Chair at the UC
Davis School of Medicine and Medical Center. “The disorder
appears later in life in men who are generally healthy throughout
childhood and early-to-mid-adulthood and have normal to above-average
intelligence, yet is caused by a defect in a gene known to cause
mental retardation usually diagnosed in early childhood.”
The underlying cause of FXTAS is a change, or mutation,
in the fragile X mental retardation 1 gene, or FMR1. Under normal
conditions, this gene produces a protein that maintains the proper
functioning of nerve cells in the brain. The gene causes both
fragile X syndrome and FXTAS when a particular segment of DNA
is repeated too many times. The repetition informally is called
a “CGG repeat” because it contains the same trio of
DNA building blocks—cytosine, guanine, and guanine in the
same repetitive order.
The average person has 30 CGG repeats in the FMR1
gene. When an individual has 200 or more CGG repeats in the FMR1
gene, the individual makes little or no FMR1 protein and has fragile
X syndrome. With 55 to 200 CGG repeats, an individual is considered
a carrier of the premutation, which can lead to FXTAS later in
life and to fragile X (the full mutation) in the next generations.
Male carriers are at high risk to develop FXTAS, as well as for
passing on the gene mutation to all of their daughters, who in
turn are at risk to have children with fragile X syndrome.
Tissue and postmortem studies of brains from FXTAS
patients, led by Paul Hagerman and UC Davis assistant professor
of pathology Claudia Greco, showed accumulations of abnormal cellular
material in the form of inclusion bodies in the nuclei of brain
cells, (specifically neurons and astrocytes) throughout the cortex
and brainstem regions. The greatest densities were found in the
hippocampus and frontal cortical regions, areas of the brain that
control movement and are important in learning, memory and emotion.
“The formation of inclusion bodies in the
nuclei of nerve cells offers an important clue about the cause
of the disorder, one that may ultimately help with the development
of therapies for both FXTAS and fragile X syndrome,” said
Paul Hagerman. In 2001 the Hagerman team reported the first cases
of FXTAS in men and suggested that the neurological dysfunctions
could be due to the elevated levels of messenger RNA from the
FMR1 gene mutation, which are consistently observed in the blood
of premutation carriers. As a result, they proposed the hypothesis
that FXTAS results from an RNA toxic gain-of-function.
“Further study of these cellular processes
can lead to a better understanding of the mechanisms leading to
fragile X syndrome and may offer new targets for developing treatments,”
Paul Hagerman said. In addition, because some carriers of the
premutation develop FXTAS while others appear protected, other
factors also may play a role in disease development, offering
additional clues to the origin of this disorder.
The UC Davis M.I.N.D. Institute, in Sacramento,
Calif., was founded in 1998 as a unique research center where
parents, community leaders, researchers, clinicians and volunteers
to discover treatment and cures for autism, learning disabilities,
fragile X syndrome and other neurodevelopmental disorders. Its
Fragile X program is a leading international center for the diagnosis,
research and treatment of fragile X-related disorders.
Additional information about Fragile X and FXTAS
for both physicians and patients is available by calling (916)
703-0200 at the UC Davis MIND Institute as well as the
National Fragile X Foundation (1-800-688-8765).
This study was supported by grants from the
National Institute of Neurological Disorders and Stroke and
the National
Institute of Child Health and Development, as well as general
support from the UC Davis M.I.N.D. Institute.
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