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Articles of Interest - Fragile X Syndrome

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Diagnosis and Management of Fragile X Syndrome

Fragile X-Related Disorder Difficult to Diagnose

Fragile X and Company: Finding the Right Diagnosis




Diagnosis and Management of Fragile X Syndrome

Daniel J. Wattendorf, MAJ, MC, USAF, and Maximilian Muenke, M.D., The American Academy of Family Physicians, News and Publications, Vol. 72/No. 1 (July 1, 2005)



Fragile X-Related Disorder Difficult to Diagnose

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 chemotherapy stopped.


“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 Right Diagnosis

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 grandsons.


What 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. 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 falls.

  • Poor hand coordination and unclear speech.

  • Slow movements, stiff muscles, lack of facial expression and poor balance that may look like Parkinson disease (PD).

  • Fainting that 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 to recognize?


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 recognize FXTAS?

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.


For more information

American Academy of Neurology Foundation

American Academy of Neurology

National Fragile X Foundation



  1. Hall DA, Berry-Kravis E, Jacquemont S, et al. Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS). Neurology 2005;65:299–301.

  2. 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.

  3. Kamm C, Gasser T. The variable phenotype of FXTAS: A common cause of "idiopathic" disorders. Neurology 2005;65:190–191.

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