Fragile X and company: Finding the right diagnosis
S. H. Subramony, MD,
Christopher Freidrich, MD and
Janet Jankowiak, MD
Fragile X syndrome (FXS) is a common cause of inherited mentalretardation in boys. (More information about FXS can be foundon the next page.) It is caused by a defect in a gene locatedon the X chromosome that is inherited from the mother. The genein the mother carries a "premutation" which, when passed onto her son, expands to a "full" mutation that produces the signsof fragile X syndrome. The mother who carries the "premutation"does not have mental retardation because she also carries anormal X chromosome. She may have inherited the premutationfrom her father. This grandfather does not have mental retardationeither 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 fragileX tremor-ataxia syndrome (FXTAS). Even more rarely, the motherwith the premutation may develop FXTAS.
This issue of Neurology has two papers that further describeFXTAS, as well as an editorial on the subject. One of the papers,by Hall et al.,1 is from the same group of researchers who originallyreported this syndrome in 2001. In the clinics where the boyswith FXS were treated, the mothers indicated that their fathers(the boys’ maternal grandfathers) were having neurologicproblems. Sixty-two family members were found to have the fragileX premutation by genetic testing. "Definite" FXTAS was diagnosedif the patients had a tremor with movement (intention tremor)or ataxia when walking with either 1) a very typical abnormalityon 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 butno typical MRI change, or the patient had the MRI change witha disorder that looked like Parkinson disease (PD) or memoryloss. Forty-two of the 62 fit in this category; 35 were menand seven were women. It was noted that these 62 patients hadbeen diagnosed by other doctors (mostly neurologists and familydoctors) as having some other disease such as PD (24%), essentialor alcohol-related tremor (20%), ataxia of various causes (17%),dementia (13%) and stroke (10%). Thus, in families with fragileX syndrome, family members over age 50 who have been diagnosedwith these other neurologic conditions may need a second lookby a clinician who is more familiar with FXTAS to exclude thediagnosis.
A second paper, by O’Dwyer et al.,2 describes a womanwith the fragile X premutation who developed severe ataxia whengiven a usually non-toxic dose of chemotherapy (carbo-platin)for a cancer. The authors thought the gene abnormality madeher unusually vulnerable to damage to the nervous system. Ofinterest, her symptoms returned to her baseline level of mildataxia, intention tremor and some problems with thinking whenchemotherapy was stopped. Kamm and Gasser,3 who wrote an editorialon FXTAS, suggested that environmental factors might contributeto the severity of FXTAS.
Most of the information on FXTAS has come from studying familymembers of children with known fragile X syndrome. Other studieshave tried to see if the fragile X premutation is present ina subset of people with some of the other diagnoses that havebeen confused with FXTAS. It was not found in any of 81 patientsdiagnosed with essential tremor or 414 patients diagnosed withPD. However, in two reports of patients with "ataxia" of uncertaintype, a small number turned out to have the premutation.
So, where do we go from here? Since it is estimated that asmany as one in 3,000 men over age 50 may have FXTAS, largerstudies 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 canindeed cause similar nervous system problems in laboratory animals.In the mean time, the guidelines suggested by Hall and colleaguesseem reasonable (table 1). Although fragile X premutations mayexplain only a very small fraction of the cases of ataxia, findingthe premutation will make a major difference to the familieswith fragile X syndrome. Genetic counseling will be needed regardingthe chances of fragile X mental retardation in their grandsons.
Fragile X syndrome is the most common inherited cause of mentalretardation in boys. Normally, women have two X chromosomes,one that is passed on from their mother and the other from theirfather. On the other hand, men have one X chromosome and oneY 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) locatedon one of the mother’s X chromosomes (figure 1). The defectivegene contains an abnormal expansion of a chain of DNA "nucleotides"known as the "CGG repeat." Normal X chromosomes have fewer than54 CGG repeats. The mother who passes on a "fragile X" has agene that carries a "premutation" with 55 to 200 CGG repeats.She does not have mental retardation because she also has asecond X chromosome that is normal. However, in her son, thegene may expand to a "full" mutation with more than 200 CGGrepeats. This results in FXS. Because this disease is inheritedthrough the mother it is called an "X-linked" disease.
Figure. Inheritance of fragile X and fragile X tremor-ataxia syndrome (FXTAS). The paired rectangles represent X and Y chromosomes (long and short respectively). The turquoise box in the X chromosome in the maternal grandfather and the mother represent a CGG expansion in the premutation range. It expands to the full expansion in the grandson and causes mental retardation. The grandfather and, more rarely, the mother with the premutation are at risk for FXTAS.
Some of the maternal grandfathers of the boys with FXS carrythe "premutation" on their X chromosome and may develop a progressiveshaking and unsteadiness as they get older. "Ataxia" refersto a problem with coordination and balance. The "tremor" (shaking)and ataxia in FXTAS are due to damage to a part of the braincalled the cerebellum and its connections. In even more rarecases, mothers of boys with FXS who carry the premutation canalso develop FXTAS.
FXTAS generally comes on slowly in men (and rarely women) over50 years old. Problems may include:
Tremor (shaking) that can occur with activity or at rest.
Poorbalance and falls.
Poor hand coordination and unclear speech.
Slow movements, stiff muscles, lack of facial expression andpoor balance that may look like Parkinson disease (PD).
Faintingthat occurs with standing due to a drop in blood pressureandproblems with erection that suggest problems with the autonomicnervous system (part of the nervous system that controls more"automatic" functions such as heart rate, blood pressure, andsweating).
FXTAS has only been recognized in the last 5 years or so andmany doctors are not yet familiar with it. Also, there seemsto be a wide variety of symptoms and signs in different patientsand the disease progresses at different rates. Many patientsmay 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 helpfulbecause it shows some typical changes in an area close to thecerebellum called the middle cerebellar peduncles. The diagnosisis made by finding the premutation in such a patient by DNAanalysis.
At this time, FXTAS cannot be treated with any medication thatwill stop it. However, discovering it brings "diagnostic" closureto patients who may have been told that the cause of their neurologicdisease is "unknown." Also, it is very important for familieswith FXTAS to get genetic counseling because all the daughtersof men with FXTAS will carry the gene defect. This means thatthese daughters can have sons with mental retardation and thedaughter herself may go through early menopause and rarely evendevelop FXTAS.
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.[Abstract/Free Full Text]
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 Full Text]
Kamm C, Gasser T. The variable phenotype of FXTAS: A common cause of "idiopathic" disorders. Neurology 2005;65:190–191.[Free Full Text]
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What is fragile X...
What is fragile X...
