Fragile X and company: Finding the right diagnosis

Definition of Advanced paternal age

Advanced paternal age: A man who is age 40 years or older at the time of conception. (There is no universally accepted definition of advanced paternal age but this criterion is often used in genetic counseling.)

Advanced paternal age is associated with an increased risk of new mutations in the offspring. This risk for genetic defects does not increase dramatically at age 40, but rather increases linearly with the age of the father. The risk of genetic defects due to new dominant mutations is 4 to 5 times greater for fathers aged 45 and above than for men in their early twenties.

There are two types of paternal age effects. One relates to the autosomes and the other to the X chromosome. New autosomalmutations for dominant conditions show up in the children. Their diseases are due directly to advanced paternal age.

New mutations on the X chromosome are usually not evident in the children. They are transmitted to daughters who are at risk for having sons with X-linked diseases. This is an indirect paternal age effect; it is the effect of the age of the maternal grandfather.

Examples of autosomal dominant conditions associated with advanced paternal age include achondroplasia, neurofibromatosis, Marfan syndrome, Treacher Collins syndrome, Waardenburg syndrome, thanatophoric dysplasia, osteogenesis imperfecta, and Apert syndrome.

Examples of X-linked conditions associated with increased maternal grandfather's age include fragile X, hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), Duchenne muscular dystrophy, incontinentia pigmenti, Hunter syndrome, Bruton-type agammaglobulinemia, and retinitis pigmentosa.







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Experts call for universal fragile X screening
Andrea Anderson
1 Apr 2008 1:01 PM

Clean sweep: Universal screening would detect evenasymptomatic carriers of fragile X.
Screening for genetic precursors to fragile X syndrome, the most well established genetic risk factor for autism, should be expanded to all women who are pregnant or plan to be, some geneticists say.
Prenatal fragile X testing is generally reserved for those women who have a family history of fragile X syndrome. But a study published online on 19 March suggests that doctors should be more vigilant about screening women who could be carriers of the disease — for example, those with autism or other behavioral conditions1.
Some fragile X carriers have no obvious risk factors. “Nothing short of universal screening” would detect those carriers, says author Owen Phillips, an obstetrician and medical geneticist at the University of Tennessee Health Sciences Center. “A lot of people are recommending universal screening.”
Fragile X syndrome is the most common inherited form of mental retardation, affecting about 1 in 4,000 males and 1 in 8,000 females. The syndrome is characterized by delayed learning and unusual facial features, including elongated heads and large, pronounced ears. A subset of those who have fragile X — between 5 and 60 percent — are also diagnosed with autism spectrum disorders.
Unlike autism however, fragile X is known to be a monogenic condition: it is caused by a mutant version of a single gene on the X-chromosome called FMR1. Three bases in a regulatory region of the FMR1 gene are repeated as many as a few hundred times, altering or inactivating the gene. FMR1 gene codes for a protein called fragile X mental retardation protein, believed to influence the activity of some glutamate receptors in the brain.
The severity of fragile X depends on the size of the expansion in FMR1. Someone with 55 to 200 DNA sequence repeats has what’s called a pre-mutation, whereas those with 200 or more are classified as having the full mutation.
Better tests:
At one time, fragile X testing was limited to looking for kinks in the X chromosome, but the discovery of FMR1 in the early 1990s opened the door for DNA-based tests. Molecular techniques such as PCR and Southern blot analysis can be used in tandem to detect the size of FMR1 expansions and subsequent genetic modifications.
With the advent of these molecular tests, “It’s like night and day,” says Flora Tassone, a biochemist at the University of California at Davis’ MIND Institute. “Now we can really screen both genders for normal [sequence], pre- and full mutations.”
The tests are primarily used diagnostically — for instance, for children with unexplained mental retardation, developmental delays or autism. But they can also be used to screen asymptomatic X carriers with a family history of fragile X. “The problem is that there are not very good numbers [regarding carriers],” Tassone says. “There’s not very good epidemiology.”
The American College of Obstetricians and Gynecologists2 and the American College of Medical Genetics3 both recommend prenatal testing for fragile X if the mothers-to-be are known carriers of a fragile X mutation.
But those with pre-mutations often don’t have symptoms, and if they do, have different features that appear later in life. In the latest study, for example, the researchers looked at family histories for 17 children diagnosed with fragile X syndrome.
What they found was surprising: though the mothers are all carriers of pre-mutations, only eight — who came from families with a history of fragile X syndrome or unexplained mental retardation — had risk factors that would definitely raise red flags. Five others had relatives with autism, speech or hearing problems, attention deficit hyperactivity syndrome or other behavioral disorders. Four had no established risk factors.
More carriers would be detected if testing guidelines were followed in their broadest sense, Phillips says. “If they had a very low [testing] threshold, they might have picked them up.” One reason is that the tests are relatively expensive and many doctors lack the experience to interpret the results. That means trained genetic counselors may need to help families decipher the results of the test and the implications.
Universal screening is also controversial because there’s no cure for fragile X. Still, there are early interventions that can benefit those with Fragile X syndrome. As Phillips, says, “Fragile X is more common than Down Syndrome and we do extraordinary things to detect Down Syndrome.”
References:
Rajendra K. et al. Am. J. Obstet. Gynecol. in press (2008) PubMed ↩
American College of Obstetricians and Gynecologists Committee on Genetics Obstet. Gynecol. 107, 1483-1485 (2006) PubMed ↩
Sherman S.S. et al. Genet. Med. 7, 584-587 (2005) PubMed ↩
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NEUROLOGY 2005;65:E3-E4
© 2005 American Academy of Neurology --------------------------------------------------------------------------------
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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 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.,1 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.,2 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,3 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 (table 1). 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.




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Table Guidelines for genetic testing for fragile X in older persons with neurologic disease








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.





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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 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

www.thebrainmatters.org

American Academy of Neurology

www.aan.com

National Fragile X Foundation www.fragilex.org


References






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]