National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland

To complement the 2005 Annual Clinical Focus on medical genomics, AFP will be publishing a series of short reviews on genetic syndromes. This series was designed to increase awareness of these diseases so that family physicians can recognize and diagnose children with these disorders and understand the kind of care they might require in the future. The first review in this series discusses fragile X syndrome. (Am Fam Physician 2005;72:111-3. Copyright© 2005 American Academy of Family Physicians.)

 

Fragile X syndrome is caused by an expansion mutation in the Fragile X mental retardation 1 (FMR1) gene located on the X chromosome. It characteristically leads to some degree of mental retardation. The phenotype is subtle, with minor dysmorphic features and developmental delay during childhood. Characteristic features during adolescence are an elongated face, prominent jaw, large ears, macro-orchidism, and a range of behavioral anomalies and cognitive deficits (Figure 1). Recently recognized manifestations in premutation carriers include premature ovarian failure and tremor/ataxia.1 Premature ovarian failure occurs in up to 20 percent of women who are premutation carriers of the FMR1 gene.1 Fragile X-associated tremor/ataxia syndrome (FXTAS) affects 30 percent of premutation carrier men between the ages of 50 and 60 years, and its prevalence increases with age.1

 

Epidemiology

Fragile X syndrome, the phenotype associated with full mutation, occurs in approximately one in 4,000 men and one in 6,000 to 8,000 women. The premutation in the FMR1 gene occurs in approximately one in 800 men and up to one in 100 to 200 women. Premutation male carriers are susceptible to FXTAS after age 50. Premature ovarian failure may be detected in as many as one third of women with a premutation.

 

Clinical Presentation

Although fragile X syndrome occurs in males and females, females generally present with milder symptoms. The first clinical clue in children often is delayed attainment of one or more developmental milestones.2,3 On average, boys with fragile X syndrome sit without support at 10 months of age and walk and talk at 20 months.2 With few exceptions, affected males have mental retardation, generally of moderate degree. About one third of affected females have mild to severe mental retardation.2 There is a specific pattern of deficits in abstract reasoning, sequential processing, and mathematics. Clinical findings during early childhood may include macrocephaly and frontal bossing (unusually prominent forehead). After puberty, macro-orchidism is present in affected men. Additional findings may include strabismus and mild connective tissue dysplasia, such as mitral valve prolapse, hyperextensible joints, and pes planus. Behavior is characterized by attention deficits, hand flapping, hand biting, and gaze aversion. Family physicians are most likely to encounter the undiagnosed child before school age, when formal testing can confirm cognitive deficits. However, the average age of diagnosis currently is eight years, reflecting the subtlety of features in young children.4

 

FXTAS is a neurodegenerative disorder with progressive intention tremor and cerebellar ataxia.5 Affected persons present with parkinsonism, peripheral neuropathies, and dementia after age 50 years.

 

Premature ovarian failure may occur as an isolated clinical finding in women with premutations.1,6 Follicle-stimulating hormone (FSH) levels are elevated in these women even before the onset of premature ovarian failure. Approximately 1 percent of women in the general population have premature ovarian failure, but the prevalence in women with a premutation is 30 times higher.6 Women who are infertile and have prematurely elevated FSH levels should be considered for carrier status testing of the FMR1 premutation. A family history of FXTAS or premature ovarian failure in a child with cognitive deficits is another indicator to initiate genetic testing for fragile X syndrome .

 

Diagnosis

The diagnosis of fragile X syndrome is confirmed by molecular genetic testing of the FMR1 gene. Prenatal testing is available. FMR1 is characterized by a repetitive CGG trinucleotide sequence, which is repeated six to 50 times in unaffected persons (Figure 2). A full mutation consists of more than 200 CGG repeats in the FMR1 gene, plus hypermethylation, which leads to an inability to produce the FMR1 protein. Almost all males and more than one half of females with full mutations have fragile X syndrome.2 Premutation carriers, who have between 50 and 200 CGG repeats, are not cognitively affected but may have physical or psychiatric findings. In addition, they are susceptible to developing premature ovarian failure and FXTAS. Rarely, the fragile X phenotype occurs in a premutation carrier if hypermethylation is present. Conversely, the phenotype may be absent in a person with a full mutation without hypermethylation, confirming that fragile X syndrome results from the absence of FMR1 protein.

 

Genetic Counseling and Inheritance

Fragile X syndrome is an X-linked inherited disorder. It is important to diagnose affected patients as early as possible to provide early intervention and supportive care (i.e., specific developmental therapy and an individualized education plan) and to inform parents for further family planning. One half of families in a 2002 survey4 reported having an additional child with fragile X syndrome before the older affected child was diagnosed. Family history collection should include questions about other family members, with particular attention to developmental delay, mental retardation, and psychiatric disorders. In addition, a family history of women with premature ovarian failure and men with FXTAS should be ascertained. A positive family history in a proband with developmental delay should prompt consideration of genetic testing of the FMR1 gene. The American College of Medical Genetics7 recommends testing, regardless of family history, for all males and females with mental retardation of unknown etiology.

 

Management

Treatment is supportive, requiring a multidisciplinary team and including anxiety-reducing measures, behavior modification, and medications to manage associated psychiatric disorders. Individual education plans are necessary for school-age children.

 

Resources

Additional information about the diagnosis and management of fragile X syndrome is available at the following Web sites: National Fragile X Foundation (http://www.FragileX.org); GeneTests (http://www.genetests.org); and the American College of Medical Genetics (www.acmg.net/resources/policies/pol-014.asp).

 

REFERENCES

1. Hagerman PJ, Hagerman RJ. The fragile-X premutation: a maturing perspective [published correction appears in Am J Hum Genet 2004;75:352]. Am J Hum Genet 2004;74:805-16.

2. Maes B, Fryns JP, Ghesquiere P, Borghgraef M. Phenotypic checklist to screen for fragile X syndrome in people with mental retardation. Ment Retard 2000;38: 207-15.

3. Shevell M, Ashwal S, Donley D, Flint J, Gingold M, Hirtz D, et al. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society. Neurology 2003;60:367-80.

4. Delayed diagnosis of fragile X syndrome-United States, 1990-1999. MMWR Morb Mortal Wkly Rep 2002;51:740-2.

5. Jacquemont S, Hagerman RJ, Leehey MA, Hall DA, Levine RA, Brunberg JA, et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004;291:460-9.

6. Machado-Ferreira Mdo C, Costa-Lima MA, Boy RT, Esteves GS, Pimentel MM. Premature ovarian failure and FRAXA premutation: positive correlation in a Brazilian survey. Am J Med Genet A 2004;126:237-40.

7. American College of Medical Genetics. Fragile X syndrome: diagnostic and carrier testing. Accessed online May 31, 2005.

 

Fragile X-Related Disorder Difficult to Diagnose

 

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 www.neurology.org.

 

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 www.aan.com.

 

Fragile X and Company: Finding the Right Diagnosis

S. H. Subramony, MD, Christopher Freidrich, MD and Janet Jankowiak, MD

The Patient Page - at www.neurology.org

 

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).

www.thebrainmatters.org

American Academy of Neurology

www.aan.com

National Fragile X Foundation www.fragilex.org

  

References

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.