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The many faces of Fragile X syndrome.

Case Presentation: A 56-year-old woman was referred for connective tissue genetic evaluation because of lifelong diffuse joint laxity, with fatigue and pain onset in her 40s. Medical history was notable for premature menopause at age 32 years, and she had an unrevealing endocrine work-up. Her physical examination was notable only for joint laxity. The patient had one miscarriage and an adult son with no learning problems. One of her two sisters had joint laxity and premature menopause at age 31 years. Her brother had minor learning difficulties. Her father had some tremor and gait disturbance in his late 70s and died of unrelated causes at age 78. One of several paternal cousins had premature menopause at age 25 years. Diagnostic testing revealed heterozygosity for a Fragile X syndrome premutation (CGG repeat length 31 for the normal allele; 72 for the premutation allele).

Most physicians are aware that Fragile X syndrome is one of the more common causes of male mental retardation but likely don't expect to encounter it in a practice comprising primarily adults with normal intelligence. While the classic presentation of Fragile X syndrome has a prevalence in the range of 1/2,000 to 1/4,000 males, milder forms and associated conditions now are recognized as occurring much more frequently.

The inheritance of Fragile X syndrome and related disorders is complicated. Excessive expansion of the CGG trinucleotide repeat within the FMR1 gene on the X chromosome is the underlying genetic problem. Normally, there are up to approximately 40-50 repeats, with only rare symptoms occurring in the upper part of this range. More than 200 repeats cause mental retardation in all males and roughly half of females. A slight oversimplification is that anything between approximately 51 and 200 repeats is considered a premutation, with increased risk for clinical manifestations. Recent studies suggest that 0.9%-1.3% of the general female population may be premutation carriers; the prevalence of males with premutations is approximately half that.

Both males and females with premutations are at risk for developing clinical symptoms. True mental retardation is very unlikely, but there is increased risk for mild to moderate learning difficulties and/or developmental delay. Other psychiatric manifestations occur in 20%-45% of people with premutations, including autism spectrum disorder, anxiety, depression, and attention-deficit disorder with or without hyperactivity.

Men and women with premutations may also have some degree of hypotonia and joint laxity, as in the woman described above. These individuals may go through life with pain, fatigue, and mild to moderate psychiatric problems, but with no other features to suggest the underlying diagnosis.

Premature ovarian failure also is associated with FMR1 repeat expansions, potentially including repeat sizes in the up per part of the normal range. Risk estimates for premature ovarian failure range from 15% to 27% for women with 35-80 repeats, compared with 1% in the general population. Interestingly, repeat lengths of more than 80 confer less risk for premature ovarian failure, and there is no increased risk among women with more than 200 repeats.

The most recently recognized complication of FMR1 premutation is the Fragile X Tremor/Ataxia syndrome (FXTAS). This condition is characterized by intention tremor and progressive cerebellar ataxia, beginning as early as the late 50s or 60s, although symptoms might not begin until much later in life. Other manifestations may include memory loss, cognitive dysfunction, parkinsonism, peripheral neuropathy, proximal lower extremity weakness, and autonomic dysfunction.

The overall prevalence of FXTAS among men with premutations is estimated at 40% after age 50 years, starting as low as 17% in the 50s and peaking at 75% beyond age 80 years. FXTAS also has been described in women but is probably less common than in men. Many of the clinical features of FXTAS are not that unusual as sporadic occurrences among a geriatric population and could also be confused with adult hydrocephalus. Thus, it is possible that this condition is widely underdiagnosed.

Testing for FMR1 repeat expansions is widely available through most clinical laboratories and requires only a small blood sample. Some labs also offer testing on a saliva sample.

So why does any of this matter?

Although there is no specific treatment for FXTAS, FMR1-associated premature ovarian failure, or the psychiatric and musculoskeletal manifestations of Fragile X premutation, establishing the correct diagnosis might prevent unnecessary additional testing and procedures.

Of much greater significance, however, is the ability to counsel the patient and his or her family about the risk that a son, grandson, or even great-grandson might be born with the full Fragile X mental retardation syndrome. The complexity of such counseling is beyond the scope of this article.

More information about Fragile X syndrome and related disorders (as well as hundreds of other genetic conditions) is available at Assistance in identifying a genetics clinic is available at the same site, as well as at and

DR. LEVY is an assistant professor in the division of general internal medicine and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore.
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Author:Levy, Howard P.
Publication:Internal Medicine News
Article Type:Case study
Geographic Code:1USA
Date:Dec 1, 2010
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