Fragile X syndrome

Fragile X Syndrome: causation and controversy

What is known as "Fragile X syndrome" actually refers to a specific collection of often quite diverse physical, behavioral, and mental afflictions -- but all have the same genetic origin. The common feature they share is that they are caused by gene changes in the same gene, the FMR1 gene ("What is Fragile X," 2008, National Fragile X Foundation). The condition can be passed on in a family by individuals who have no apparent signs of this genetic condition. Full-blown

Fragile X syndrome usually manifests itself as a mental and social impairment. Individuals often display autistic symptoms, like an inability to speak or relate to others. "Between 5 and 10% of autism cases occur in association with...Fragile X" (Hertz-Picciotto et al. 2006: 1119).

The impairment, which is the most common inherited cause of mental impairment (it occurs in approximately 1 in 3600 males and 1 in 4000 to 6000 females), can also reveal its presence in physical features such as enlarged ears, a long face with prominent chin, and large testicles. Physical complaints Fragile X suffers manifest more than the general population are: frequent ear infections, mitral valve prolapse, flat feet, double-jointed fingers, overly flexible joints and a variety of skeletal problems ("Summary of Fragile X Syndrome," 2008, National Fragile X Foundation).

Overall, females tend to exhibit fewer symptoms than their male counterparts, particularly tremors and hyperactivity. Some females with Fragile X experience early ovarian failure and menopause. Those females that do not suffer early menopause risk having affected children, and in each successive generation of a family with Fragile-X the risk of having affected offspring increases (Nelkin 1996: 538) Older male

Fragile X carriers may exhibit associated tremor/ataxia syndrome, a destabilization of balance, frequent involuntary tremors and memory in some older male gene carriers ("Summary of Fragile X Syndrome," 2008, National Fragile X Foundation). However, not all Fragile X carriers manifest all of these symptoms, just as not all autistic or developmentally delayed person are Fragile X carriers. A genetic test must be done to determine that someone is a Fragile X carrier.

The gene responsible for Fragile X syndrome has been conclusively identified. It is called the FMR1 (fragile X mental retardation 1) gene on the X chromosome. "The gene appears in three forms that are defined by the number of repeats of a pattern of DNA called CGG repeats. Individuals with less than 60 CGG repeats have a normal gene. Individuals with 60-200 CGG repeats have a permutation which means they carry an unstable mutation which can expand in future generations" ("Summary of Fragile X Syndrome," 2008, National Fragile X Foundation). In other words, someone can be a carrier, exhibit no symptoms, but still pass on the trait to his or her offspring because of the potential for this unstable mutation to multiply.

About 20% of males and 70% of females who are carriers exhibit no symptoms of Fragile X (Nelkin 1996: 537). "Individuals with over 200 repeats have a full mutation which causes Fragile X syndrome. The full mutation causes the gene to shut down or methylate a region of the FMR-1 gene. Normally, the FMR-1 gene produces an important protein called FMRP ("Summary of Fragile X Syndrome," 2008, National Fragile X Foundation).

The lack of this specific protein causes the syndrome. Although it is identified with the X chromosome, both males and females can be carriers and manifest the syndrome.

The potential for individuals to be silent carriers is due to the gene's inherent instability, as the gene undergoes frequent changes in its premutation phase before manifesting itself as a full mutation, until FMRP is absent or significantly reduced to produce the full syndrome. "Females with either a premutation or full mutation have a risk to have a child, male or female, with Fragile X syndrome. The magnitude of this risk is related to the number of CGG repeats identified. A male can be a carrier of a premutation; however, the vast majority of males with a full mutation have Fragile X syndrome. A male premutation carrier will pass this premutation (as a premutation, not a full mutation) on to all of his daughters and none of his sons, and therefore, is at negligible risk to have a child with Fragile X syndrome. However, there is a risk for Fragile X syndrome in his grandchildren through his daughters" (Abrams 2008).

Given that it is a genetic disorder, and to address concerns regarding the transmission of the syndrome, in 1995 the American College of Human Genetics issued guidelines for Fragile- X Syndrome testing. It "recommended testing males and females with any physical or behavioral characteristics of the syndrome, individuals with a family history of the disease, and those who, though asymptomatic, were at risk for being carriers" (Nelkin 1996: 537). DNA analysis is required to identify the mutation and permutation, and thus have provided a means of identifying whether someone is a carrier, but tests cannot predict the "phenotype," or how the syndrome will manifest itself in the individual, whether the individual will suffer learning disabilities, hyperactivity, sterility, autism, etcetera (Nelkin 1996: 538).

Although parents of Fragile X children are hopeful that children can benefit through speech therapy, resource room support, and physical therapy, the "benefits of predictive diagnosis for therapeutic or educational intervention are unknown," and it is difficult to predict, given the wide variation of symptoms the system can manifest, and how the disease will progress in any given individual (Nelkin 538). Because Fragile X can go undiagnosed, and the National Fragile X Foundation estimates that 2-3% of children with autism or mental retardation have the syndrome, but are not identified as such. "In 1993, a Fragile-X testing program was organized in the Colorado public school system. This was part of an effort to develop an inexpensive test that could eventually be used as a model for a national program," to identify Fragile X children (Nelkin 1996: 538).

The intention behind the program was to target children with delayed development or autistic-like symptoms, to see if their learning or behavioral problems could be traced to a conclusive genetic cause. At the school, resource room support staff identified children who had the defining characteristics and behavior patterns, and parents were asked to consent to testing, to see if additional diagnostic information could be helpful in dealing with Fragile X problems. "Those who tested positive or were identified as possible carriers were further examined and, if found to be carriers, were offered genetic counseling. However, after two years the program failed to turn up the anticipated number of cases and was suspended" (Nelkin 1996: 538).

Medical ethicists like Dorothy Nelkin oppose such programs, even with the parent's consent, arguing that the school system should treat the symptoms of the syndrome, if it is present -- in short, an autistic-like Fragile X sufferer should be treated in the same method as a child with autism with another cause, just as a Fragile X sufferer experiencing difficulty reading should receive resource room help. The argument is that because the level of impairment is so varied, a relatively mildly impaired child could be unfairly tarnished with the label of hopelessly unable to learn because of a genetic defect. Of course, the issue of genetic testing is, invariably a thorny one, as is the danger of identifying a child with a mild case as 'marked' may do more harm than good, and stigmatize him or her for life. Nelkin even argues that there is a danger that "a false diagnosis of Fragile-X could stigmatize a child as potentially disabled" wrongfully (Nelkin 1996: 540). However, there is no denying that this disease is genetic, and an unidentified individual could pass on the trait to his or her offspring