Magazine article The Exceptional Parent

Recent News about Fragile X: What's All the Fuss about? (Research Reflections)

Magazine article The Exceptional Parent

Recent News about Fragile X: What's All the Fuss about? (Research Reflections)

Article excerpt

This April brings more than showers and taxes. It is the 50th anniversary of the unveiling of the double helix model of DNA by James Watson and Francis Crick. It is also the time (or close to the time) that the completed sequence of the human genome is expected. "Compared with the knowledge to be gleaned from the genome, the whole of the rest of biology is but a thimbleful," wrote Matt Ridley in his book, Genome.

So, what's all the fuss about? Some fear the new knowledge that decoding of the human genome brings. On a positive note, such knowledge may produce treatments based on information available at birth, based on one's chromosomes rather than on one's symptoms. Ultimately, according to Francis S. Collins, M.D., Ph.D. and Director of the Human Genome Institute of the National Institutes of Health, the unraveling of the human genome will help to identify the causes of many rare diseases and disorders. However, Dr. Collins is cautious with regard to conditions that have affected a child's brain development. He told EP (October, 2002), "The idea of being able to fix a condition where there are multiple genes present in too many or too few copies, as in the case of many chromosomal disorders, is difficult to contemplate at the present time." Such is the case with fragile X syndrome (FXS).

Why fragile X? I have chosen fragile X (FXS) for this month's Research Reflections because there is a rapidly growing body of research on how new knowledge about the genetics of this disorder impacts families. Furthermore, fragile X is currently the most common inherited cause of mental retardation. We know a great deal about this disorder, from detailed descriptions to explanations of the disorder's heritability to the dilemmas posed in identifying the odds for carrying or expressing the disorder.

Bear with me for a brief mini-lecture. Fragile X syndrome is an outcome of gene malfunction. It involves a mutation of the FMR1 gene on the X chromosome. Matt Ridley eloquently describes the process as a "stuttering repetition" of the protein CGG. In the normal case, individuals have roughly 6 to 54 CGG repeat sequences; carriers have 55 to 200 repeats, but themselves are unaffected. A full mutation involves over 200 repeats, with up to 1,000 repeats possible; at this point the production of the FMR1 protein is turned off completely. The lack of the FMRP protein (made by the FMR1 gene) is what causes the disorder known as fragile X.

The inheritance pattern of FXS is complicated, but well enough understood. Most individuals have a stable pattern of the FMR1 gene and pass that on. The unstable version is referred to as a permutation; males with this will pass it on to all of their daughters but to none of their sons (because sons inherit their X chromosome material from their mothers). Each child born to a woman with a permutation has a 50% chance of receiving it. In addition, the longer the repetition sequence of CGG, the longer it is likely to grow when copied for the next generation.

What are the consequences of having fragile X? There are a variety of physical and behavioral features (or "phenotypes") seen in males with fragile X; these are usually seen in a smaller percentage of females, and to a lesser degree. Only about a third of females will have significant intellectual disability, because they have two X chromosomes with genetic material so one can compensate for a nonfunctioning gene on the other X.

Fragile X syndrome can result in intellectual impairment ranging from subtle learning disability to severe mental retardation, or even autistic-like behavior. A variety of maladaptive behaviors have been ascribed to individuals with full mutation fragile X. They include the following (though all of these would rarely be seen in one individual): gaze avoidance, attention deficits, hyperactivity, shyness, social isolation, social anxiety, perseveration, hyperarousal, tactile defensiveness, self-injury, stereotyped behavior, low self-esteem, depressive features or oddities in thinking and affect. …

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