Sherman Paradox While the location of this fragile site established that fragile X syndrome was indeed X-linked,

inheritance of this disorder was clearly not typical of other X-linked disorders. At first, it was believed that fragile X syndrome was an X-linked recessive genetic disorder. However, there were many observations inconsistent with this inheritance pattern. If the disorder was truly inherited in an X-linked recessive manner, heterozygote carrier woman would not display any characteristics of the syndrome, and all carrier males would. But there were reports if affected females, and of males who carried the fragile site but were unaffected.

Because of these observations, Stephanie Sherman and her colleagues studied the inheritance pattern of fragile X syndrome more closely. They demonstrated that the risk of expressing mental retardation was dependent on the individual s position in the pedigree, with risk increasing in later generations. The daughter of an unaffected male carrier was more likely to have affected offspring than the mother of the unaffected male carrier was: something had changed on the X chromosome over the 2 generations. This observation became known as the Sherman paradox and was crucial to the understanding of the genetic mutation that causes fragile X syndrome. The Sherman Paradox refers to an anomalous pattern of inheritance found in Fragile X syndrome. The phenomenon is also referred to as anticipation or dynamic mutation. The paradox was ultimately explained by insights into the mutation process that gives rise to the syndrome. Sherman and her colleagues hypothesized that the gene responsible for Fragile X syndrome becomes mutated through a two-step process: 1. Premutation Does not cause any clinical symptoms premutations must pass through females in order to transform into the full mutation

2. Conversion to Full mutation Required to convert the permutation into a full mutation capable of causing the clinical symptoms asscociated with Fragile X syndrom

A (CGG)ntrinucleotide repeat located in the coding sequence of a gene of unknown function. The repeat is capable of expanding as it passes to successive generations. The number of repeats in normals ranges from 6 to 50. When the number expands into the range of 50-200 repeats it is termed a pre-mutation because it is prone to further expansion into a range of from 200 to over 1,000 repeats. This last expansion causes the fragile X syndrome. The Sherman paradox was explained by the observation that pre-mutations must pass through females to expand and cause the syndrome. The probability of expansion increases with the existing size of the repeat, and this explains another genetic paradox anticipation: the tendency for some diseases to exhibit earlier onset, increased severity, or greater penetrance in successive generations. It should be reassuring to behaviour geneticists that a complex pattern of inheritance at the phenotypic level was accounted for by a simple mechanism once the genetics were understood. Since Fragile X syndrome is an X-linked disorder, According to sources, it cannot be resolved and it can worsen with each passing generation but it can be managed by using drugs such as Trazadone and Melatonin for sleep disturbances, Fluoxetine (Prozac) and Setraline (Zoloft) for aggression, obsessive compulsive disorder and intermittent explosive disorder. For attention deficit (with or without hyperactivity, Methylphenidate (Ritalin, Concerta), Folic acid and dexamthamphetamine (Adderall, Dexedrine) can be used. Other drugs such as Carbamazepine (Tegretol), Valproic acid or divalproex (Depakote) are genetic medications that can be used for seizures and mood instability. References: Internet: http://www.gale.cengage.com/pdf/samples/sp656067.pdf http://en.wikipedia.org/wiki/Sherman_paradox http://www.acnp.org/g4/GN401000176/CH172.html