Sherman paradox
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The Sherman Paradox refers to an anomalous pattern of inheritance found in Fragile X syndrome.[1] The phenomenon is also referred to as anticipation or dynamic mutation.
The paradox is named after Stephanie Sherman, who studied the inheritance patterns of people with Fragile X syndrome. Sherman observed that the effects of Fragile X syndrome seemed to worsen with each passing generation. This observation is now known as the Sherman Paradox.
The paradox was ultimately explained by insights into the mutation process that gives rise to the syndrome. Sherman theorized that the gene responsible for Fragile X syndrome becomes mutated through a two-step process. The first mutatation, called the 'premutation', doesn't cause any clinical symptoms. A second mutation was required to convert the 'premutation' into a 'full mutation' capable of causing the clinical symptoms associated with Fragile X syndrome. Additionally, premutations must pass through females in order to transform into the full mutation.
The Fragile X syndrome is so named because of the appearance of the X chromosome in individuals with Fragile X. Under an electron microscope, a region on the long arm of the chromosome resembles a thin string. Investigation showed that this region consists of a CGG repeat triplet in both normal and diseased individuals.[1] The difference between normal and diseased is the length of the repeat; the repeat is longer where Fragile X syndrome is present. When the length of the repeat surpasses a critical threshold, symptoms of the disorder appear and they increase in likelihood and severity with further length. Even below this threshold there is a range where the repeat becomes unstable during meiosis.
In normal individuals, an insertion of extra CGGs is unlikely. However, as the length of the repeat increases, the probability of additional triplet insertions increases. When the expansion reaches the danger range, the carrier is still unaffected, but the risk of further mutation becomes significant. This is called the premutation range. Once the Fragile X syndrome emerges, symptoms worsen from generation to generation because of the self promoting aspect of the mutation.
Triplet repeats and disease
A similar mechanism, involving triplet repeats, underlies myotonic dystrophy, spinocerebellar ataxia and Huntington's disease. In Huntington's disease, in contrast to Fragile X, somatic as well as germline mutations occur. Autopsies of affected individuals reveal an accumulation of long repeats of CAG in DNA in the striatum. In both conditions, effects are less severe if the long repeat is interspersed with other triplets.
References
External links
- Anticipation & the Sherman Paradox - jmu.edu
- Genetic Research in Other Neuropsychiatric Diseases - acnp.org
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
