Saturday, July 07, 2007

Advanced paternal age is associated with an increased risk of new mutations. Fragile X Hemophilia, Duchenne's, autism, schizophrenia

Advanced paternal age is associated with an increased risk of new mutations. All populations are at risk. The relative increased risk for these defects is related to advanced age of the father for autosomal dominant conditions and the maternal grandfather for X-linked conditions. Family histories will not provide clues as these types of mutations are sporadic. Examples of autosomal dominant conditions associated with advanced paternal age include achondroplasia, neurofibromatosis, Marfan syndrome, Treacher Collins syndrome, Waardenberg syndrome, thanatophoric dysplasia, osteogenesis imperfecta, and Apert syndrome Examples of X-linked conditions associated with increased maternal grandfather's age include fragile X, hemophilia A (Factor VIII deficiency), Hemophilia B (Factor IX deficiency), Duchenne muscular dystrophy, incontinentia pigment), Hunter syndrome, Bruton agammaglobulinemia, and retinitis pigmentosa.

1 The FMR-1 gene is located on the X chromosome. This gene is responsible for instructing the cell to make FMRP, a protein assumed to be essential for normal brain functioning.
A Single Gene Disorder
Fragile X Syndrome is a single gene disorder located on the X chromosome. Understanding the basics of fragile X syndrome requires an understanding of how genes themselves are constructed and what they do.
Genes are made up of DNA, which provides the blueprint for life. This blueprint is a code containing four letters (C, G, A, T), abbreviations for four different nucleotides (cytosine, guanine, adenine, and thymine). Nucleotides are the essential building blocks that make DNA. The letters and the sequences in which they are arranged construct the messages that lead the body to produce key proteins.

Fragile X syndrome results from a mutation (a change in the typical DNA sequence) known as trinucleotide repeat expansion. This means that a series of three particular nucleotides (CGG) in the DNA is greatly expanded beyond its normal size, disrupting the normal messages that need to be sent. This fact was discovered in 1991 by several teams of researchers studying the X chromosome.

In the FMR-1 gene located on the X chromosome, most individuals have CGG repeat that occurs between 5 and 50 times, the average being around 30. These individuals are normal with respect to fragile X syndrome, and usually carry no risk of transmitting it, although the 40—60 repeat range is sometimes considered a "gray zone" which may or may not be unstable (have a risk of expanding). Some individuals have CGG sequences that are repeated in the range of about 50 to 200. These individuals are generally referred to as premutation carriers. This means that they carry the syndrome and can transmit it to their children. Premutation carriers, however, are not usually affected by fragile X syndrome. When the number of CGG repeats expands beyond 200, the individual usually has the full mutation. This means that they have fragile X syndrome and will experience the impairments and delays associated with the syndrome.

Detecting Fragile X Syndrome

Fragile X syndrome is detected through a DNA analysis that almost always requires drawing blood. The technique for identifying fragile X syndrome is a specialized process and not all genetic labs have this capability. For those that do have this capability, the procedure is virtually 100 percent reliable. Fragile X can be detected prenatally or in newborns through DNA testing. Also, the carrier status of parents can be accurately determined. However, these tests are not routinely done and must be specifically requested. It is impossible to determine how severely affected the child might be based on this procedure.

Inheriting Fragile X Syndrome

Fragile X syndrome is carried on the X chromosome. Since both males (XY) and females (XX) each have at least one X chromosome, both can be carriers or have the syndrome. If a father is a carrier, he can only pass the gene defect to his daughters, since he transmits a Y chromosome to his sons. All of his daughters will inherit the gene, and as far as is known, transmission from father to daughter only occurs in the premutation state. In other words, if a daughter inherits the gene from her father, she will have the premutation, not the full mutations. Interestingly, this happens even if the father has the full mutation, as the sperm cells of males with the full mutation have been shown to be in the premutation phase.

If a mother is the carrier, she can pass the gene defect to either sons or daughters, since she contributes an X chromosome to each. Children of carrier mothers have a 50 percent chance of inheriting the gene, since the mother has two Xs to give and only one is affected. It is through mothers that the gene can expand from the premutation to the full mutation. So, a carrier mother can have normal children, children with the premutation, or children with the full mutation.

The chances of expansion into the full mutation increase with successive generations. Thus the gene could be passed down in the premutation phase for several generations without anyone suspecting that the family has a genetic disorder that ultimately will lead to mental retardation or other developmental disabilities.

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