Glossary of Terms

Relating to Fragile X Syndrome, this term refers to an individual that has been diagnosed with Fragile X Syndrome and expresses characteristics of the disorder. The problems may or may not include mental retardation. Some individuals have learning disabilities and/or emotional problems only. The physical features are variable and may or may not be present.

An individual is considered a carrier for Fragile X Syndrome if the FMR-1 premutation is present on one of their X chromosomes.

• Female Carrier: This refers to a female who has been identified as carrying either the premutation, 55 to 200 CGG repeats, or the full-mutation of more than 200 CGG repeats, but is unaffected. Research has shown that a minority of carriers of the premutation may also experience effects. Most common in females is premature menopause, also referred to as premature ovarian failure.
• Male Carrier: This refers to a male that has been identified as carrying the premutation of 55 to 200 CGG repeats and is unaffected and is unaffected by Fragile X Syndrome. These individuals are also sometimes referred to as non-penetrant males. Older male carriers may have problems with tremor and/or ataxia.

This refers to a specific region within the FMR-1 gene containing a repeat sequence of cytosine(C), guanine(G), guanine(G) nucleotide bases that reads CGG-CGG-CGG, etc. The CGG repeat sequence is used to identify those who carry the FMR-1 gene mutation and those that do not. Analyses of variation in length of the CGG repeat region indicate the following pattern:

Although these ranges are most frequently seen, it is possible to receive a result that does not correlate with this chart.

Chromosomes are tiny threadlike structures composed of nucleic acids and proteins that are found in all plant and animal cells. A chromosome contains DNA, which is divided into small units called genes. In general, all chromosomes have similar structures with slight variations. The genes are located at specific sites along the chromosomes. The two arms of the chromosome can usually be identified as the short arm and the long arm. There is a narrow area on each chromosome called the centromere. The centromere is the point that appears to attach to the spindle fibers during mitosis.

Each species has a specific number of chromosomes; humans have 23 pairs of chromosomes. During fertilization the sperm and egg unite making pairs of chromosomes in the new organism, half the number coming from each parent. Although the basic genetic components of heredity are passed equally, they combine themselves in an almost infinite number of ways. When unexpected changes occur in gene combinations, they are called mutations. These mutations can cause physical malformation due to the absence of a substance the body needs for proper functioning.

FMR-1 is a gene whose definition is Fragile X Mental Retardation-1. This gene codes for FMRP. Although the structure of this gene has not fully been characterized, it does contain some unusual elements. These elements include a highly repetitive sequence of molecules (CGG repeats) that appears to lengthen dramatically in affected individuals.

FMRP is a specific protein product of the FMR-1 gene. FMRP has important functions within the cell. These functions particularly impact the way the brain cells work and when FMRP is not present in the brain, mental retardation occurs.

This refers to the FMR-1 gene region in individuals that have CGG repeat numbers of greater than 200. Individuals affected with Fragile X Syndrome have been found to have from 200 to more than 1,000 CGG repeats; these individuals are said to have the full mutation. The extreme amplification of this CGG repeat sequence is likely to be the Fragile X mutation site in the great majority of cases. Males that have greater than 200 CGG repeats will have Fragile X Syndrome. One-half of all females with greater than 200 CGG repeats will have intellectual and cognitive deficits. Of the remaining one half of all females with greater than 200 CGG repeats, 60% will experience learning disabilities.

A unit of inheritance. A part of genetic material that determines the inheritance of a particular characteristic or group of characteristics.  Genes are carried by chromosomes in the cell nucleus and are arranged in a line along each chromosome.

The genetic material is deoxyribonucleic acid, or DNA. The DNA in each chromosome is a single, long, thin, continuous molecule and genes are parts of that molecule. DNA is a chain of minute subunits known as nucleotide bases, so each gene includes many bases. Four different kinds of bases exist in the chain, adenine(A), guanine(G), cytosine(C) and thymine(T), and their sequence in a gene determines its properties.

Genes exert their effects through the molecules they produce, known as proteins. Proteins are chains of amino acids and the sequence of bases in the DNA determines the sequence of amino acids in the protein by means of the genetic code. The sequence of amino acids in a protein dictates whether it will become part of the structure of the organism or an enzyme for promoting a particular chemical reaction. Thus, changes in the DNA can produce changes that affect the structure or the chemistry of an organism.

This form of genetic engineering involves supplying a functional gene to cells lacking that function, with the aim of correcting a genetic disorder or acquired disease. Gene therapy can be broadly divided into two categories. The first is alteration of germ cells, sperm or eggs, which results in a permanent genetic change for the whole organism and subsequent generations. Presently, germ line gene therapy is not considered an option in humans for ethical reasons. The second type of gene therapy, somatic cell gene therapy, is analogous to an organ transplant. In this case, specific tissues are targeted either by direct treatment or by removal of the tissue, addition of the therapeutic gene or genes in the laboratory, and return to the patient.

Experiments with recombinant DNA are closely regulated and those involving infectious agents are permitted only under the strictest conditions of containment. In the United States, experimental protocols for the use of somatic cell gene therapy are reviewed by the National Institute of Health (NIH) and the Food and Drug Administration (FDA). The FDA has already approved human drugs and vaccines, diagnostic devices, and food processing enzymes produced through recombinant DNA technology.

Genetic disorders are diseases resulting from abnormalities in the human genetic makeup. Some genetic disorders are apparent at birth, while others may develop in childhood or adult life. In addition to having a genetic cause, some of these disorders may also be affected by environmental influences, such as diet or lifestyle. Genetic disorders can be inherited, such as Fragile X Syndrome, or somatic, such as cancer. Some genetic disorders may be amenable to gene therapy.

Genetic engineering is a method of changing the inherited characteristics of an organism in a predetermined way by altering its genetic material. This is often done to cause microorganisms, such as bacterial or viruses, to synthesize increased yields of compounds, to form entirely new compounds, or to adapt to different environments. Other uses of this technology, which is also called recombinant DNA technology, include gene therapy.

Genetic engineering involves the manipulation of deoxyribonucleic acid, or DNA. Important tools in this process are restriction enzymes, which are produced by various species of bacteria. Restriction enzymes can recognize a particular sequence of the chain of chemical units, called nucleotide bases that make up the DNA molecule and cut the DNA at that location. Fragments of DNA generated in this way can be joined using other enzymes called ligases. Restriction enzymes and ligases therefore allow the specific cutting and reassembling of portions of DNA. Also important in the manipulation of DNA are vectors, which are pieces of DNA that can self-replicate (produce copies of themselves) independent of the DNA in the host cell in which they are grown. Examples of vectors include plasmids, viruses, and yeast. These vectors permit the generation of multiple copies of a particular piece of DNA, making this a useful method for generating sufficient quantities of material with which to work. The process of engineering a DNA fragment into a vector is called “cloning,” because multiple copies of an identical molecule are produced.

This refers to the FMR-1 gene region in individuals that have CGG repeat numbers between 40 and 54. For reasons that are currently under investigation, some individuals in this range will have a gene that behaves normally, while others will have a gene that behaves like a premutation (a gene that could expand to a full mutation when passed to children).

Methylation refers to a chemical change in DNA structure that alters its activity. In Fragile X Syndrome, a site in the FMR-1 gene located before the CGG repeat sequence can be methylated (have a methyl group attached) or be non-methlyated (have no methyl group attached). If the site is non-methylated, then the FMR-1 gene stays turned on and produces the FMR-1 protein product. If the site is methylated, then the FMR-1 gene is turned off and does not produce the FMR-1 protein product. Usually when there are greater than 200 CGG repeats present, the FMR-1 gene is methylated, or turned off.

This refers to an individual who has DNA test results showing that the cells in their body may vary in the CGG repeat size. An example would be someone with a premutation in some cells and a full mutation in others.

Mutation means change. During the molecular maneuvering that occurs with DNA replication, if nucleotides are lost, rearranged, or paired in error, the resulting change in instruction of the genetic code could lead to a protein that does not function properly. Genetic mutations can be caused by both internal and external factors.

A mutation can lead to a change in an organism resulting from a chemical change in the structure of the gene. Change will first be reflected in the RNA copy, then in the enzyme or other protein that the RNA supervises, and finally in the appearance of new traits in the living organism. The mutation occurs because of the alteration in one or more base pairs of the DNA molecule, garbling the existing genetic code. In the long DNA strand, it takes only a single different pair of bases to produce a different organism. As with other genes, mutations may be either dominant or recessive. Mutations may result in no change in the organism or produce minimal to drastic alterations.

The FMR-1 gene region in individuals that have CGG repeats of an intermediate length, between 40 and 200. Individuals with CGG repeats within this range are said to be carriers. Individuals with a premutation are generally unaffected. Women with a premutation are at risk for having children with a full mutation; the CGG repeat can expand when passed through a woman. Men with a premutation are not generally at risk for having children with a full mutation; expansion is not typically seen in men.

Some genetic disorders result from a mutation in a single gene, which usually results in the absence or alteration of the corresponding protein. Such an alteration may disrupt some metabolic or developmental process, leading to disease. A single gene disorder with a dominant inheritance requires only one copy of a defective gene for the disease to develop. Because males have one X chromosome and females have two, recessive single gene disorders are more likely to affect males than females if the corresponding gene lies on the X chromosome. Fragile X Syndrome is the result of a single gene disorder.

Genetic tests can identify mutations within genes, and therefore offer accurate diagnosis of patients with single gene disorders. These tests can also identify unaffected carriers of genetic disease or even unaffected individuals before onset of their symptoms.