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Subtelomeric rearrangements in unexplained intellectual disability

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Also listed as: Intellectual disability
Related terms
Background
Methods
Research
Implications
Limitations
Safety
Future research
Author information
Bibliography

Related Terms
  • CGH, chromosomes, comparative genomic hybridization, cytogenetics, developmental delay, deoxyribonucleic acid, DNA, FISH, genetics, genome, impaired cognition, intellectual disability, IQ, learning difficulty, learning disability, M-TEL, MAPH, mental handicap, MLPA, molecular genetics, multiallelic marker analysis, multiplex amplifiable probe hybridization, multiplex FISH telomere integrity assay, multiplex ligation-dependent probe amplification, multiprobe fluorescence in situ hybridization, PCR, polymerase chain reaction, quantitative real-time PCR, primed in situ labeling, PRINS, S-COBRA FISH, SKY, spectral karyotyping, subtelomeric combined binary ratio labeling FISH, subtelomeric rearrangements, telomeres, telomeric multiplex FISH, TM-FISH.

Background
  • Intellectual disability, formerly known as mental retardation, is a common condition, affecting about 3% of the population.
  • The intelligence quotient (IQ) is a ratio of a person's performance on certain intelligence tests compared with the average for all persons of that age. Normal, or average intelligence, is defined as an IQ of around 100. People with moderate to severe intellectual disability, defined as an IQ of less than 50, generally require institutional care. People with mild intellectual disability (IQ of 50-75) generally need assistance to meet their basic survival needs, and about half are significantly impaired throughout life. With IQs above 75, abilities progressively increase from menial tasks to theoretical physics.
  • Although intellectual disability carries with it immense clinical, social, and psychological burdens, its origins remain poorly understood. Prenatal conditions such as infection, malnutrition, or drug exposure; mishaps during childbirth; social disadvantages such as poor nutrition, unsanitary living conditions, or physical abuse; and heredity have all been identified as factors associated with intellectual disability. So far effective treatments have not been developed because the damage to the brain is permanent.
  • There is no known cure for intellectual disability. It may be possible to prevent intellectual disability in some children through improved medical care during pregnancy and childbirth and efforts to improve living conditions among the poor.
  • Among the common causes for intellectual disability is genetic damage. When intellectual disability is due to genetic damage, it is often accompanied by physical malformations because the disturbances in the genetic code extend to multiple organ systems. The typical characteristics of Down syndrome, for example, include poor muscle tone, a single crease across the palm of the hand, a slightly flattened facial profile, and an upward slant to the eyes. Other, more serious, problems can occur anywhere in the body. Heart or other internal organ defects and facial or limb deformities are a reliable indication of a genetic cause associated with the intellectual disability.
  • Genetic damage can occur when genes are not copied perfectly from one generation to the next. Although there are systems in place to prevent and repair copying errors, errors may still occur. A single error can cause a host of defects, and intellectual disability is one of the more common. There are many different types of errors. Genes can be duplicated, missing, misplaced, broken, or miscopied from their parent molecule. At first it was believed that genes provided instructions only for making proteins, but it now appears there are many other functions for genes.
  • Scientists are now able to explore in great depth the genetic causes for intellectual disability. Previously, only gene defects large enough to be seen under a microscope, such as those that cause Down syndrome, could be detected. Techniques in molecular biology, the study of the chemicals of life, are now available for researchers to identify errors in genes so small they are not visible even by an electron microscope. This is the result of the Human Genome Project, an expensive, exhaustive work that identified the complete chemical structure of human DNA (deoxyribonucleic acid). DNA is made up of a linear series of four chemicals that encodes the complete instructions for building a human being. The chemicals are denoted by letters that indicate their linear arrangement on the very long DNA molecule. If the complete code were printed in an ordinary book, the book would be 1.5 million pages long. Among the many errors that can occur in copying the genetic code, very small mistakes in telomeres, "subtelomeric rearrangements," have been identified in patients who have intellectual disability. A telomere is a segment of DNA at each end of a chromosome. Telomeres do not code for proteins, but rather are involved in the process of cell division.

Methods
  • General: There are many methods now available to analyze the structure of a person's DNA and to identify errors at the molecular level that lead to problems such as intellectual disability. The list of currently available methods includes multiprobe fluorescence in situ hybridization (FISH), multiallelic marker analysis, multiplex amplifiable probe hybridization (MAPH), multiplex ligation-dependent probe amplification (MLPA), quantitative real-time polymerase chain reaction (PCR), comparative genomic hybridization (CGH), and multicolor FISH, including spectral karyotyping (SKY), subtelomeric combined binary ratio labeling FISH (S-COBRA FISH), multiplex FISH telomere integrity assay (M-TEL), telomeric multiplex FISH (TM-FISH), and primed in situ labeling (PRINS). Each method has its particular application in the search for causes of disease. Using these advanced techniques it is now possible to identify molecular changes that are related to conditions such as intellectual disability. These changes have been found in genes that code for proteins and also in segments of DNA that do not code for proteins, such as telomeres. Two of the most commonly used methods in this field are PCR and DNA microarrays. The other methods listed above are variations on these specimen amplification and visible marker techniques.
  • Polymerase chain reaction (PCR): Polymerase chain reaction (PCR) is a technique that multiplies a single piece of DNA, RNA (ribonucleic acid), or protein hundreds of times so that it can be detected by fluorescence. Fluorescent labeling is a complex process that occurs in several steps. The first step is to create a "probe" that identifies a specific segment of genetic code. The probe attaches only to that specific piece of genetic code. The second step is to make the probe glow under ultraviolet (UV) light by hooking a fluorescent chemical to it. The third step is to mix the probe with the genetic material. The probe will attach to the segment of interest and, if present, will glow under the UV light.
  • DNA microarrays: It is now possible to search for hundreds or even thousands of gene pieces at once using many probes in a single test. This process is called DNA microarray testing. In this process a large number of tiny wells are created in a solid substrate such as a gel. A marker, or probe, is placed into each well and will attach to only one specific DNA molecule. When a solution of DNA molecules is washed through the wells, each marker picks up its specific molecule. When the whole array is analyzed, the DNA molecules that are picked up can be seen because their marker glows.

Research
  • Genes from hundreds of persons with intellectual disabilities have been tested by medical researchers using numerous gene and DNA segment identification techniques. About 5% of them have errors in their DNA. Some of these errors are found in the telomere segments of the DNA. Other errors are found in the chromosomes and in the protein-coding genes.
  • Current research is limited to data collection. Practical uses for the knowledge gained from correlating subtelomeric rearrangements with the types of mental and physical disabilities they cause are at least a generation away.

Implications
  • So far research has only identified relationships between intellectual disability and genetic changes. The genetic error in Down syndrome was identified years ago, for example, and still nothing can be done to prevent or treat the condition.
  • The process of biological and medical research begins with very basic knowledge and builds methodically upon that foundation. Medical knowledge has been increasing steadily for the past 400 years, and still we have no cures for most diseases. It is naive to expect early research such as the discovery of subtelomeric rearrangements to yield clinical uses in the same generation. Treatment is the second to last step in the discovery process with cures being the final achievement. Only from an understanding of the basic mechanisms of disease, meticulously worked out by many researchers through much trial and error, great lengths of time, and huge expense, can progress be eventually made toward useful applications.

Limitations
  • One of the limitations of this technology is that it is very new and is still in the discovery stage. Effective prevention and treatment based on knowledge gained from subtelomeric rearrangements will take time to materialize.

Safety




Future research
  • Medical science is just passing the threshold of molecular medicine. Agents such as bevacizumab, imatinib, and etanercept are targeted therapies being used against gene products that cause cancer and chronic diseases such as rheumatoid arthritis. For example, if a subtelomeric rearrangement can be shown to result in a protein or other chemical that causes intellectual disability, a targeted agent can be created to block the production or the action of that protein. Researchers are currently seeking such chemicals for the treatment of Alzheimer's disease.
  • In time, the genes themselves may be targets for modification. Already, genes have been introduced into agricultural products and laboratory animals using viral vectors. A very few early studies have been attempted in humans, but the results have not yet been encouraging.
  • Cancer and chronic diseases such as arthritis, Alzheimer's disease, psoriasis, diabetes, and atherosclerosis are prime targets for genetic modification. Intensive research is currently underway in these diseases to identify and modify their genetic causes.

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography
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