The fragile X syndrome is one of the most prevalent mental retardation problems that are inherited to generations. The clinical features of people with this syndrome are very subtle and hard to diagnose. Recent progress in the field of molecular biology and genetics has outlined the molecular mutation, that causes the syndrome was a triplet repeat mutation. Due to repetitive CGG repeat the respective proteins are not expressed. New molecular methods including direct probe analysis and pcr analysis, have simplified the process of diagnosis. The nature of the gene, their respective gene product and its function has not been yet found clearly. Inheritance may be found due to common ancestral flow of X chromosome at birth.
Fragile x syndrome is a genetic disorder that affects the intellectual, physical and mental factors of a human being. It is also known to be martin-bells syndrome and the effects range widely from mild to severe. It is caused by the mutation on the x chromosome of the individual in a single gene called the fragile x mental retardation gene (FMR1).
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Psychological problems such as mental retardation may be caused by two main factors, the physical environment or the genetic factor that is hereditary. As we mainly focus on the genetic factor the fraxa locus in xq27.3 is associated in causing fragile x mental retardation. Therefore based on molecular genetic testing of FMR1 gene fragile x syndrome can be diagnoised. Women are only 50% affected by this syndrome when compared to males due to the fact that they have two x chromosomes where as males have one. Most common symptoms found are seizures, mood instability, attention deficit, sensory over stimulation, aggression, autism, speech disorder and sleep differences.
This syndrome also shows certain physical symptoms such as long narrow face, large ears enlarged testacles in males, flexible joints etc., various research is being done across the world to find a solution for the disease.
Various genetic techniques has been developed and handled to identify the fragility of the chromosome. There has been so much improvement in research but a definite solution has not been obtained. The treatment for this syndrome is usually a multidisciplinary approach which includes occupational therapy, medical managements, education and linguistics.
THE FRAGILE X MUTATION:
Genes are the precursors of specific protein molecules which in turn are specific for various functions of the body. The major cause for the fragile x syndrome is due to the mutation in one single gene called the fragile x mental retardation 1 (FMR1) gene which is the precursor for the fragile x mental retardation protein FMRP. This protein is responsible for the normal development and functioning of the brain. Men have only one x chromosome so presence of mutation in that chromosome will cause the disease whereas in females, they have two x chromosomes and hence full mutation in one copy makes them carriers of the syndrome and they may be affected partially according to the amount of mutation and number of cells expressing the FMR-1 gene copy. The inheritance found on the chromosomes is termed as x linked recessive inheritance which is more complex than the normal x linked genes.
Fig.1 X chromosome with fragile site Fig. 2 A photograph of X chromosomes showing a fragile site from both a male and a female
The number of CGG repeats on the FMR-1 gene determines the complexity of the syndrome. The repeats are classified as short, medium and long repeats. The short repeat of about six to fifty times which is found very common. These short repeats are mostly unstable and do not definitely cause the syndrome. Yet a genetic counseling along with certain tests are recommended. The medium repeat is about 50 to 200 times and is called permutation. They to
The fragile x mental retardation protein (FMRP) have lower risk of the syndrome as short sequence repeats. The long repeats are usually more than 200 and is termed as full mutation where the complete FMR-1 gene is altered and production of the FMRP protein is totally stopped. Among the people with full mutation or long repeats, men will have the fragile x syndrome and women will be carriers.
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Fragile x mental retardation protein (FMRP)
The FMRP protein is found in the ribo nucleoprotein complex and is encoded by the FMR1 gene. The FMRP weighs upto 60-70 kD. This protein is associated with the polyribosomes or polysomes. Two RNA-binding domains, KH domains or K homology domains are possessed by this protein and it binds to fetal human brain to 4% approximately. It also has the ability to bind to its own mRNA. Even a small amount of mutation in one of the KH domain could stop its interaction with the polysomes leading to the fragile x syndrome.
Inheritance of fragile x syndrome
Males have xy chromosome and hence have only one FMR-1 gene where as females have xx chromosomes and hence they have two FMR-1 genes. On the F1 generation each parent transfers one chromosome each to the offspring where the transfer of the FMR-1 gene is determined. Therefore the possibilities of their offspringââ‚¬â„¢s being affected are grouped under two conditions.
If a male has a mutated gene in his chromosome it can be transferred only to his daughter because only the Y chromosome can be transferred to his son by him. So if he was crossed with a female with normal genes all their sons will be normal and the daughters will have one fragile gene and remain as carriers.
If a female has one mutated gene in her chromosome and is crossed with a normal male then there is 50% chance of all the offspringââ‚¬â„¢s, be it male or female to have the syndrome.
The symptoms of fragile x syndrome are categorized into
Social and emotional
Speech and language
Rapid and repetitive
Inability to adopt words
Flapping of hands
Poor eye contact
All these symptoms need not be necessarily seen. A combination of various symptoms may vary from person to person based on the amount of gene altered in their chromosome. Sometimes there may also be no visible symptoms making the chances of early diagnosis even worse.
Diagnosis ââ‚¬" Tools and Methods
With the advancement in technology DNA tests are always effective in diagnosis of fragile x syndrome. With the findings of Sutherland et al. that folic acid deficient cell culture medium was able to induce a fragile site at xg27.3 cytogenetics was the major way to determine the presence of the syndrome but after cloning of the FMR-1 gene direct methods for identifying the x linked gene has become possible. by using monoclonal antibodies specific to FMRP it is also possible to show the expression of FMR-1.
The most common methods used for diagnosis in the genetic level are
polymerase chain reaction
non-radioactive molecular diagnosis.
Polymerase chain reaction
Polymerase chain reaction may be defined as a technique where one copy of a DNA is amplified into numerous copies at a rate of 2n where n is the number of cycles. It is achieved under specific conditions of temperature, along with polymerase enzyme.
PCR amplification is one of the preliminary methods in diagnosing fragile x syndrome. Since the syndrome is associated with CGG repeats PCR is not considered as the best method always, since the amplification across C-G composition could be unreliable for PCR technique. However now its very much possible for a PCR to identify CGG repeats in combination with various techniques.
methylation specific PCR of the FMR1 locus
fluorescent methylation ââ‚¬" specific PCR
Some of the major advantages of PCR is that it is less time consuming, a very small amount of the sample is enough to produce numerous copy and the tri-nucleotide repeat in the FMR-1 gene is accurately sized. There are also various disadvantages of this technique. When there are more than hundreds of tandem repeats it is impossible for the PCR to determine the complete mutation which may give a different result. Due to differential amplification PCR is incapable of detecting mosacism between pre mutation and normal alleles.
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Southern blotting is one of the best methods of diagnosing fragile x syndrome. It is modtly used as the confirmatory test after PCR. The variations between the mutations and permutations along with the amount of methylation occurred can be clearly obtained by the southern blotting technique. The process can be summed up in two simple steps:
Step 1: the patients DNA is digested using restriction enzymes.
Step 2: southern hybridization is carried out along with specific radioactive probes after separation of FMRI region.
Using southern blotting the differences in full mutation and pre mutation can be easily identified. Full mutations usually cause smearing of the band and are always unstable. The only advantage of this technique is that its accuracy whereas its labor intensive, time consuming. The major drawback of this method is its inability to determine the exact number of tandem repeats of the CGG nucleotides which is very much necessary in determining whether the patient is completely affected or a carrier.