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The Fragile X Syndrome

The delicate X syndrome is one of the most prevalent mental retardation issues that are inherited to years. The specialized medical features of men and women with this symptoms are very understated and hard to diagnose. Recent improvement in the field of molecular biology and genetics has outlined the molecular mutation, that triggers the symptoms was a triplet repeat mutation. Because of repetitive CGG repeat the respective proteins are not portrayed. New molecular methods including immediate probe analysis and PCR examination, have simplified the process of diagnosis. The nature of the gene, their respective gene product and its function is not yet found clearly. Inheritance may be found due to common ancestral circulation of X chromosome at birth.


Fragile S symptoms is a hereditary disorder that affects the intellectual, physical and mental factors of the human being. It is also known to be martin-bells symptoms and the consequences range widely from minor to severe. It really is triggered by the mutation on the X chromosome of the average person in a single gene called the Fragile X mental retardation gene (FMR1). Subconscious problems such as mental retardation may be caused by two main factors, the physical environment or the hereditary factor that is hereditary. Even as mainly concentrate on the genetic factor, the FRAXA locus in xq27. 3 is associated in leading to fragile X mental retardation. Therefore based on molecular genetic evaluation of FMR1 gene, fragile X syndrome can be diagnosed. Women are just 50% influenced by this symptoms when compared to males due to the fact that they have two X chromosomes where as guys have one. Most usual symptoms found are seizures, feelings instability, attention deficit, sensory over arousal, aggression, autism, talk disorder and sleeping differences. This syndrome also shows certain physical symptoms such for as long slim face, large ears enlarged testacles in guys, flexible bones etc. , various studies has been done across the world to find a solution for the disease.

Various hereditary techniques has been developed and completed to recognize the fragility of the chromosome. There has been a great deal improvement in research but a particular solution has not been obtained. The procedure for this symptoms is generally a multidisciplinary approach which include occupational remedy, medical managements, education and linguistics.

The Fragile X Mutation:

Genes will be the precursors of specific proteins molecules which in turn are specific for various functions of your body. The major cause for the fragile x syndrome is due to the mutation in one single gene called the delicate x mental retardation 1 (FMR1) gene which is the precursor for the delicate x mental retardation protein FMRP. This necessary protein is accountable for the normal development and performing of the mind. Men have only one x chromosome so existence of mutation for the reason that chromosome will cause the condition whereas in females, they may have two x chromosomes and hence full mutation in one copy makes them carriers of the symptoms and they may be affected partially based on the amount of mutation and variety of skin cells expressing the FMR-1 gene duplicate. The inheritance on the chromosomes is termed as x associated recessive inheritance which is more complex than the standard x connected genes.

Fig. 1 X chromosome with delicate site [1] Fig. 2 A photograph of X chromosomes showing a delicate site from both a men and a lady [2]

The range of CGG repeats on the FMR-1 gene can determine the complexity of the symptoms. The repeats are categorised as short, medium and long repeats. The short repeat around six to fifty times which is available very common. These short repeats are usually unstable and don't definitely cause the symptoms. Yet a genetic counseling along with certain testing is preferred. The medium duplicate is approximately 50 to 200 times and is named permutation.

The fragile x mental retardation proteins (FMRP) has lower threat of the symptoms as short collection repeats. The long repeats are usually more than 200 and are termed as full mutation where the complete FMR-1 gene is changed and development of the FMRP health proteins is totally quit. Among the people with full mutation or long repeats, men will have fragile x syndrome and women will be providers.

Fragile x mental retardation health proteins (FMRP)

The FMRP health proteins is found in the ribo-nucleoprotein complex and is encoded by the FMR1 gene. The FMRP weighs in at up to 60-70 kD. This health proteins is associated with the polyribosome 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% around. It also has the capacity to bind to its mRNA. Even a tiny amount of mutation in one of the KH domains could stop its discussion with the polysomes resulting in the fragile x symptoms.

Inheritance of fragile x syndrome

Males have xy chromosome and therefore have only one FMR-1 gene where as females have xx chromosomes and therefore they may have two FMR-1 genes. Over the F1 generation each parent exchanges one chromosome each to the offspring where in fact the copy of the FMR-1 gene is set. Therefore the possibilities of their offspring's being afflicted are grouped under two conditions.

Condition-1 [3]

If a men has a mutated gene in his chromosome it can be transferred only to his little princess because only the Y chromosome can be used in his kid by him. So if he was crossed with a female with normal genes almost all their sons will be normal and the daughters will have one fragile gene and remain as providers.






xє№ (carrier little princess)

Xy (normal kid)


xє№ (carrier child)

Xy (normal boy)

є№ - delicate x gene

Condition-2 [4]

If a lady has one mutated gene in her chromosome which is crossed with a standard male then there is certainly 50% potential for all the offspring's, be it female or male to really have the syndrome.






xє№ (carrier princess)

є№ y (fragile son)


xx(normal child)

Xy (normal child)

є№ - fragile x gene


The symptoms of delicate x syndrome are categorized into :


Large eyes

Prominent forehead

Large testecles


Cognitive development

Social and emotional




Social anxiety

Speech and language

Rapid and repetitive

Inability to adopt words



Flapping of hands

Poor eyeball contact

All these symptoms need not be automatically seen. A mixture of varied symptoms may vary from person to person based on the amount of gene changed in their chromosome. Sometimes there can also be no noticeable symptoms making the chances of early diagnosis even worse.

Molecular examination [5]

The chromosome from the syndrome is labeled into three major types predicated on the amount of CGG repeats as

Normal allele

the CGG do it again in FMR1 is 6-50

PCR analysis is enough to review all normal type genes

Specific point mutations and mosaicism must be studied using specific types of pcr or other molecular methods

Visualization is achieved either by radio-active labeling or vehicle radiography accompanied by automated sequencing

Agarose gel electrophoreses can be utilized for simple separation analysis with discolorations such as ethidium bromide. Appropriate size markers and size adjustments are incredibly important.

Controls used for evaluation mut approximately contain 50 repeats.

Pre mutation

The CGG repeat in FMR1 is 55-200

PCR research is extremely hard hence southern blot is actually preferred.

Since both premutation and full mutation have methylation status, specific methylation very sensitive enzymes such as EagI or NreI is used to resolve the size of the fragment.

Methylated alleles are trim only by one enzyme while non methylated normal alleles are cut by both enzymes.

Prenatal diagnosis is vital for pre mutation providers.

Rather than normal PCR a radioactive PCR may be used to test for premutation and then the effect can by verified using southern research.

Full mutation

The CGG repeats in FMR1 amounts from 200 to thousands

This can be analysed only by the southern blot strategy.

At complications, if a confirmable result cannot be obtained from a southern examination a radio effective PCR can be run combined with a linkage analysis and the result can be confirmed with southern blotting.

Intermediate alleles

The CGG repeats in FMR1 gene is usually between 45-55

Since they may be in the overlapping region between secure normal allele and unpredictable premutation alleles, prognosis and interpretation is very difficult

Diagnostic Tools and Methods

With the progress in technology DNA exams are always effective in identification of delicate x syndrome. With the findings of Sutherland et al. that folic acid deficient cell culture medium was able to induce a delicate site at xg27. 3 cytogenetics was the major way to determine the existence of the syndrome but after cloning of the FMR-1 gene direct methods for discovering the x connected gene is becoming possible. Through the use of monoclonal antibodies specific to FMRP additionally it is possible to show the appearance of FMR-1.

The most popular methods used for prognosis in the hereditary level are

Polymerase String Reaction

Southern Blotting

Antibody test

Denaturing gradient gel electrophoresis

Single strand confirmation polymorphism

Non-radioactive molecular prognosis.

Polymerase string reaction

Polymerase chain effect may be defined as a method where one duplicate of a DNA is amplified into numerous copies at a level of 2n where n is the amount of cycles. It is achieved under specific conditions of heat range, along with polymerase enzyme.

PCR amplification is one of the preliminary methods in diagnosing delicate x syndrome. Since the syndrome is associated with CGG repeats PCR is not regarded as the best method always, since the amplification across C-G composition could be unreliable for PCR approach. But now its quite definitely possible for a PCR to recognize CGG repeats in combo with various techniques.

methylation specific PCR of the FMR1 locus

fluorescent methylation - specific PCR

methyl-CpG-binding PCR

Some of the major advantages of PCR are that it's less time consuming, a very small amount of the sample is enough to produce numerous backup and the tri-nucleotide do it again in the FMR-1 gene is effectively sized. There are also various disadvantages of the technique. When there are more than a huge selection of tandem repeats it is impossible for the PCR to determine the complete mutation which may provide a different result. Because of differential amplification PCR is not capable of detecting mosacism between pre mutation and normal alleles.

Fig 3: delicate x analysis using PCR [6]

Southern Blotting

Southern blotting is among the best methods of diagnosing fragile x syndrome. It really is modtly used as the confirmatory test after PCR. The variations between the mutations and permutations combined with the amount of methylation took place can be evidently obtained by the southern blotting approach. The procedure can be summed up in two easy steps:

Step 1: the patients DNA is digested using restriction enzymes.

Step 2: southern hybridization is carried out along with specific radioactive probes after parting of FMRI region.

Using southern Blotting, the variations in full mutation and pre mutation can be easily revealed. Full mutations usually cause smearing of the music group and are always unpredictable. The only advantage of this technique is the fact that its accuracy whereas its labor rigorous, time consuming. The major downside of the method is its inability to look for the exact quantity of tandem repeats of the CGG nucleotides which is very much indeed necessary in determining if the patient is totally damaged or a carrier.

Fig 4: delicate x research by southern blot [7]

N refers to normal

Specific tools for analysis

DNA probe

A DNA probe can be explained as a single strand of DNA which act as a template to recognize the prospective DNA molecule. To identify the fragility of chromosome on the DNA specific probes were designed which increases the accuracy rate of the examination. Chemicon (Millipore) [8] has designed a particular probe named "The CHEMI" probe which is labeled with dioxegenin to find the CGG repeats in the FMR-1 gene.


There were special markers called the microsatelite markers used in linkage analysis. This came to an end with the development of modern techniques. However these markers are now used under special circumstances like prenatal prognosis where southern blotting has failed. Some of the markers used are DXS548, FRAXAC1 and FRAXAC2 coupled with PCR. They are considerably accurate and they undergo low recombination mechanism with CGG repeats.


There are no gene treatments or genetic treatments designed for fragile x syndrome though a lot of other remedies are available such as speech-language therapy, occupational remedy, physiotherapy and behavioral therapy.

There are also a big number of medications available as listed in the table below:




Mood instability

Carbamazepine (Tegretol)

Valproic acid or divalproex (Depakote)

Lithium carbonate

Gabapentin (Neurontin)

Lamotrigine (Lamictal)

Topiramate (Topomax), tiagabine (Gabitril), and vigabatrin (Sabril)

Phenobarbital and primidone (Mysoline)

Phenytoin (Dilantin)

Attention deficit (With or without hyperactivity)

Methylphenidate (Ritalin, Concerta) and dexamethamphetamine (Adderall, Dexedrine)


Venlafaxine (Effexor) and nefazodone (Serzone)

Amantadine (Symmetrel)

Folic acid


Sensory over-stimulation (Often occurs with ADD/ADHD)

Clonidine (Catapres TTS areas)

Guanfacine (Tenex)


Intermittent explosive disorder

Obsessive-compulsive disorder

(Often occurs with anxiety and/or depression)

Fluoxetine (Prozac)

Sertraline (Zoloft) and citalopram (Celexa)

Paroxetine (Paxil)

Fluvoxamine (Luvox)

Risperidone (Risperdal)

Quetiapine (Seroquel)

Olanzepine (Zyprexa )

Sleep disturbances

Trazadone Melatonin

Table 2: symptoms and medications for FRAXA [9]

(*these prescriptions have serious effects. DO NOT Consumption THESE WITHOUT CONSULTING A PHYSICIAN)

Current Research

Gene Remedy: studies are completed on the recombination strategy of the target gene, whether removal or substitute of the faulty gene with a recombinant gene would get rid of the syndrome.

Protein Replacement Remedy: research is being carried out on the opportunity of producing FMR necessary protein and supplying to the patients through exterior options like food or tablets.

Psychopharmacology: research is being carried out in finding medications for all your symptoms of fragile x syndrome.


Fragile x syndrome is one of the genetic diseases that causes psychological problems because of the lack of FMR protein responsible for the mental habit of the person. The necessary protein is not indicated in the individual due to fragility of the FMR1 gene in the x chromosome. Though PCR and southern blotting are the only tools available for diagnosis they are really considerably appropriate and research is being carried out on various re-combinative tools for examination. A complete treat has not been still devised for the symptoms though various behavioral and physical treatments help the patients gain psychological strength.

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