Fragile X Syndrome

Alternative Names: Martin-Bell syndrome; Marker X syndrome

Definition:-
Fragile X syndrome is a genetic condition involving changes in part of the X chromosome. It is the most common form of inherited mental retardation in males and a significant cause of mental retardation in females.

Fragile X is a family of genetic conditions, which can impact individuals and families in various ways. These genetic conditions are related in that they are all caused by gene changes in the same gene, called the FMR1 gene.

click to see the picture

Boys are usually more severely affected as they have only one X chromosome (they carry one X and one Y chromosome). Girls have a second X chromosome, which can to some extent make up for problems with the faulty one and so they may have only mild disabilities. They may also be carriers of the condition – that is, they are not affected themselves but can pass the condition on to their children.

However the genetics of fragile X are actually more complicated as some people only have a small change called a premutation in the FMR1 gene. While they don’t usually have problems from this , it makes the gene unstable and can develop into a full mutation when passed on to the next generation.

Fragile X affects about one in 3,600 men and one in 4,000 to 6,000 women of all races and ethnic groups. It shows an X-linked recessive pattern of inheritance and changes in the gene can become more serious as it’s passed from parent to child (especially when it is passed from a woman who carries it to her child).

Some people with a permutation of FMR1 may have no, or minimal, fragile X symptoms. But those with full mutation, where larger changes in the gene exist, demonstrate more severe signs of the condition.

click to see

Despite being carriers, some men aren’t affected (even though they have no normal copy of their X chromosome). But men who have the full mutation are almost always affected.

In women with the full mutation, a third have a below-normal IQ, a third have a borderline-normal IQ and the remaining third have a normal IQ

Fragile X includes:
fragile X syndrome (FXS), the most common cause of inherited mental impairment. This impairment can range from learning disabilities to more severe cognitive or intellectual disabilities. (Sometimes referred to as mental retardation.) FXS is the most common known cause of autism or “autistic-like” behaviors. Symptoms also can include characteristic physical and behavioral features and delays in speech and language development.

fragile X-associated tremor/ataxia syndrome (FXTAS), a condition which affects balance, tremor and memory in some older male gene carriers.

fragile X-associated primary ovarian insufficiency (FXPOI), a problem with ovarian function which can lead to infertility and early menopause in some female gene carriers.

Some gene carriers do not exhibit any of these features. To learn more about carriers click here.

Fragile X can be passed on in a family by individuals who have no apparent signs of this genetic condition. In some families a number of family members appear to be affected, whereas in other families a newly diagnosed individual may be the first family member to exhibit symptoms.

Since 1984, The National Fragile X Foundation (NFXF) has been helping individuals with Fragile X, their families, and the professionals who work with them. As research into Fragile X continues, our understanding of who it affects and how it affects them will grow. The NFXF is committed to: 1) supporting and funding all efforts that will increase awareness, 2) improving education, 3) advancing research toward improved treatments and an ultimate cure, and 4) keeping the Fragile X community always well-informed about the progress of these efforts.

Understanding Fragile X: A short, independent film produced by Image Union at station wttw11 in Chicago. (26 min.)

Symptoms:
The main problem in fragile X is intellectual impairment. This can range from very minor, so that the person has a normal IQ and shows no sign of fragile X, to severe learning difficulties. How badly someone is affected depends on the degree of change in the gene.
Click to see the picture
*Hyperactive behavior
*Large body size
*Large forehead or ears with a prominent jaw
*Large testicles (macro-orchidism) after the beginning of puberty
*Mental retardation
*Tendency to avoid eye contact

Family members who have fewer repeats in the FMR1 gene may not have mental retardation, but may have other problems. Women with less severe changes may have premature menopause or difficulty becoming pregnant. Both men and women may have problems with tremors and poor coordination.

Causes:-
Fragile X syndrome is a genetic disorder caused by mutation of the FMR1 gene on the X-chromosome. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. (Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females.)

Prominent characteristics of the syndrome incl...

Prominent characteristics of the syndrome include an elongated face, large or protruding ears, and low muscle tone. (Photo credit: Wikipedia)

Click to see pictures

Normally, the FMR1 gene contains between 6–55 (29 in Robbins–Kumar pathology textbooks) repeats of the CGG codon (trinucleotide repeats). In people with the fragile X syndrome, the FMR1 allele has over 230–4000 repeats of this codon.

Expansion of the CGG repeating codon to such a degree results in a methylation of that portion of the DNA, effectively silencing the expression of the FMR1 protein.

This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears ‘fragile’ under the microscope at that point, a phenomenon that gave the syndrome its name.

Mutation of the FMR1 gene leads to the transcriptional silencing of the fragile X-mental retardation protein, FMRP. In normal individuals, FMRP is believed to regulate a substantial population of mRNA: FMRP plays important roles in learning and memory, and also appears to be involved in development of axons, formation of synapses, and the wiring and development of neural circuits

Possible Complications:-
Complications vary depending on the type and severity of symptoms.

*Recurrent infections in children
*Seizure disorder

Transmission:
Fragile X syndrome is an X-linked dominant condition with variable expressivity and possibly reduced penetrance.

Because males normally have only one copy of the X-chromosome, those males with significant trinucleotide expansion at the FMR1 locus are symptomatic. They are intellectually disabled and may show various physical features of the fragile X syndrome.

Females have two X-chromosomes and thus have an increased probability of having a working FMR1 allele. Females carrying one X-chromosome with an expanded FMR1 gene can have some signs and symptoms of the disorder or be normal. Although the extra X-chromosome can serve as a backup, only one X-chromosome is active in each cell due to X-inactivation.

Males with the fragile X cannot transmit it to any of their sons (since males contribute a Y-chromosome, not an X, to their male offspring), but will transmit the premutation to all of their daughters, as males contribute their X to all of their daughters. Males never transmit their full mutation (males with full mutations in their blood have premutations in their sperm), and expansion to full mutations never occurs through paternal transmission.

Females carrying one copy of the fragile X can transmit it to their sons or daughters; in this case each child has a 50% chance of inheriting the fragile X. Sons who receive the fragile X are at high risk of intellectual disability. Daughters who receive the fragile X may appear normal or they may be intellectually disabled, usually to a lesser degree than boys with the syndrome. The transmission of fragile X often increases with each passing generation. This seemingly anomalous pattern of inheritance is referred to as the Sherman paradox.

Diagnosis:
Fragile X syndrome was originally diagnosed by culturing cells in a folate deficient medium and then assessing the cultures for X-chromosome breakage by cytogenetic analysis of the long arm of the X-chromosome. This technique proved unreliable for both diagnosis and carrier testing.

The fragile X abnormality is now directly determined by analysis of the number of CGG repeats and their methylation status using restriction endonuclease digestion and Southern blot analysis.

Not everyone with fragile X syndrome has the same signs and symptoms. Even affected people in the same family don’t show the same symptoms. The signs and symptoms fall into six categories:

*Intelligence and learning
*Physical
*Social and emotional
*Speech and language
*Sensory
*Disorders commonly associated or sharing features with Fragile X

Autism and Fragile X syndrome:
Fragile X syndrome can cause a child to have autism or an Autism Spectrum Disorder (ASD) though not all children with fragile X syndrome have autism or an ASD.

For 2% to 6% of all children diagnosed with autism, the cause is the Fragile X gene mutation. Approximately one-third of all children diagnosed with fragile X syndrome also have some degree of autism. Fragile X syndrome is the most common known single gene cause of autism.

From Dr. Randi Hagerman’s statement to the United States House of Representatives Subcommittee on Health and Environment: “…Fragile X represents a portal through which we hope to view and treat a wide variety of other disorders of brain development and function. All children with autism…should be tested for Fragile X.”

Genetic mouse models of Fragile X syndrome have also been shown to have autistic-like behaviors

Treatment:
As yet there are no specific treatments or a cure for fragile X, but emotional and educational support for children and their families are vital to help them reach their best potential.

Most affected children have delayed speech and language development and specialised help from a speech and language therapist is vital. Behavioural therapy may help children and their families to cope with problems such as hyperactivity and impulsivity, and sometimes medication is tried. Behavioural therapy may also help those children who have problems developing relationships to develop social skills and to cope with stressful situations.

Some children cope in mainstream schools, sometimes with some extra help, while others need to go to a school which can provide for their special educational needs.

Prognosis:-
The outcome depends on the extent of intellectual impairment that is present as well as emotional and social skills.

Prevention:-
Genetic counseling may help both existing and prospective parents with a family history of Fragile X syndrome, or a family history of other symptoms such as tremor. Genetic testing can help determine the level of risk in these families.

Research:
Recent studies have focused on a number of critical areas. The role of FMRP’s RNA partners, many of which have now been validated through in vitro assays, is of primary importance. Also being examined is the function the various domains of FMRP, an RNA-binding protein, which is still relatively unknown. One hypothesis is that many symptoms are caused by unchecked activation of mGluR5, a metabotropic glutamate receptor, which was found in a 2007 study to contribute significantly to the pathogenesis of the disease;  this suggests that mGluR5 blockers could be used to treat fragile X syndrome

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.

Resources:

http://www.bbc.co.uk/health/physical_health/conditions/fragilex1.shtml

http://www.fragilex.org/html/what.htm

http://en.wikipedia.org/wiki/Fragile_X_syndrome

http://healthtools.aarp.org/adamcontent/fragile-x-syndrome?CMP=KNC-360I-GOOGLE-HEA&HBX_PK=fragile_x_syndrome&utm_source=Google&utm_medium=cpc&utm_term=fragile%2Bx%2Bsyndrome&utm_campaign=G_Diseases%2Band%2BConditions&360cid=SI_148902589_6495451981_1

http://drugster.info/ail/pathography/635/

http://psychology.wikia.com/wiki/Fragile_X_syndrome

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2 thoughts on “Fragile X Syndrome

  1. Sarah

    Great article. Would it be permissible for me to use the photographs in a university project to produce an information leaflet please? this leaflet will not be published and is purely an academic exercise. Many thanks. Sarah

    Reply

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