Fragile X syndrome
| Fragile X syndrome Classification and external resources |
|
 |
|
|---|---|
| Location of FMR1 gene | |
| ICD-10 | Q99.2 |
| ICD-9 | 759.83 |
| OMIM | 309550 |
| DiseasesDB | 4973 |
| eMedicine | ped/800 |
| MeSH | D005600 |
Fragile X syndrome, or Martin-Bell syndrome, is a genetic syndrome which results in a spectrum of characteristic physical, intellectual, emotional and behavioural features which range from severe to mild in manifestation. The syndrome is associated with the expansion of a single trinucleotide gene sequence (CGG) on the X chromosome, and results in a failure to express the FMR-1 protein which is required for normal neural development. There are four generally accepted forms of Fragile X syndrome which relate to the length of the repeated CGG sequence; Normal (29-31 CGG repeats), Premutation (55-200 CGG repeats), Full Mutation (more than 200 CGG repeats), and Intermediate or Gray Zone Alleles (40 - 60 repeats).[1]
Martin and Bell in 1943, described a pedigree of X-linked mental disability, without considering the macroorchidism.[2] In 1969 Chris and Weesam first sighted an unusual "marker X chromosome" in association with mental disability.[3] In 1970 Frederick Hecht coined the term "fragile site" (Renpenning's syndrome is not synonymous with the syndrome). In Renpenning's syndrome there is no fragile site on the X chromosome. Renpenning's cases had short stature, moderate microcephaly, and neurological disorders.
Escalante's syndrome is synonymous with the fragile X syndrome. This term has been used in Brazil and other South American countries.
Contents |
Causes
The 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 disease itself is about 1 in every 4000 females.)
Normally, the FMR1 gene contains between 6 and 55 repeats of the CGG codon (trinucleotide repeats). In people with the fragile X syndrome, the FMR1 allele has over 230 repeats of this codon.[4]
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 binds and (usually) inhibits the translation of a number of essential neuronal RNAs. In fragile X patients, however, these RNAs are translated into excessive amounts of protein.[5] However, certain RNAs seem to be stabilized by FMRP through a different mechanism.
Transmission of the fragile X
Technically, fragile X syndrome is an X-linked dominant condition with reduced penetrance.[6]
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 double the chance 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 at a time 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 it to all of their daughters, as males contribute their X to all of their daughters.
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.
Symptoms
Aside from intellectual disability, prominent characteristics of the syndrome include an elongated face, large or protruding ears, flat feet, larger testicles in men (macroorchidism), and low muscle tone. Speech may include cluttered speech or nervous speech[7]. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness and limited eye contact. Some individuals with the fragile X syndrome also meet the diagnostic criteria for autism. Most females experience symptoms to a lesser degree because of their second X-chromosome, however they can develop just as severe symptoms. While full mutation males tend to present with severe intellectual disability, the symptoms of full mutation females run the gamut of minimally affected to severe intellectual disability, which may explain why females are underdiagnosed relative to males.
In short, similarities between X-linked recessive inheritance and fragile X are:
- Males are predominantly affected;
- Females (mothers) are obligatory carriers if a male child is affected, but not necessarily if female children are.
Differences are:
- Females may also have clinical symptoms.
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
Treatment and current 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;[8] this suggests that mGluR5 blockers could be used to treat fragile X syndrome.[9]
While there is no current cure for the syndrome, there is hope that further understanding of its underlying causes would lead to new therapies. Currently, the syndrome can be treated through behavioral therapy, special education, medication, and when necessary, treatment of physical abnormalities. Persons with the fragile X syndrome in their family histories are advised to seek genetic counseling to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants.
Researchers at the Picower Institute for Learning and Memory at MIT have reversed symptoms of mental retardation and autism in mice.[10]
References
- ↑ Sherman, S. (2002). "Epidemiology". Chapter 3 in Fragile X Syndrome, Diagnosis Treatment and Research. Ed. Hagerman, R. J. & Hagerman, P.J. (3rd Edition). Johns Hopkins University Press: Baltimore.
- ↑ Martin, J. P. & Bell, J. "A pedigree of mental defect showing sex-linkage". Journal of neurology, neurosurgery, and psychiatry (J. Neurol. Psychiat.). BMJ Publishing Group, London 6.1943, 154-157. ISSN 0022-3050
- ↑ Lubs HA (1969). "A marker X chromosome". Am. J. Hum. Genet. 21 (3): 231–44. PMID 5794013.
- ↑ Nolin SL, Brown WT, Glicksman A, et al (2003). "Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles". Am. J. Hum. Genet. 72 (2): 454–64. PMID 12529854. PMC: 379237. http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60554-0.
- ↑ Qin, M., Kang, J., Burlin, T.V., Jiang, C., Smith, C.B (18 May 2005). "Postadolescent changes in regional cerebral protein synthesis: An in vivo study in the Fmr1 null mouse". Journal of Neuroscience 25 (20): 5087–95. doi:. PMID 15901791.
- ↑ Garber KB, Visootsak J, Warren ST (2008). "Fragile X syndrome". Eur J Hum Genet. doi:. PMID 18398441.
- ↑ Signs of Fragile-X Syndrome - WrongDiagnosis.com
- ↑ Dölen G, Osterweil E, Rao BS et al. (2007). "Correction of fragile X syndrome in mice". Neuron 56 (6): 955–62. doi:. PMID 18093519.
- ↑ Highfield R (2007-12-19). "Fragile X study offers hope for autism treatment", Daily Telegraph. Retrieved on 2007-12-22.
- ↑ MIT researchers reverse symptoms in mice of leading inherited cause of mental retardation
External links
- CDC’s National Center on Birth Defects and Developmental Disabilities
- FraXA.org - The Fragile X Research Foundation
- http://www.fragilex.org.uk/index.asp - The United Kingdom National Fragile X charity
- FragileX.org - The National Fragile X Foundation (US) - Support, Awareness, Education, Research and Advocacy since 1984
- The Colorado Fragile X Consortium
- Stanford.edu - 'Trinucleotide Repeat Disorders Part 9: Non-Polyglutamine Diseases: Descriptions of other diseases that involve codon repeat expansions' (September 18, 2002)
- Genetics of Fragile X Syndrome
- Gene Reviews
|
||||||||||||||||||||
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||
|
|||||||||||||