Fragile X syndrome
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| ICD-10 | Q99.2 |
|---|---|
| ICD-9 | 759.83 |
Fragile X Syndrome, also known as the Martin-Bell syndrome, is a syndrome of X-linked mental retardation. Boys with the syndrome may have macroorchidism, prognathism, hypotonia and autism, and a characteristic but variable facies with large ears, long face, high-arched palate, and malocclusion. Additional abnormalities may include lordosis, heart defect, pectus excavatum, flat feet, shortening of the tubular bones of the hands, and joint laxity. Females who have one fragile chromosome and one normal X chromosome may range from normal to mild manifestations of the fragile X syndrome. The fragile X syndrome has an estimated incidence of 1 in 4,000-9,000 males and 1 in 7,000-15,000 females <ref>Crawford DC, Acuna JM, Sherman SL: FMR1 and the Fragile X syndrome: Human genome epidemiology review. Genet Med 2001, 3: 359-371</ref>
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[edit] History
Martin and Bell in 1943 described a large pedigree without knowledge of the cytogenetic anomaly and without considering the macroorchidism.<ref>J. P. Martin, J. Bell: A pedigree of mental defect showing sex-linkage. in: Journal of neurology, neurosurgery, and psychiatry (J. Neurol. Psychiat.). BMJ Publishing Group, London 6.1943, 154-157. ISSN 0022-3050</ref> In 1969 Herbert Lubs first sighted an unusual "marker X chromosome" in association with mental retardation.<ref>H. Lubs: A marker X chromosome. Am Hum Genet 1969; 21: 231.</ref> In 1970 Frederick Hecht coined the term "fragile site" (in connection with a heritable fragile site on another chromosome) and soon thereafter the marker X became known as the fragile X.<ref>R.E. Magenis, F. Hecht, E.W. Lovrien: Heritable Fragile Site on Chromosome 16: Probable Localization of Haptoglobin Locus in Man. Science 1970: Vol. 170. no. 3953, pp. 85 - 87.</ref> In 1977 Grant Sutherland described a special cell culture method that permits the consistent cytogenetic diagnosis of the fragile X chromosome.<ref>G.R. Sutherland: Fragile sites on human chromosomes: demonstration of their dependence on the type of tissue culture medium. Science 1977: Vol. 197. no. 4300, pp. 265 - 266.</ref> This was an extraordinarily important technical advance because it provided a reliable means of detection of the fragile X.
[edit] Other terms
Renpenning's syndrome is not synonymous with the Martin-Bell (fragile X) syndrome. In Renpennig'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.
[edit] 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 1250 males and 1 out of about every 2500 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.
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 and fragility of the X chromosome 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 facilitates the translation of a number of essential neuronal RNAs. In fragile X patients, however, these RNAs are not translated into proteins. The various sequelae of fragile X syndrome.
[edit] Transmission of the Fragile X
The diagram (right) of X-linked recessive inheritance is not entirely inappropriate but it markedly oversimplifies the situation and does not provide a sufficient foundation for genetic counseling about the fragile X syndrome. Technically, fragile X syndrome is an X-linked dominant condition with 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 intellectally 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.
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. 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.
[edit] Symptoms
Aside from intellectual disability (mental retardation), prominent characteristics of the syndrome include an elongated face, large or protruding ears, flat feet, large testicles (macroorchidism), and low muscle tone. 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. While full mutation males tend to present with severe intellectual disability, the symptomology of full mutation females runs the gamut of minimally affected to severe intellectual disability, which may explain why females are underdiagnosed relative to males.
[edit] 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.
[edit] 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.
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.
[edit] References
<references />
[edit] 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 United States National Fragile X Foundation
- 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)
- Gene Reviews
- Mendelian Inheritance in Man (OMIM) 309550 - 'Fragile Site Mental Retardation 1 Gene; FMR1' (Fragile X syndrome OMIM entry)
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