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Fragile X Syndrome
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Fragile X syndrome (FXS) is the commonest cause of sex-linked mental retardation. It is what is known as a repeat expansion disorder. In DNA coding it is common to see repeated sequences of the nucleotides that make up the genetic strand. In Fragile X Syndrome there is an expansion of the number of repeat sequences in the Fragile X mental retardation (FMR1) gene. The nucleotides involved are cytosine (C) and guanine (G) and the repeated sequence is CGG. In the commonest form of the condition, the CGG sequence is repeated more than 200 times. The metabolic result of this is to block production of a substance called fragile X mental retardation protein (FMRP).2
MicroRNAs (miRNAs), a newly discovered class of small noncoding RNAs, are thought to be involved in the aetiology of this condition.3
Family studies have identified both a full mutation and a "premutation" (less than 50 CGG repeats per segment) which is unstable and can become a full mutation on female transmission (but not on male transmission of the X chromosome to their daughters). This happens more frequently the larger the mutation, and the mutation may become larger in subsequent generations until the gene expression is blocked. About a third of female carriers of the full mutation have mild mental retardation.
One study has identified specific neuroanatomic changes in FXS patients.4
A UK screening study in 2003 estimated an overall prevalence in the general population of 2.3/10,000 (or 1 in 4425).5 Two to four times as many females as males carry the gene abnormality. However, only a third of females carry the abnormal gene responsible for decreased intelligence.6
Fragile X Syndrome presents with mental retardation (IQ 20-70), delayed milestones, high forehead, large testicles (> 3-4 mL), facial asymmetry, large jaw, long ears and short temper. Other symptoms may include attention deficit, repetitive actions, clumsiness, avoidance of gaze, and sleep disturbance. Certain personality traits such as obsessiveness and anxiety can occur, Specific speech disorders may include echolalia and perseveration (the inability to complete a sentence due to repetition of words at the end of a phrase). The diagnosis is usually made before the child is one year old, but can be delayed if the symptoms are subtle.1,5
- Attention deficit hyperactivity disorder
- Ehlers-Danlos syndrome
- Marfan syndrome
- Pervasive developmental disorder - a spectrum of behavioural problems, sometimes associated with autism or Rett syndrome (a genetic disorder causing gross motor delay and other developmental problems)
- Learning disabilities
- Lujan-Fryns syndrome - tall (marfinoid) stature, arachnodactyly, joint hyperextensibility, narrow face, small chin, large testes, hypotonia, mental retardation
A blood sample (or chorionic villus biopsy) can be sent for DNA analysis. Most laboratories currently use a combination of Southern blotting (detects full mutations) and polymer chain reaction (PCR) tests (identifies pre-mutations and smaller CGG repeats). Southern blotting (named after Edward Southern, who developed the technique at Edinburgh University in the 1970s) involves transferring DNA material from an agar gel onto a membrane. Electrophoresis applied to this membrane can then be used to identify a particular DNA sequence. PCR used as polymerase enzyme to amplify a particular DNA region, making identification easier.7
FMRP antibody testing is available on a blood smear (this can detect affected males)8 and has also been developed on a pulled hair sample (this can detect males and females with a full mutation).9
The management of Fragile X syndrome is currently palliative and may involve special needs education, behaviour therapy and speech therapy.10
Research is currently focussing on gene therapy,11 protein replacement,12 transcriptional regulation,13 nutritional intervention6 , regulation of neurotransmission.14 and microRNA-based therapeutics.15
Folate therapy has been tried in the past in the hope that it would help to control inattention and aggressiveness in prepubertal males, but folate deficiency has never been demonstrated, and the evidence base is equivocal.6
Atypical antipsychotics, serotonin reuptake inhibitors and anticonvulsants have all been found to be helpful in treating various aspects of abnormal behaviour.16
The genetic counselling and support of the parents and other family members should not be forgotten.17
There is no shortening of life expectancy.6
Document references
- OMIM; Fragile Site Mental Retardation Gene1 2006
- Bittel DC, Kibiryeva N, Butler MG; Whole genome microarray analysis of gene expression in subjects with fragile X syndrome. Genet Med. 2007 Jul;9(7):464-72. [abstract]
- Li Y, Lin L, Jin P; The microRNA pathway and fragile X mental retardation protein. Biochim Biophys Acta. 2008 Nov;1779(11):702-5. Epub 2008 Jul 18. [abstract]
- Gothelf D, Furfaro JA, Hoeft F, et al; Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP). Ann Neurol. 2008 Jan;63(1):40-51. [abstract]
- Song F, Barton P, Sleightholme V et al; Screening for fragile X syndrome: a literature review and modelling study; Health Technol Assess 2003; 7(16).
- Jewell J; Fragile X Syndrome. eMedicine, Sept 2008.
- Mullis KB; Target amplification for DNA analysis by the polymerase chain reaction. Ann Biol Clin (Paris). 1990;48(8):579-82. [abstract]
- Willemsen R, Smits A, Mohkamsing S, et al; Rapid antibody test for diagnosing fragile X syndrome: a validation of the technique. Hum Genet. 1997 Mar;99(3):308-11. [abstract]
- Willemsen R, Anar B, De Diego Otero Y, et al; Noninvasive test for fragile X syndrome, using hair root analysis. Am J Hum Genet. 1999 Jul;65(1):98-103. [abstract]
- Families and Fragile X Syndrome booklet; National Institute of Child Health and Human Development 2006
- Gomes-Pereira M, Monckton DG; Chemical modifiers of unstable expanded simple sequence repeats: what goes up, could come down. Mutat Res. 2006 Jun 25;598(1-2):15-34. Epub 2006 Feb 28. [abstract]
- Conquer Fragile X Foundation; All About Fragile X. 2008.
- Lin SL, Ying SY; Gene silencing in vitro and in vivo using intronic microRNAs. Methods Mol Biol. 2006;342:295-312. [abstract]
- Berry-Kravis E, Krause SE, Block SS, et al; Effect of CX516, an AMPA-Modulating Compound, on Cognition and Behavior in Fragile X Syndrome: AControlled Trial. J Child Adolesc Psychopharmacol. 2006 Oct;16(5):525-40. [abstract]
- Stenvang J, Lindow M, Kauppinen S; Targeting of microRNAs for therapeutics. Biochem Soc Trans. 2008 Dec;36(Pt 6):1197-200. [abstract]
- Hagerman R 2006; Medical Treatment of Aggression; National Fragile X Foundation
- Welch JL, Williams JK; Fragile X syndrome. Neonatal Netw. 1999 Sep;18(6):15-22. [abstract]
DocID: 2169
Document Version: 21
DocRef: bgp1409
Last Updated: 10 Dec 2008
Review Date: 10 Dec 2010
The authors and editors of this article are employed to create accurate and up to date content reflecting reliable research evidence, guidance and best clinical practice. They are free from any commercial conflicts of interest. Find out more about updating.
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