Fragile X syndrome (FXS) is an inherited condition which presents with typical behavioural, developmental and physical problems.

Genetics¹

Fragile X syndrome (FXS) is the most common cause of sex-linked, general learning disability. It is what is known as a repeat expansion disorder.² In DNA coding it is common to see repeated sequences of the nucleotides that make up the genetic strand. In FXS 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 most common 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).³

MicroRNAs (miRNAs), a newly discovered class of small noncoding RNAs, are thought to be involved in the aetiology of this condition.⁴

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 neuro-anatomical changes in FXS patients.⁵

Epidemiology

A UK screening study in 2003 estimated an overall prevalence in the general population of 2.3/10,000 (or 1 in 4,425).⁶ 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 learning difficulties.⁷

Presentation

• Fragile X syndrome (FXS) presents with learning difficulties (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.^1,6

Differential diagnosis⁷

• Attention deficit hyperactivity disorder.
• Ehlers-Danlos syndrome.
• Marfan's syndrome.
• Pervasive developmental disorder - a spectrum of behavioural problems, sometimes associated with autistic spectrum disorder or Rett's syndrome (a genetic disorder causing gross motor delay and other developmental problems).
• Learning disabilities.
• Lujan-Fryns syndrome - tall (Marfanoid) stature, arachnodactyly, joint hyperextensibility, narrow face, small chin, large testes, hypotonia, mental retardation.

Investigations

• 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 polymerase chain reaction (PCR) testing (identifies pre-mutations and smaller CGG repeats). Southern blotting involves transferring DNA material from an agar gel on to a membrane.⁸ Electrophoresis applied to this membrane can then be used to identify a particular DNA sequence.⁹ PCR is used as polymerase enzyme to amplify a particular DNA region, making identification easier.¹⁰
• A refinement of this technique, using capillary action to separate DNA fragments of differing size, enables the rapid testing of large numbers of samples, making the method suitable as a newborn screening test.^11,12
• FMRP antibody testing is available on a blood smear (this can detect affected males)¹³ and has also been developed on a pulled hair sample (this can detect males and females with a full mutation).¹⁴
• A method recently developed, called methylation-specific melting curve analysis (MS-MCA), relies on the fact that the transcription errors seen on the FR1 gene results in hypermethylation of the genetic material. It can be used in males only, but allows rapid and reliable identification of patients.¹⁵

Management

The management of fragile X syndrome (FXS) is currently palliative and may involve special needs education, behavioural therapy and speech therapy.¹⁶

Research is currently focusing on gene therapy,¹⁷ protein replacement,¹⁸ transcriptional regulation,¹⁹ nutritional intervention.⁷ regulation of neurotransmission.²⁰ and miRNA-based therapeutics.²¹

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.⁷

Atypical antipsychotics, serotonin reuptake inhibitors and anticonvulsants have all been found to be helpful in treating various aspects of abnormal behaviour.²²

The genetic counselling and support of the parents and other family members should not be forgotten.²³

Prognosis

There is no shortening of life expectancy.⁷

Prevention

The UK National Screening Programme Committee decided not to institute a national newborn screening programme (January 2011). Currently, the policy is to restrict screening to carrier identification within affected families. It may also be worthwhile screening children with learning difficulties, aiming to identify more families and to enable carriers to have prenatal counselling.

Document references

1. Fragile Site Mental Retardation Gene1, Online Mendelian Inheritance in Man (OMIM), 2006
2. What Are Repeat Disorders?, The National Fragile X Foundation, September 2008; (American site)
3. 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]
4. 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]
5. 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]
6. Song FJ, Barton P, Sleightholme V et al; Screening for fragile X syndrome: a literature review and modelling study; Health Technol Assess 2003; 7(16)
7. Jewell J et al, Fragile X Syndrome, Medscape, Jul 2010
8. Southern-blot Analysis, Flemington lab - 2008
9. Wolf J; Southern Blotting, University of Maryland Biological Sciences (2006)
10. Mullis KB; Target amplification for DNA analysis by the polymerase chain reaction. Ann Biol Clin (Paris). 1990;48(8):579-82. [abstract]
11. Strom CM, Huang D, Li Y, et al; Development of a novel, accurate, automated, rapid, high-throughput technique suitable for population-based carrier screening for Fragile X syndrome. Genet Med. 2007 Apr;9(4):199-207. [abstract]
12. Tassone F, Pan R, Amiri K, et al; A rapid polymerase chain reaction-based screening method for identification of J Mol Diagn. 2008 Jan;10(1):43-9. Epub 2007 Dec 28. [abstract]
13. 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]
14. 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]
15. Dahl C, Gronskov K, Larsen LA, et al; A homogeneous assay for analysis of FMR1 promoter methylation in patients with fragile X syndrome. Clin Chem. 2007 Apr;53(4):790-3. Epub 2007 Jan 26. [abstract]
16. Families and Fragile X Syndrome booklet; National Institute of Child Health and Human Development 2006
17. 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]
18. All About Fragile X, Conquer Fragile X Foundation, 2008; (American site)
19. Lin SL, Ying SY; Gene silencing in vitro and in vivo using intronic microRNAs. Methods Mol Biol. 2006;342:295-312. [abstract]
20. 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]
21. Stenvang J, Lindow M, Kauppinen S; Targeting of microRNAs for therapeutics. Biochem Soc Trans. 2008 Dec;36(Pt 6):1197-200. [abstract]
22. Hagerman R 2006; Hagerman R; Medical Treatment of Aggression, National Fragile X Foundation
23. Welch JL, Williams JK; Fragile X syndrome. Neonatal Netw. 1999 Sep;18(6):15-22. [abstract]

Internet and further reading

• The Fragile X Society

Acknowledgements