Fragile X Syndrome

Synonyms: Martin-Bell syndrome

Aetiology¹

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
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.

A UK screening study in 2003 estimated an overall prevalence in the general population of 2.3/10,000 (or 1 in 4425).³ 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. ⁴

Fragile X Syndrome presents with mental retardation (IQ 20-70), delayed milestones, high forehead, large testicles (> 3-4ml), 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.^1,3

• 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.⁵FMRP antibody testing is available on a blood smear (this can detect affected males)⁶ and has also been developed on a pulled hair sample (this can detect males and females with a full mutation).⁷

The management of Fragile X syndrome is currently palliative and may involve special needs education, behaviour therapy and speech therapy.⁸
Research is currently focussing on gene therapy,⁹ protein replacement,¹⁰ transcriptional regulation,¹¹ nutritional intervention⁴ and regulation of neurotransmission.¹²
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.⁴
Atypical antipsychotics, serotonin reuptake inhibitors and anticonvulsants have all been found to be helpful in treating various aspects of abnormal behaviour. ¹³
The genetic counselling and support of the parents and other family members should not be forgotten. ¹⁴

There is no shortening of life expectancy.⁴

See Screening for Fragile X Syndrome