Fragile X syndrome

What is fragile X syndrome?

Fragile X syndrome (FXS) is an inherited condition which presents with typical behavioural, developmental, and physical problems. Fragile X syndrome is the most common cause of sex-linked general learning disability, accounting for half of all sex-linked intellectual disabilities.¹ It is also the commonest single gene cause of autism.¹²It is also the most prevalent cause of inherited intellectual disability and the commonest cause of intellectual disability after Down syndrome.¹

Males with a full mutation will display a complete penetrance and are more likely to exhibit symptoms of FXS; females with a full mutation display a penetrance of about 50%, with symptoms ranging from mild to severe.¹

Fragile X syndrome is one of a number of repeat expansion disorders. 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. This gene is on the X chromosome (Xq28) and the nucleotides involved are cytosine (C) and guanine (G) making up the repeated sequence CGG. In the most common form of the condition, the CGG sequence is repeated more than 200 times. This results in the blocked production of a substance called fragile X mental retardation protein (FMRP).

In individuals without fragile X syndrome, the trinucleotide sequence is repeated 6-54 times. People in whom the sequence is repeated over 200 times have the full mutation, which causes a deficiency in FMRP and thereby the full clinical syndrome. If there are between 55 and 200 repeats, there may be a 'premutation'. In these individuals, FMRP is produced but there is a risk of expansion of the repetition in subsequent generations. The premutation alleles also confer a risk of associated fragile-X disorders (fragile X-associated tremor/ataxia disorder and fragile X-associated primary ovarian insufficiency).

The greater the number of CGG repeats in a female with the premutation, the greater the chance of expansion of a full mutation in the male offspring.

Fragile X syndrome affects 1:7,000 men and 1:11,000 women.¹

The pre-mutation is far more common. Two to four times as many females as males carry the gene abnormality. This has an estimated prevalence of 1 in 130-260 females and 1 in 250-810 males. However it is difficult to define the number of carriers precisely as there is a difference between carriers of the full-mutation allele and those of the pre-mutation allele.⁵

There is a region of Colombia with a genetic cluster of Fragile X Syndrome, with 1 in 19 men and 1 in 46 women affected. Within this region, 48.2 per 1000 men and 20.5 per 1000 women carry the full-mutation allele and 14.1 per 1000 men and 35.9 per 1000 women carry the pre-mutation allele.⁶

• It is common for a baby with fragile X syndrome to often show few early signs with initial examinations being normal.

• Symptoms often only present in early childhood. The diagnosis is often made at around the age of 3.

• An individual with fragile X syndrome typically has learning difficulties (IQ less than 70); males with the full mutation have an average IQ of 40.

• There are often delays in all language skills, but particularly expressive language skills.

• 90% of males and 17% of females with the full mutation have autism.

• ADHD is present in approximately 80% of people with fragile X syndrome; obsessive-compulsive behaviours, aggressive behaviours, and increased emotional lability are also more common.

• The typical physical features include an elongated narrow face, broad forehead, broad philtrum, high arched palate, and protruding ears. Pubertal macro-orchidism (testicles 2-3 times normal size) is a hallmark of fragile X syndrome.

• There may be features due to changes in connective tissue including prominent ears, hyperextensible finger joints, mitral valve prolapse, soft skin, and flat feet.

People with the pre-mutation often have less significant cognitive deficits and are often undiagnosed. They have high risks of the complications mentioned later in this article.

• Other causes of general learning disability.

• Other chromosomal abnormalities causing learning difficulty, such as Down's syndrome and other sex chromosome anomalies such as Klinefelter's syndrome, Rett syndrome and Lujan-Fryns syndrome.

• Sotos syndrome.

• ADHD.

• Autistic spectrum disorder.

• Marfan's syndrome.

• A detailed family history is useful as there may be features across the generations of premutation.

• 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. Electrophoresis applied to this membrane can then be used to identify a particular DNA sequence. PCR is used as polymerase enzyme to amplify a particular DNA region, making identification easier.

• 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.^{7 8}

• Second-level analysis involves CGG methylation testing to evaluate lack of FMRP production ('silencing') and molecular techniques to identify loss of function mutations.⁹

• Antenatal testing is now possible and is generally offered to parents with an affected child or family history as well as those with a personal or family history of a child with intellectual disability of unknown cause.¹⁹

There is currently no cure for fragile X syndrome but a number of pharmacological, behavioural, and cognitive interventions may improve quality of life.

Interventions include:

• Speech therapy.

• Special needs education.

• Behavioural therapy.

• Stimulants such as dextroamphetamine and methylphenidate for those with associated ADHD.

• Selective serotonin reuptake inhibitors (SSRIs) for symptoms of anxiety.

• Antipsychotics for mood stabilisation, improving attention and reducing anxiety - particularly aripiprazole.

• Anticonvulsants where seizures are present.

• Genetic counselling and support of the parents and other family members.

As understanding of the role FMRP plays at cellular and molecular level continues to improve. Reduced FMRP production results in hyperacti­vation of the extracellular-signal-regulated kinase (ERK) sign­alling pathways as well as the mammalian target of rapamycin complex 1 (mTORC1). Behavioural and biochemical results in an FXS animal model (FMR1 knockout mice) suggest that metformin could play a beneficial role in blocking these pathways.¹²

Support for parents and carers is essential as they bear a significant personal and financial burden.

Fragile X-associated tremor ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with men over 50 who carry the fragile X syndrome pre-mutation. It is associated with early-onset cognitive impairment, tremor, and ataxia. Although rare (life-time prevalence in the general population is thought to be 1 in 8,000),¹³ it is important to consider FXTAS in the differential diagnosis of adults presenting with movement disorders, especially if there is a family history consistent with FXS or premutation disorders. ¹⁴¹⁵¹⁶

In men with the pre-mutation, the risk of developing FXTAS is thought to be 17% aged between 50 and 59, 38% from 60-69, 47% from 70-79 and 75% over 80. Females with the pre-mutation have a lower risk of between 8 and 16%.¹³

Fragile X-associated premature ovarian insufficiency is a chronic disorder characterised by oligo/amenorrhea and hypergonadotropic hypogonadism before age 40 years.¹⁷ About a quarter of women with fragile X syndrome pre-mutation experience POI as a result (about 1 in 800 women in the general population).¹⁸The severity of FXPOI is variable. The most severely affected women have overt premature ovarian insufficiency, having irregular or absent menstrual periods and elevated FSH levels before the age of 40 (but can be as young as 20) alongside reduced or absent fertility. Other women have occult POI; they have normal menstrual periods but may have reduced fertility and raised FSH levels. Women with FXPOI undergo menopause an average of 5 years earlier than women without the condition.¹⁸

There is no shortening of life expectancy specifically with fragile X syndrome although patients with an intellectual disability tend to have a higher mortality rate than the general population.¹ Outcome in general varies with the degree of intellectual disability and expression of other characteristics, which vary widely.

In 2019, the UK National Screening Programme Committee decided not to institute a national newborn screening programme on the grounds that there was lack of evidence that screening would improve outcomes in affected children compared to usual healthcare.¹⁹In 2025, a further consultation was opened into whether antenatal or newborn screening should be offered in the UK.

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.