Fragile X syndrome (FXS) or Martin-Bell Syndrome: risk factors, causes and treatment

Definition

Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females.

Fragile X  syndrome affected boy

History

In 1943, Martin and Bell showed that a particular form of mental retardation (later known as fragile X syndrome) was X-linked. In 1969, Herbert Lubs developed the chromosomal test for Fragile X. The test was not used extensively until the late 1970’s. In 1991 the FMR1 gene that causes Fragile X was identified.

Epidemiology

Conservative estimates are that fragile X syndrome affects approximately 1 in 2500-4000 males and 1 in 7000-8000 females. The prevalence of female carrier status has been estimated to be as high as 1 in 130-250 population; the prevalence of male carrier status is estimated to be 1 in 250-800 population.

Causes

FXS is caused by a defect in the FMR1 gene located on the X chromosome. The X chromosome is one of two types of sex chromosomes. The other is the Y chromosome. Women have two X chromosomes while men have one X chromosome and one Y chromosome.

Defects in X chromosome

The defect, or mutation, on the FMR1 gene prevents the gene from properly making a protein called the fragile X mental retardation 1 protein. This protein plays a role in the functioning of the nervous system. The exact function of the protein is not fully understood. A lack or shortage of this protein causes the symptoms characteristic of FXS.

Risk factors

The main risk factor for FXS is having a parent with an FMR1 mutation. Most people who inherit a minor mutation, which is sometimes called a premutation, do not develop the symptoms and signs of FXS. A few premutated children may show signs that resemble autism. Others, primarily males, may develop a set of neurological symptoms called fragile X tremor ataxia syndrome in later adult life. Females may develop FMR1-related premature ovarian insufficiency.

Children of mothers with FMR1 premutations are at risk of inheriting a fully mutated FMR1 gene severe enough to cause symptomatic FXS. If a woman does not have symptoms and is a carrier of an FMR1 mutation or premutation, each child of hers has a 50% chance of inheriting that gene. Of the children that inherit that gene, boys are much more likely to develop symptoms than girls. The severity of the disorder may vary between different individuals in the same family.

In general, each generation tends to have worse mutations and a higher risk of FXS than the previous one.

Symptoms

The signs and symptoms of fragile x syndrome have five general categories where individuals often show altered or arrested development.

  • Intelligence and learning (low IQs)
  • Physical (long face or jaw, short stature, enlarged testicles)
  • Social and emotional (anxiety)
  • Speech and language (stuttering and disorganized speech)
  • Sensory (sensitive to certain stimuli like sounds, balance problems)

Diagnosis and tests

  • A diagnosis of Fragile X is made through a DNA blood test. You can organise the test though your GP or paediatrician or any medical doctor.
  • The blood can be collected by your doctor or a pathology centre. Test results are usually available approximately 4 to 8 weeks after the sample is taken but the time taken can vary.
  • The test that is required is DNA studies for Fragile X syndrome. Five to ten ml of blood will be collected into a lithium heparin or EDTA tube. your doctor will check which anticoagulant is required by the laboratory. The blood is then transported immediately without freezing.

Treatment and medication

FXS cannot be cured. Treatment is aimed at helping people with the condition learn key language and social skills. This may involve receiving extra help from teachers, therapists, family members, doctors, and coaches.

There may be services and other resources available in your community to help children learn important skills for proper development. Medications that are typically prescribed for behavior disorders, like attention deficit disorder (ADD) or anxiety, may be prescribed to treat the symptoms of FXS. Medications include:

  • Methylphenidate (Ritalin)
  • Guanfacine (Intuniv)
  • Clonidine (Catapres)
  • Selective serotonin reuptake inhibitor (SSRI), such as sertraline (Zoloft), escitalopram (Lexapro), duloxetine (Cymbalta), and paroxetine (Pail, Pexeva)

Prevention

Currently, there is no known method of prevention of fragile X syndrome (FXS). Individuals who have FXS can meet with genetic counsellors to learn about the risks of having a child with the disorder.

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