Fragile X syndrome

Content

Introduction

Introduction

Fragile X Syndrome (FXS, from English Fragile X Syndrome), or Martin-Bell syndrome, is a genetic disease caused by an alteration (mutation) of the FMR1 gene (from the English Fragile X Mental Retardation 1), located on the X chromosome.

The complete mutation of the FMR1 gene interferes in the production of a protein called FMRP (Fragile X Mental Retardation Protein) causing fragile X syndrome.

Fragile X syndrome can occur in both men and women but its frequency in males (1/4000) is higher than that in females (1/8000).

Symptoms

Symptoms

People with Fragile X syndrome have problems that can be different from individual to individual and although not evident at the time of birth they appear later. In males, there may be a delay in the main stages of development, problems in language and behavior, anxiety, attention deficit hyperactivity disorder (ADHD) and intellectual disability of varying degrees (mild / moderate).

In some cases (about one third), behaviors referable to an autism spectrum disorder may occur.In females, problems with memory, attention, reasoning (cognitive impairments) and behavior are usually mild and more often include shyness, social anxiety and mild learning disorders with an IQ in the Attention Deficit / Hyperactivity Disorder (ADHD) is found less frequently.

Some nuanced physical characteristics may become evident as we age such as:

  • face narrow and elongated
  • prominence of the ears and forehead
  • extreme laxity of the joints of the fingers
  • flat feet
  • enlarged testicles (macroorchidism), in males after puberty
Causes

Causes

Fragile X syndrome is caused by an alteration (mutation) in the FMR1 gene located on the X chromosome. This alteration consists of the expansion of a segment of DNA, known as the CGG triplet, within the FMR1 (Fragile X Mental Retardation) gene. 1).

In fragile X syndrome, the number of repeats of the CGG triplet exceeds 200 (complete mutation). The FMR1 gene has several functions. These include the production of a protein called FMRP (Fragile X Mental Retardation Protein) involved in numerous processes of nerve cells (neurons) In the case of a complete mutation, the FMR1 gene is no longer able to produce the FMRP protein and this causes the onset of the syndrome.

The condition in which the CGG triplet is repeated in a number between 55 and 200 is defined premutation. This sequence, when passed on to offspring, can expand producing over 200 CGG triplets, and is called a complete mutation.

Genetic counseling should be offered to people with the mutation or premutation, and their families, to inform them comprehensively about the causes and inheritance.

Being a person with the premutation does not mean having Fragile X syndrome. The most recent research has identified some conditions that may affect some people with the premutation. Between these:

  • Tremor syndrome and Ataxia associated with fragile X (FXTAS), a condition that can arise in old age (over 50 years of age) and that mainly affects males
  • Premature Ovarian Failure (POF) syndrome associated with fragile X (FXPOI), a condition that can manifest itself with reduced or abnormal ovarian activity

It is recommended that qualified personnel discuss the significance and implications of this condition with people carrying the premutation.

Diagnosis

Diagnosis

In some cases, the specialist doctor may suspect the presence of Fragile X syndrome on the basis of certain disorders; in other cases, it is the appearance of intellectual disability that makes genetic testing necessary. Advanced diagnostic suspicion based on physical signs is less common, especially in young children.

The detection of fragile X syndrome is performed through the study (genetic analysis) of the FMR1 gene. The analysis consists of a blood sample and is performed in numerous specialized structures distributed throughout the national territory. Within some of them it is also possible to undergo genetic counseling carried out by a specialist doctor. The person is evaluated clinically and the results of this evaluation and genetic analyzes are shared with his family.

It is recommended that qualified personnel provide comprehensive information on the genetic test, the significance of the result and the inheritance mechanisms of Fragile X syndrome. Any indication as to which other family members, in addition to the person concerned, might be interested in carrying out the genetic test must be provided by the doctor.

The detection (diagnosis) of Fragile X syndrome before birth is proposed, according to the international guidelines, to women with a premutation and / or a complete mutation of the FMR1 gene. The genetic analysis is performed on a DNA sample collected via amniocentesis or CVS. Information on how prenatal diagnosis can be performed and on genetic pre-implantation (PGD) and preconception (PCGD) investigations should be provided by the physician.

Therapy

Therapy

The person with Fragile X syndrome and his family are followed by a team of experts (multidisciplinary team) with different skills. The doctor who follows the patient in the developmental age is the child neuropsychiatrist specialist. It is up to him to coordinate all the other professional figures involved in the rehabilitation of the child. Early intervention can help children increase their skills. The care prescribed to the child with fragile X syndrome must be individualized and directed to help his development also at school and in the family through the involvement of parents.

In some cases, it is possible that the specialist doctor prescribes drug therapy.

Living with

Living with

People with Fragile X syndrome and their families must receive the necessary support to promote the quality of life, participation and inclusion in school, society and work.

The Registers

Children with Fragile X syndrome can be referred by the treating physicians for insertion into the Regional and National Registers of Rare Diseases. These are useful tools for studying strategies for preventing and treating the syndrome. However, it will be possible, at any time, to request cancellation from the register.

Associations

There are Italian and international associations that offer support to families in acquiring information on rights and on projects to develop autonomy. You can find information by visiting the websites or by contacting the associations directly (Italian Association of Fragile X Syndrome).

Bibliography

Bibliography

National Institutes of Health (NIH). Fragile X syndrome (English)

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