Fragile X syndrome

Generality

Fragile X syndrome is an inherited genetic disorder, which, in the carrier subject, mainly involves: developmental delay, learning difficulties, social problems and behavioral problems.

Boy with fragile X syndrome. Image from wikipedia.org

Example of a triplets expansion genetic disease, the fragile X syndrome is due to a mutation of a gene, called FMR1, which produces, in normal conditions, a protein (FMRP) fundamental for the correct development of the human nervous system.

In addition to learning difficulties, developmental delays, etc., the typical symptomatic picture of fragile X syndrome also includes: stuttering, echolalia, autism, impulsiveness, difficulty in understanding body language, hyperactivity, convulsions, anxiety, disorders of the sleep as well as a series of fairly characteristic physical anomalies.

People with fragile X syndrome are, almost always, non self-sufficient subjects, who struggle to fit into a social context.

Typically, the diagnosis is based on: physical examination, medical history, analysis of family history and a genetic test for the FMR1 gene.

Unfortunately, there is no cure for the fragile X syndrome. Therefore, those born with this disease are destined to live with it and with its consequences for life.

What is fragile X syndrome?

Fragile X syndrome is a genetic hereditary disease which, in the subject concerned, is responsible for learning difficulties, developmental delays, social problems and behavioral problems.

Fragile X syndrome is also known by the acronym FXS - which stands for Fragile X Syndrome - and with the name of Martin-Bell syndrome .

Epidemiology

Fragile X syndrome is more common among male subjects. In fact, according to a reliable statistical research, it would affect a male individual every 4, 000, compared to a female individual every 8, 000.

Fragile X syndrome holds the sad record of being the most common inherited cause of mental disability in male youth .

Causes

A pair of particular chromosomes, called sex chromosomes, determines the sex of a human being.

There are two types of sex chromosomes: the sex chromosome X and the sex chromosome Y. From this, it follows that the possible pairs of sex chromosomes that can determine the sex of an individual are two: the XY pair and the XX pair .

The presence in the cells of a new human organism of a pair of XY chromosomes determines the male sex, while the presence of a pair of XX chromosomes determines the female sex .

This premise was a must to understand the causes and other details of fragile X syndrome.

Fragile X syndrome occurs due to mutations in the FMR1 gene, present on the X chromosome.

Under normal conditions, the FMR1 gene produces (in technical jargon, it is said that it encodes) a protein called FMRP, which plays a fundamental role in the correct development of the human nervous system.

In individuals with a mutation of FMR1, the production of FMRP is altered and this compromises the neurological development of the human being concerned.

CHARACTERISTICS OF THE MUTATION: TRIPLETTE EXPANSION

Fragile X syndrome is an example of a "triplet expansion" genetic disease.

"Triplet expansion" genetic diseases are particular conditions, whose triggering mutation involves an exaggerated and abnormal lengthening of a specific repeated section of a gene.

They are defined as "triplet expansion" because the exaggerated lengthening (expansion) involves repeated sections of three nucleotides (triplets).

* NB: nucleotides are the units that make up DNA.

Deepening: the triplet of nucleotides that causes fragile X syndrome

On a strictly genetic level, the expansion of the fragile CGG (Cytosine-Guanine-Guanine) triplet, which occurs at one end of the FMR1 gene, is the cause of the fragile X syndrome.

In a completely healthy individual, the CGG triplet is repeated between 5 and 44 times (the average is 29-30 repetitions);
In an individual with fragile X syndrome, the CGG triplet is repeated over 200 times;
There are also two intermediate situations. An intermediate situation provides for between 44 and 54 repetitions; in these situations, doctors speak of a "gray area", to define a condition of slight instability of the FMR1 gene, even if it is often without repercussions. The other intermediate situation provides for between 54 and 200 repetitions; in such circumstances, doctors talk about premutation, to describe a very particular condition in which the individual concerned can develop, over time, some problems (eg: the ataxia and tremor syndrome associated with fragile X) and has a high probability of giving birth to children with fragile X syndrome.

INHERITANCE

Because its presence depends on a defect in the X chromosome, fragile X syndrome is one of the inherited diseases linked to the X chromosome, such as haemophilia or color blindness .

According to most genetic experts (however the debate on this is very open), the inheritance of the fragile X syndrome is dominant with incomplete penetrance in women .

The characteristic of incomplete penetrance in women means that, although women present a mutation in FMR1, they do not always develop fragile X syndrome. The above is important, because it is one of the reasons why fragile X syndrome is less common in the female population.

Symptoms, signs and complications

Fragile X syndrome is responsible for a symptomatic picture whose severity varies from patient to patient, in relation to the severity of the FMR1 gene mutation (the longer the gene is abnormally long, the larger and more severe the symptomatic picture).

That being said, the possible symptoms of Fragile X syndrome are:

Developmental delay (eg, affected children take longer to learn to walk than their peers);
Intellectual and learning disabilities;
Social problems and behavioral problems (ex: the sick don't like the looks on them, they don't like someone touching them, they tend to repeat certain gestures continually and obsessively);
Stuttering;
Ecolalia (trend continues to repeat sentences or words spoken by other people);
Autism;
Impulsivity;
Difficulty understanding body language;
Difficulty concentrating;
Hyperactivity;
Convulsions;
Depression;
Sleep disorders;
Anxiety and anxiety disorders.

POSSIBLE CLINICAL SIGNS

Quite frequently, fragile X syndrome is also responsible for some characteristic physical abnormalities, such as:

Large front, large ears and prominent jaw;
Long and / or asymmetrical face;
Protruding ears, forehead and chin;
Joints, especially those of the fingers, loosened abnormally and hyper-stretched;
Flat feet;
Large testicles (in humans).

DIFFERENCES BETWEEN MAN AND WOMAN

While the man with fragile X syndrome always shows a certain degree of intellectual and learning disability, the woman with fragile X syndrome can also possess a completely normal intelligence

This difference between the two sexes is explained by the aforementioned incomplete penetrance of fragile X syndrome, as far as the female population is concerned.

COMPLICATIONS

As a rule, developmental delays, intellectual and learning disabilities and, finally, social and behavioral problems mean that the patient is a subject incapable of providing for himself, that he tends to social isolation and has major problems in school / work environment.

Diagnosis

In general, the diagnostic procedure for detecting a disease such as fragile X syndrome includes:

A thorough physical examination. It serves to detect those disabilities (intellectual, learning, etc.) typical of the individual with fragile X syndrome;
A precise medical history;
The study of family history. It clarifies if the individual in question has more or less distant relatives, affected by fragile X syndrome;
A genetic DNA test, performed on the patient's blood and specific for the FMR1 gene.

In general, the diagnosis of fragile X syndrome occurs at the 35th-37th month of life, for male subjects, and at 41-42 months of age, for female subjects.

Therapy

Currently, there is no cure that can cure fragile X syndrome. Therefore, those born with fragile X syndrome must live with the latter and with the related problems for their entire lives.

The lack of a specific cure, however, does not exclude that supportive treatments exist, able to alleviate the symptomatology and help the patient in everyday life.

SUPPORTING THERAPY: WHAT DOES IT INCLUDE?

Generally, the supportive treatments indicated in the case of fragile X syndrome consist of:

Language therapy (or speech therapy);
Behavioral therapy;
Sensory integration therapy (it is a type of occupational therapy);
Special education for disabled patients;
Periodic genetic counseling.

Sometimes, supportive care also includes drug administration . Among the drugs that can be useful in the case of fragile X syndrome, we note:

Selective serotonin reuptake inhibitors (eg, sertraline, escitalopram and duloxetine). They are indicated when the patient shows anxiety and anxiety disorders;
Stimulants such as dextroamphetamine or methylphenidate, when the patient shows difficulty concentrating and / or hyperactivity;
Anticonvulsants (or antiepileptics), when the sufferer suffers from epilepsy;
Antipsychotics, when the patient shows mood instability.

THERAPEUTIC IMPORTANCE OF FAMILIES

Doctors and experts in the field of fragile X syndrome believe that the closest relatives of patients have a great importance in determining the effectiveness of supportive therapies.

For this reason, they argue that families should inquire about the characteristics of fragile X syndrome, so as to know precisely how to behave in the face of particular behaviors or symptoms manifested by the sick relative.

Prognosis

Fragile X syndrome has a poor prognosis. This is true for at least three important reasons:

It is incurable;
It lasts a lifetime;
It has such repercussions that the patient is often unable to lead a life independent of other people.

This last point, however, deserves a brief study. According to some recent studies, the negative influence that fragile X syndrome has on patient self-sufficiency preserves 44% of female patients and 9% of male patients; moreover, most sick women are able to obtain a high school diploma, a diploma which only a few male patients can obtain.

LIFE HOPE IN PATIENT WITH FRAGILE X SYNDROME

According to some studies, the life expectancy of patients with fragile X syndrome is the same as that of normal people; according to other research, however, it would be at least 12 years old (NB: it is an average).