What Is Fragile X Syndrome?

Fragile X syndrome is an inheritable genetic condition that doesn't follow the typical distribution patterns of these pathologies. Its expression mechanism is fascinating, and we'll explain it to you below.

Written and verified by el biólogo Samuel Antonio Sánchez Amador.

Last update: 08 June, 2021

Fragile X syndrome is the second most common form of functional diversity, second only to Down syndrome. Due to its clear genetic component, it’s the most widespread hereditary intellectual disability condition in the world. The incidence in men is 1 in 1250 and, in women, 1 in 2500.

This pathology is caused by a mutation in the FMR1 gene, located on the X chromosome. Therefore, it’s a disorder that follows a sex-linked inheritance pattern (men are more likely to express the mutation). If you want to know more about this interesting condition, in addition to learning certain information about genetics, then keep reading.

The bases of genetic inheritance

First of all, it’s necessary to lay a certain foundation on human genetics. Each of the somatic (tissue) cells of an adult is diploid (2n). This means that, within the cell nucleus, there are two copies of each chromosome of the karyotype, one inherited from the mother and another from the father.

Diploidy is a clear evolutionary strategy product of sexual reproduction. Since humans inherit two copies of each chromosome, if one of them has a mutation, then the other is expected to be able to solve it. The karyotype of our species has a total of 46 chromosomes, 22 autosomal pairs and one sexual.

In this case, the pair of chromosomes that we’re interested in is the one that determines the sex. When an embryo product of the fertilization between gametes presents a sex chromosomal pair XX it will be a female, while if it’s XY it will be a male. In pathologies linked to sex (such as fragile X syndrome), this chromosomal endowment explains many things.

It should be noted that the human being contains about 25,000 genes enclosed in all its chromosomes, both autosomal and sexual. Each of these genes has alternative forms, called alleles. Depending on the distribution of the alleles in each individual, this can be categorized as follows:

• Homozygous: a living being is homozygous when the 2 alleles (one from the father and one from the mother) are the same.
• Heterozygous: a living being is heterozygous when the 2 inherited alleles are different.

It must be taken into account that any allele can be dominant (A) or recessive (a). The dominant allele is expressed independently of its partner (whether it’s the Aa or AA individual, homozygous, or heterozygous, “comes out”), while the recessive one is only expressed when its partner is equal to it (aa, homozygous recessive).

Fragile X syndrome causes

As indicated by the magazine Colombia Médica, fragile X syndrome is a dominant condition linked to sex. However, it does not follow the typical Mendelian inheritance patterns, since there are male carriers who don’t manifest symptoms, something not common in X-linked diseases.

The chromosomal alteration, in this case, occurs on the X chromosome, specifically in the FMR1 gene, locus Xq27.3. As a curiosity, it should be noted that the pathology presents a phenomenon known as penetrance, that is, the more generations of sick people that intersect, the worse the symptoms will be.

As for the specific mutation, this is due to the pathological presence of trinucleotides (CGG) in the FMR1 gene, which shouldn’t be there. Depending on the number of trinucleotide repeats, 4 types of alleles are differentiated with slightly different symptoms and prognosis. In summary, due to the mutation, the gene is methylated and not expressed.

The FMR1 gene is essential for development. This encodes the information necessary for the formation of a protein (FMRP) responsible for maintaining normal cognitive development, promoting neural connections and much more.

A most unusual inheritance mechanism

This pathology doesn’t follow a Mendelian inheritance pattern. In other words, the fact that a father is a carrier doesn’t necessarily mean that he will get sick, despite the fact that the mutation is dominant and is present on the only male X chromosome (remember that males are XY).

What determines the onset of the disease is the number of trinucleotide repeats in the mutant FMR1 gene. At general levels, the following statements can be made:

1. In the general healthy population, the number of CGG repeats is less than 52.
2. Carriers have a mutated gene with about 53-200 copies of the nucleotide triplet.
3. In symptomatic people (with fragile X syndrome), most of them have 200 or more repeats of the gene.

It’s estimated that one in 240 women carries the mutated gene, while in men this value rises to one in 800. The more generations that are produced from parents with mutated genes, the more likely it is that the offspring will accumulate enough CGG repeats and express the disease.

On the other hand, it should be noted that there are more men than women with this condition. Since girls have two copies of the X chromosome, even if one of the FMR1 genes is inactivated, the other can prevent the disease from manifesting itself. As males only have one X chromosome and one FMR1 gene, as soon as it’s inactivated, the condition is always produced.

Symptoms of Fragile X syndrome

At a genetic level, this pathology is fascinating, as it breaks with all the genetic bases established by Gregor Mendel in his day. In any case, we can’t forget that we’re facing a chronic disease, with all that this entails. People with fragile X syndrome have a series of associated symptoms that vary in severity.

This condition occurs in different ways and the Statpearls medical portal reveals the most characteristic medical signs. Don’t miss them:

1. Physical signs: Flat feet, flexible joints and reduced muscle tone, large ears and forehead, prominent jaw, long face, larger than normal body proportions and smooth skin, among others. Macroorchidism, an abnormal development of the testicles, is also common.
2. Autism: 30 to 60% of fragile X patients have autism. This causes social problems beyond cognitive development.
3. Behavioral problems: Attention deficit when learning, hyperactivity, confrontational behaviors, social anxiety, and more.
4. Variable mental retardation.

Notably, the clinical signs of this condition are a spectrum . Depending on the amount of FMRP protein that can be synthesized (linked to the number of nucleotide repeats of FMR1 ), the degree of delay and the symptoms will be more or less evident.

A disease or a condition?

Neither do we want an ethical debate, but it’s worth stopping to wonder whether we’re really talking about a disease, problems, or other concepts. People with Fragile X have an excellent visual memory, good long-term memory, an exceptional sense of direction, and a very good sense of humor.

It’s true that they also have certain cognitive problems, but perhaps we shouldn’t consider them as being ill, but, rather, as people located at a different point on the human cognitive and emotional spectrum. All the information presented here analyzes the condition from a clinical point of view, but, at a social level, there’s still much to do.

Diagnosis

As indicated by the MSD Manuals medical portal, the diagnosis is usually made once the child has been born, through DNA tests. However, the number of CGG repeats is quantifiable on the X chromosome, so the risk of a child being born with fragile X can also be calculated by analyzing the genome of both parents.

In addition, the baby’s genome can be analyzed during pregnancy, by obtaining DNA from chorionic villi (cells of the placenta that are the same as those of the fetus). This can help to establish a series of early treatments and, above all, it helps the parents to carry out the necessary family planning.

Most people don’t suspect that they carry mutations in the FMR1 gene.  For this reason, the diagnosis of the patient is usually made when they have reached a certain age and their symptoms are obvious.

Fragile X syndrome treatment

Unfortunately, epigenetic mechanisms haven’t gone far enough to reliably modify human DNA. In addition, all this would entail a series of ethical approaches, which are, to say the least, doubtful. For all these reasons, there’s currently no treatment for Fragile X syndrome.

However, as indicated by the Centers for Disease Control and Prevention (CDC), occupational therapy, special education, sensory integration methods and many other approaches can help the patient. With proper attention during cognitive development, these people can lead happy and fulfilling lives.

Apart from psychological approaches, certain medications are sometimes prescribed for people with this condition. These aren’t aimed at treating fragile X syndrome, but at alleviating the symptoms of the autism spectrum to which the condition is usually associated. Among them, we can highlight the following:

1. Stimulants: These work in the field of hyperactivity, impulsivity, and attention problems.
2. Antidepressants: Useful in the treatment of anxiety, obsessive-compulsive symptoms, and extreme fluctuations in emotional state.
3. Antipsychotics and anticonvulsants –  to treat aggressive attacks and seizures, respectively.

Does Fragile X require treatment?

We want to close this article with an interesting reflection. The World Health Organization (WHO) defines the term disease as the ‘alteration or deviation of the physiological state in one or more parts of the body, for generally known causes, manifested by characteristic symptoms and signs, and whose evolution is more or less predictable. ‘

Does Fragile X syndrome fall within this definition? The truth is that it doesn’t, as the life expectancy of the people who have it is practically the same as that of the general population. The most defining aspect of this condition is the tendency to the autism spectrum, and, in general, this condition is no longer considered to be a pathology.

What is actually treated in people with fragile X syndrome are psychological problems, but the general population have them too, and require the aforementioned drugs despite not having the condition. Therefore, it’s a good idea to reflect on the subject and ask ourselves whether the non-neurotypical should be considered to be an illness or not.

A fascinating condition

Fragile X syndrome is a fascinating condition, both on a social and genetic level. Their non-Mendelian heritage exemplifies that it’s sometimes very difficult to predict whether a child will have the condition or not, even if both parents are carriers.

The life expectancy of people with fragile X and their multiple aptitudes make us wonder if this “disease” can really be categorized as such. From here, the only possible path is the reflection of the readers themselves and the advancement of science in the field of genetics.