Overview

Fragile X Syndrome, commonly abbreviated as FXS, is a genetic condition that leads to developmental delays and learning disabilities that are usually asymptomatic (or without symptoms) until puberty (NICHD). FXS is a genetic disorder caused by a mutation in a gene called FMR1 (Fragile X Messenger Ribonucleoprotein 1) that leads to an individual’s inability to make a protein necessary for the development of synapses, and therefore, higher cognitive brain development. Consequently, parents may face challenges raising their child(ren) if they are not able to implement treatment services that improve the child’s social development. The rest of this article aims to unravel the complexity of FXS in adolescents, and the challenges and support possible with FXS.

Background

Genetics & biology

The term, genetics, refers to the biological information (DNA) that an individual has that can be inherited (i.e. passed onto future children) (National Genome Institute). Human DNA is incredibly long (two metres long) and as such requires to be coiled into a smaller form.¹ These forms are called chromosomes, and each individual will generally have 23 pairs of them (46 total).^1,2 Twenty-two of the paired chromosomes are termed ‘autosomes,’ while the remaining pair are called the sex chromosomes since they determine an individual’s sex. 

Within human chromosomes, the coiled DNA can be grouped into genes that contain the code for the body to make essential proteins.² These processes are named; transcription-the process where the body ‘reads’ the information on a gene and produces messenger RNA (mRNA); while translation is the process that takes the mRNA and translates it into proteins.³ These proteins are then used for fundamental biological processes, serving as catalysts (proteins that speed up chemical reactions) aiding in DNA repair and cell replication, necessary for growth and health.

Modes of inheritance & dysfunctional genes

When having a child, each parent will give one chromosome to their future child (hence 23 paired chromosomes). Consequently, a person will generally receive two copies of each gene.⁴ However, this means that if one gene is dysfunctional, problems can occur. The way these genes are inherited can be classified depending on the amount of dysfunctional copies (one or both) needed to cause disease. These classifications, or modes of inheritance, depend on the type of chromosomes in question. A disorder with an autosomal dominant mode of inheritance implies that only one dysfunctional gene copy (dominant) on an autosomal chromosome is needed to cause disease. Contrastingly, an autosomal recessive mode of inheritance refers to a person needing both copies (recessive) of a dysfunctional gene to cause disease.

Sex chromosomes are more complex, however, as each sex has different chromosomes: XX for females and XY for males (in humans).⁵ The Y chromosome is responsible for male processes such as testis (testicle) development and spermatogenesis (formation of sperm).⁶ This means that all male (XY) offspring inherit their X chromosome from their mother and their Y chromosome from their father. On the other hand, female (XX) offspring will receive an X from both their mother and father. The disorders related to sex chromosomes are therefore termed sex-linked. Sex-linked modes of inheritance include: X-linked dominant, X-linked recessive, and Y-linked, although inheritance of Y-linked disorders is very rare in humans.^6,7 This is because Y-linked diseases would generally lead to negative effects such as infertility, which would then mean that the father would be unable to pass on the disorder to offspring. For this article, only X-linked dominant will be discussed further, but if you are interested in reading further on other modes of inheritance, please read about X-linked disorders from the NHS.

Fragile X syndrome

Inheritance 

Fragile X Syndrome (FXS) has an X-linked dominant pattern.⁸ Dominant, meaning only one copy is needed to cause disease, and X-linked meaning a gene found on the X chromosome. Disease probability will depend on the sex of the offspring and who they received their X chromosome from. Let us use the following denotations: 

Table 1. X-linked Dominant Inheritance. Female offspring will always receive one X from their mother and one X from their father. In male offspring, the X chromosome will always come from the mother (either X^f1 or X^f2) and receive Y from their father. 

Using FXS as an example, both female and male children have a 50% chance of having the dysfunctional gene if the mother is affected and the father is healthy. This is because each child inherits one X chromosome (in this case, either X^df1 or X^f2) from the mother and one sex chromosome from the father (either X^m or Y). 

When the father is affected, 100% of female offspring will have the dysfunctional gene, while 0% of the male offspring will have the gene. Similar to the explanation above, female offspring will always inherit one of their X chromosomes from their father. Consequently, since fathers (XY) only have one X chromosome, female offspring will always get FXS. 

Conversely, male offspring will always inherit their father’s Y chromosome; therefore, if only the father is affected by an X-linked disorder, male offspring will always inherit healthy X chromosomes from their mother (0% chance of disorder). 

Despite female offspring having a 100% rate of inheritance if the father has the disordered X (X^dm), male children with FXS often have more severe symptoms in comparison to female children, and are diagnosed at higher frequencies, with 1 in 7,000 in males and 1 in 11,000 in females (CDC). This has been attributed to the process in female mammals known as X-inactivation.⁹ In many organisms, a process known as ‘dosage compensation’ occurs, where the expression of genes should be somewhat equal in number to prevent uneven copy number inheritance.¹⁰ In female mammals, due to having two X chromosomes, the ‘dosage’ of the genes on the X chromosome will be double that in male mammals. This is then where X-inactivation is used to ‘silence’ a random X chromosome to equalise the expression between the sexes.¹¹

Biology of FXS

The disordered gene in FXS patients is called the FMR1 gene, or the Fragile X Messenger Ribonucleoprotein 1 gene. As the name suggests, the gene produces Fragile X Messenger Ribonucleoprotein (FMRP). This protein is responsible for the development of synapses, particularly their structure.¹² In FXS patients, The production of this protein is defective due to impaired transcription.^12-15

Symptoms & challenges

Challenges with children or adolescents with FXS are often related to their behaviours. A list of the symptoms and challenges are listed below:

In younger children (CDC):

• Developmental delays
  • E.g. sitting, crawling, walking, and talking later than other children
• Learning disabilities
  • Difficulty learning new skills

In both younger children and older

• Behavioural problems
• Lack of eye contact
• Anxiety and depression
• Seizures
• Autistic behavioural traits
  • Doing repetitive tasks, hand-flapping
• Attention Deficit/Hyperactivity Disorder (ADHD)-like symptoms
• Obsessive Compulsive behaviours (OCD)
• Low IQ (generally <55 in males)

Physical features that are correlated with FXS children are more commonly seen as they age, which include (NICHD):

• Bigger forehead
• Bigger ears
• Flat feet
• Narrow face

A study reporting young adults (18–33) with FXS or their parents'/carers' opinions (for all the male patients with FXS) was completed, surveying the challenges that they had faced during their transitional period during adolescence.¹⁶ The study interviewed 5 patients with FXS and 33 parents of children with FXS. A summary has been made below:¹⁶

• Aggression and self-made injuries were noted by parents of male FXS patients.
  • Usually due to anxiety or frustration, arousal or overstimulation.
  • These included biting, scratching, removal of their own nails, and bleeding
  • Sometimes these behaviours were directed at siblings.
  • Problems were said to decrease generally after adolescence.
• Stress and anxiety in both male and female FXS patients were the main reported challenges, especially when the patient was affected by unknown surroundings such as doctors or hospitals.

Support

There is no cure for FXS, and therefore, early intervention and treatment are the best methods for ensuring your child can learn the necessary skills required for life in the future.⁸ 

FXS is underreported due to having similar symptoms with other cognitive impairments.⁸ Therefore, genetic testing, or talking to a genetic counsellor can also help parents discuss the probability of FXS if they would like to have more children.⁸ 

There is no drug treatment for FXS itself. Medication is restricted to treating symptoms such as depression, anxiety, ADHD, etc.⁸ 

Psychiatric counselling is often recommended for patients who have mood disorders or fears of certain objects or situations.⁸ 

It would be beneficial to reach out to possible FXS support groups surrounding the area that you live in. Websites such as the National Fragile X Foundation or the Fragile X Society have online resources that may aid you in your endeavours. 

Summary

Fragile X Syndrome (FXS) is a genetic disorder that leads to intellectual disabilities. It is an X-linked dominant disorder, requiring only one copy to cause the disorder to manifest, however, it does not manifest in the standard X-linked dominant fashion. This is because X-inactivation in female patients leads to reduced or milder symptoms in females than in males. Biologically, FXS arises from a mutation in the FMR1 gene, which stops FMRP from being made. This results in an overabundance of proteins that cause seizures and developmental delays. Challenges with FXS are often behavioural in adolescents, however, management is possible through therapy or support groups.