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Fragile X is a family of inherited genetic conditions, in particular Fragile X Syndrome. The gene which causes Fragile X Syndrome can also impact carriers of the genetic anomaly.
Fragile X Syndrome is the most common inherited form of intellectual, developmental and learning disability and autism. The genetic issue that causes Fragile X Syndrome lies on a single gene on the X chromosome. If this gene is fully mutated, the gene cannot fulfil its normal function any longer, and the protein it encodes cannot be produced anymore. The lack of the fragile X protein has various effects in different cells of the body, in particular in the brain cells, the neurons.
The name of the Fragile X gene/protein is Fragile X Messenger Ribonucleoprotein 1, abbreviated FMR1/FMRP.
Fragile X Syndrome is a rare condition, it occurs only in about 1:4000 males and about 1:6000 females.
It is believed that people with Fragile X Syndrome have a normal life expectancy. However, often due to reduced communication skills, one must be aware that the affected people might need help in recognising and reporting health problems, in particular, but not limited to, in adulthood.
No. There have been various attempts to influence the effects of the missing protein, but so far, no positive outcomes of significance have been found. Due to the complexity of the underlying alterations in the proteomics caused by Fragile X Syndrome, a pharmacological “cure” in its actual meaning is unlikely to be found.
Other theoretically thinkable interventions like the “gene-scissor” CRISPR/Cas suffer other fundamental barriers in application.
Some pharmacological treatments are available for the symptoms a person might experience (e.g. anxiety; ADHD; gastro-intestinal problems), none of them without side effects that one has to consider.
We will add a special section on Fragile X research in the future on fraxi.org.
It is very important to start giving the child support therapies as soon as the diagnosis has been reached. In some countries, there are early intervention programs for children with special needs that should be consulted. One of the most important therapies is speech and language therapy, as it will help the child communicate with the environment. Children with Fragile X Syndrome often don’t dare to begin speaking, as they think they can’t do it. Speech therapists can help overcome these anxieties. Other important therapies include physiotherapy, for example in addressing poor muscle tone, mobility issues and proprioception; behavioural therapy, addressing sensory integration issues and triggers for outbursts; occupational therapies; and educational therapies.
We recommend first consulting a national Fragile X family association, if that is available in your country. However, there may not be such an organisation yet, but an organisation in another country speaking the same language might be worth contacting. Sometimes, the social and/or health system may provide support for children with disabilities.
[To be included: Link to list of FraXI members and other FX family organisations] Why is the genetic condition called “Fragile X Syndrome”?
The gene that causes Fragile X Syndrome is located on the X chromosome. Until the gene was identified in 1991, it was only possible to diagnose the condition under the microscope, where the X chromosome then appears as if it is fragile.
Photo courtesy of Professor Christine J Harrison, Paterson Laboratories, Christie Hospital, Manchester.
Fragile X develops over multiple generations. For some still unknown reasons, a tiny bit of the gene that can cause Fragile X Syndrome eventually may mutate with a specific piece growing inside the gene from one generation to the next. This process can only happen from a mother to her offspring. Once the extension of the gene has grown to a certain size, the premutation of the gene turns into a full mutation in the next generation, and the gene does not function anymore, resulting in Fragile X Syndrome.
Mothers have two X chromosomes, and therefore can either forward the X chromosome with the healthy gene or the mutated one (premutated or fully mutated) to her children. If the gene was already fully mutated, or if it was severely premutated, the child will have a fully mutated gene and have Fragile X Syndrome.
Fathers give their sons a Y chromosome and therefore any mutation on their X chromosome will have no effect on their sons. Fathers give their daughters their X chromosome, and therefore, if the relevant gene is affected, fathers will pass it on to all their daughters. However, the mutation does not grow if forwarded by fathers, and therefore it will not cause Fragile X Syndrome in the father’s daughters: only the premutation is inherited.
Further reading: https://www.cdc.gov/ncbddd/fxs/inherited.html
First of all, it is important to seek help. It is very likely that you will run into one or two problems, and there’s nothing bad about looking for support. You are not alone. Experts and support organisations (like your country’s Fragile X association) can offer help and support.
If you have friends and family members, try to involve them. Explain the situation to them, tell them what you know about Fragile X Syndrome (FXS) and the character of your child. If they can spend some time with your child (which will then give you some time for yourself), that can be of great help!
It can be difficult to find professional help from doctors, as many will not know anything about FXS. A paediatrician may only experience one child with FXS in his or her whole practice career. It is more likely that you will find a therapist who may have seen a child with FXS before, as they are specialists in children with special needs.
Don’t wait to begin speech therapy if your child doesn’t seem to start speaking. And even then, if their speech is hard to understand or is further delayed, try to find a good speech and language therapist.
It is very important to prepare staff before the child enters kindergarten. They need to know how the child “functions”, what should be avoided, what needs to be prepared.
There are several important points:
Actually, all the points above in regard to pre-school also hold true for primary education. Having an ‘About Me’ statement for the child, that explains how best to support them in their learning, is a real help. An educational or occupational therapist can help with this.
The choice of school often depends on the possibilities a country or region offers for pupils with special needs. As the child develops, there are decisions to make that are very much based on the individual.
Some children (particularly girls) with Fragile X Syndrome (FXS) can happily continue into secondary education in a regular school. Some will even go to a college or on to a university, or decide for vocational education. Often, males may attend a regular school that can offer support for their needs in order to be able to follow education based on their individual possibilities. For others, a special school might be the better choice.
The important thing is to have a happy child who is settled. There are many possibilities and it is important to discover what they enjoy doing. For parents, it is important to carefully examine what is available in their region and to talk to teachers and school personnel in order to find out where there child will get the best education. Often, teachers never had a child with Fragile X, so it is important to explain to them what is needed in order to optimally support the child.
> Behavior and FXS
It is never too early to start with preparations, but it can easily become too late. As soon as education approaches an endpoint, one should take a look around and do some research about different possibilities. Depending on the country you live in, there will be social programs provided by the government; charities which support those with disability to find work; social enterprises for employment; shared living accommodation; training in independent living and life skills. It is important to find out what is available where you live. Your country's fragile x association can give you guidance on this. Talking to other fragile x families is also useful, as you can get ideas and learn from their experiences.
[To be included soon]
Genes are contained in the cell nucleus. They are like recipes for producing proteins or enzymes. Every time a protein is needed, the recipe for it (=gene) is read and the protein is produced inside the cell. Some of the recipe “text” is very important, while other is there for organisational purposes only. Like the headline “Cheesecake” for a cheesecake recipe, there is a little bit of information in a gene that precedes the actual recipe.
In the case of the FMR1 gene, there is a little part inside of that prefix that consists of a certain number of repeating occurrences of recipe text denoted by “CGG”. In the normal case, that number of repetitions of the CGG triplet is about 32 on average. For some still unexplained reasons, it can happen that the number of CGG repeats grows from one generation to the next. Unfortunately, this process can happen again in the next generation, until the sequence length of CGG finally becomes problematic (and the gene is considered being mutated). There are different levels of being “problematic”. The various levels are explained in the next question/answer section.
However, eventually, there can be so many CGG repeats that the gene is considered “dubious” and the gene’s information marked unreadable by the cell. The analogon of a cake recipe: imagine you read to use one pound of yeast in a single cake. You’d be better off not using that recipe, or end up with a real mess in your kitchen!
Further reading: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001625/
The Fragile X genetic mutation happens in different stages. Once the gene starts mutating, the mutation may (or may not) continue and get more severe from one generation to the next (see also above “What actually is the Fragile X mutation” and “How is Fragile X inherited”).
“Getting more severe” means that the CGG triplet repeat number in the gene grows from its average size of approx. 30 first to around 50 (the “grey zone” ranging from 45-54 CGG triplets).
At the end of this continuing mutation process, the CGG repeat size may have reached a number greater than 200, up into the thousands, and the gene will be shut off. The person carrying that gene will develop symptoms of Fragile X Syndrome (FXS).
But even before the gene has reached the full mutation stage (200+ CGGs), that is, between 55 and 200 CGGs, it may have effects on people carrying this so-called Fragile X (or FMR1) “premutation”. There are various conditions associated with the premutation, collected under the term “Fragile X Premutation Associated Conditions” (FXPAC, see next question).
About every 200th female and about every 400th male in the general population carry the FMR1 premutation.
It is important to note that the higher the number of CGG repeats of a woman with the FMR1 premutation is, the more likely it is that her offspring will be born with the FMR1 full mutation, and therefore, develop symptoms of FXS. However, most female carriers of the FMR1 premutation have a lower number of CGG repeats, making it less likely that their children will have FXS.
FXPAC (Fragile X Premutation Associated Conditions) is a term that collects the possible effects of the FMR1 premutation on those who are carriers of the fragile x gene..
The most common conditions affecting carriers of the FMR1 mutation are Fragile X associated primary ovarian insufficiency (FXPOI) and Fragile X associated tremor ataxia syndrome (FXTAS). FXPOI can only affect women, whilst FXTAS is more common and also more severe in (older) men. Both conditions are described in the next sections.
Other issues which may affect carriers are:
- Chronic pain
- Sleep apnea
However, it is believed that in general, premutation carriers are not sicker than individuals in the general population.
The exact influence of the FMR1 premutation is still under investigation. It will need more research to get a clearer view of the symptoms/conditions a premutation carrier may develop.
Further reading: https://www.science.org/doi/10.1126/sciadv.aaw7195
Fragile X Primary Ovarian Insufficiency (=FXPOI) is a condition in which the ovaries’ function is reduced. It affects about 1 in 4 women carrying the FMR1 premutation.
Symptoms can include menstrual irregularities, early menopause (before the age of 40) and infertility.
In particular for family planning, but also for their own health awareness, it is important that women who have been diagnosed with the FMR1 premutation are aware of the fact that they may develop symptoms of FXPOI. Often, diagnoses of the FMR1 premutation are made only after a child was diagnosed with Fragile X Syndrome. However, there are cases where a woman was first diagnosed with FXPOI and only after that, the child was diagnosed with Fragile X Syndrome. Women carrying the full mutation are not affected by FXPOI.
Further reading: https://medlineplus.gov/genetics/condition/fragile-x-associated-primary-ovarian-insufficiency/
Fragile X associated Tremor/Ataxia Syndrome (FXTAS) is a neurological condition that can occur in both older females and older males carrying the FMR1 premutation. It is more severe and more common in males. Normally, affected people are the grandparents of a child with Fragile X Syndrome.
As the name suggests, major symptoms of FXTAS are intention tremor (trembling/shaking hands), ataxia (balancing problems), cognition issues (short term memory problems, inability to plan things), anxiety and depression. It is sometimes misdiagnosed with Parkinson and/or Alzheimer’s disease.
About 4 out of 10 men over the age of 50 develop symptoms of FXTAS with a variable spectrum and severity of symptoms. Only about every 6th woman with the premutation is affected by FXTAS.
People with the FMR1 full mutation (and therefore, people with Fragile X Syndrome) are not affected by FXTAS.
Further reading: https://medlineplus.gov/genetics/condition/fragile-x-associated-tremor-ataxia-syndrome/#description
Girls have two X chromosomes. In each of their body cells, one X is switched off, and only the other one is responsible for all its biological cell functions. If one of the X chromosomes of a female carries the full mutation of its Fragile X gene, it depends on how many cells have that affected chromosome activated. The fewer cells (in particular the brain cells) which have the Fragile X chromosome activated, the less the girl or woman will be affected by the symptoms of Fragile X Syndrome (FXS). Unfortunately, that often means that the effects of FXS in females are not as easily visible and detectable as in males. Therefore, a diagnosis will often only be reached much later, or even never, causing the affected female to be misunderstood in a lot of situations in life.
Mosaicism in genetics basically means that there can be variations of a gene in one body. In Fragile X Syndrome (FXS), there are two forms of mosaicism, so called size and methylation mosaicism.
Size mosaicism means that there are variations of the level of mutation of the Fragile X gene among the cells (in terms of the length of the CGG repeat number). That means, in some cells, the FMR1 gene is only premutated whereas in others, it is fully mutated.
Methylation mosaicism means that the Fragile X gene is mutated in all cells, but that it is shut off by methylation in some cells and still functioning in others where the gene is unmethylated.
In both cases, the severity of the FXS symptoms may be reduced, depending on how many cells can produce FMR-protein.
Mosaicism is quite common in Fragile X (with size mosaicism occuring more often than methylation mosaicism), leading to a wide spectrum of the severity of symptoms amongst individuals with FXS.
Further reading: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924764/
Short answer: Of course! It is almost certain that you will need help and support from your family. And it is important that they understand your child, and that it will have special needs.
Also, Fragile X is a family condition. This means that due to its inheritance pattern, it can occur in various branches of the family tree. So, it might be really important that other family members know that there is something that may have affected their children or be important for future generations and family planning.
Some members of the family, particularly the grandparents (but also some mothers), may develop feelings of guilt, in the sense that they are responsible for forwarding a genetic condition to their offspring. Talk to them, tell them there is zero responsibility for forwarding a genetic condition. Zero.
Having said all of this, in some cases people choose to tell only selected family members and very few friends as they feel their child will be treated badly if the condition is known. This might be more relevant in the case of girls, where discrimination and stigmatisation can occur. Sometimes families prefer to explain that their child has mild learning difficulties, or needs support in some areas. FraXI is working against discrimination and stigmatisation, so that the world is much more accepting of people with Fragile X Syndrome.
This is a personal decision - some families choose not to tell their Fragile X Syndrome (FXS) child with severe intellectual disability as they would not understand and it might frighten them. However, other parents feel it is best for their child to grow up knowing they have something called Fragile X Syndrome. That it is a part of who they are.
Whether and when you choose to introduce the topic to your child is up to you. They might not ever fully understand the condition, but at least they have a reason for why they might struggle when seeing others around them (e.g. at school) do things more easily. Do talk this issue through with other families who have children with FXS, and seek support and advice from your country organisation.
It is often good for the child to share their condition with their classmates or in a school assembly. This can raise awareness of Fragile X Syndrome, create an understanding of the condition and lead to a more welcoming and inclusive environment at school. This sharing can be supported by a family member (parent or sibling) as appropriate. The important thing is to celebrate each person’s individuality and to promote inclusion and affirmation.
Parents of a child that has been diagnosed with Fragile X Syndrome (FXS) may want to have another child and ask themselves if their next child will also have FXS. As FXS is a genetic condition that is a possibility. The chance that the next child will also have Fragile X Syndrome is about 50:50. IMPORTANT: This probability is the same whether or not the previous children have FXS.
It is possible to use medical interventions that are aimed at ensuring a future child does not have FXS. This is an ethically problematic topic. Some parents may feel that avoiding a second child with FXS indicates that they also do not really accept their first child. Other parents may prefer to avoid a future child having FXS, much as they love their affected child. None of the available options that families have in this situation are unproblematic.
In what follows here, a few things must be kept in mind, and you must have understood and accepted these before continuing to read:
Ideally, your national Fragile X association will be contacted by researchers who want to do research about Fragile X. Your association would then do some checks to see if safety and ethical requirements are fulfilled. Provided everything looks in order, they would pass the information on to the association’s members. If you get directly contacted by research institutions, you need to make sure yourself that everything is fine. Of course, in many countries, every research project involving patients/vulnerable individuals needs to go through an ethical check process, e.g. by applying at a University’s ethical committee, in order to get confirmation that good ethical principles are met. However, often the time frame for this process is very short and experts in the field will hardly be involved in the ethical committees’ decision process. Your country association can seek advice from FraXI’s Research Committee when considering research opportunities.
Particularly in clinical trials involving new medication candidates, families should be especially careful, as there are several risks involved. Questions like “Have I really understood what is given to my child?”, “Do I really know the possible side effects?”, “Do I really think my child is willing to take part in the trial?” are of great importance and should honestly be considered and answered. In particular, the last question is far from easy to answer, as most people with Fragile X can’t give consent to participate in a medical trial on their own.
Please consult with your paediatrician or general practitioner, or whoever medical professional is responsible and would prescribe the desired medication. Make sure he/she and in particular, you yourself have completely understood what kind of side effects may occur. Plus, it needs to be kept in mind that people with Fragile X may not be able to report medical problems properly. So the time it takes until the caring persons realises there is a problem that occurred with a medication can be longer than usual, and may have gotten more severe until then. In all cases, medical professionals must be involved when considering a pharmaceutical intervention for a person with Fragile X, and there must be constant supervision.
Fragile X Syndrome is coded in several medical coding systems, among them ICD-10/11 and ORPHA-Code. The particular codes for Fragile X Syndrome are:
Diseases/conditions are coded, that is, they get a number (code), so that they can easily be identified within a country’s health system. Normally, a paediatrician who receives a genetic diagnosis from a lab, or the geneticist of a hospital that took care of the diagnosis process will write down not only the name of the condition (e.g. “Fragile X Syndrome”), but the identifying code, which would normally be Q99.2 for Fragile X Syndrome. In the future, due to extensions and changes of the coding, it might be that this will change, for instance to the newer code ICD-11, which will result in LD55 for Fragile X Syndrome. Of course, it might be that a person has more than one condition, so the records would get additional entries. For instance, it might be appropriate that a person with Fragile X Syndrome who also shows typical symptoms of autism might get another diagnosis recorded, which in the ICD-10 code could be F84.1 for Atypical Autism.
It is important to have all conditions/diseases recorded in a person’s health records with the appropriate code, as that may have an impact on the possibility of the prescription of therapies and reimbursement of the costs for them.
The Fragile X full mutation is believed to be appearing in around 1 in 4000 newborns.
Fragile X Syndrome in males occurs about as often as the full mutation, that is, 1 in 4000. Fragile X Syndrome in females happens somewhat less, about 1 in 6000 perhaps.
The Fragile X premutation occurs in about 1 in 200 females and 1 in 400 males in the general population.
The average number of cgg repeats in a premutation carrier is about 70.
The likelihood of a premutation extending to a full mutation in the next generation strongly depends on the length of the cgg chain. The average likelihood is about 1/3. However, it is much more likely in the higher cgg repeat range and lower in case of fewer cgg repeat lengths. For instance, if the mother has 100 or more cgg repeats, the likelihood of the child having the full mutation is almost 100%, provided it inherits the affected X chromosome from the mother.
[To be extended.]