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Genetic features of the fragile X syndrome

March 16, 2017

Among the group of hereditary diseases, there are two diseases related to the most common causes of intellectual disability. The most famous and most common pathology is Down syndrome, associated with the presence of an extra 21st chromosome in the human genome. In this article, we will talk about the second most common hereditary disease that leads to mental retardation, and may also be accompanied by other clinical manifestations. nine0003

Fragile X syndrome or Martin-Bell syndrome is the result of a disorder in the FMR1 (fragile X mental retardation-1) gene, which is located on the X chromosome and plays an important role in the emergence and development of neural connections, learning and memory. The frequency of this syndrome among boys is 1:4000.

The so-called “fragility” of the X chromosome is manifested in the fact that the chromosome looks atypical with special staining, as if one piece has separated, although physically it remains intact. The genetic basis for this phenomenon is an increase in the number of CGG trinucleotide repeats in the FMR1 gene located on the X chromosome. nine0003

In healthy people, the number of repeats in this gene ranges from 5 to 54. If the repeats are more than 200, then the protein production from the FMR1 gene is disrupted, which leads to the development of Martin-Bell syndrome and the clinical manifestation of the disease. A premutational state is the number of CGG repeats from 55 to 200. In this state, the disease does not typically manifest in humans, but the more repeats a carrier has in this gene, the more likely it is that her or his children will have a repeat count greater than 200. and the disease will develop. In the case of a carrier of a premutation during the formation of germ cells, the number of repeats may increase, therefore, if the parent has a number of repeats from 55 to 200, then the probability of having a child with a mutant FMR1 gene and Martin-Bell syndrome is high. At the same time, the carriage of the premutational state by the future father and mother is not equivalent in terms of the probability of the occurrence of a mutant allele in their children: if the mother is the carrier, then the probability of a significant increase in the number of repeats is much higher. The number of repeats from 45 to 54 is an intermediate form that has no effect on human health, but can lead to problems in future generations, as in the case of a premutational state of the gene. nine0003

It is important to consider that the inheritance and development of the disease depends on gender, since the FMR1 gene is located on the X chromosome. Men have only one X chromosome, which they receive from their mother. Therefore, if this one chromosome turned out to be “fragile”, they have a disease. Women have two X chromosomes, but only one of them is active. Therefore, the presence of one X chromosome with a mutant FMR1 gene may not manifest itself clinically, in the case of inactivation of the “fragile” chromosome, or lead to the development of the disease in 30-50% of cases. A man with a fragile X chromosome can pass it on to all his daughters, but not to any of his sons. A woman with a mutant chromosome has a chance to pass it on to both sons and daughters with equal probability. nine0003

The premutation state of a gene affects both the fate of the descendants of the carrier of such a gene and directly on his health:

1. Development of primary ovarian failure (FXPOI) (decrease in ovarian reserve and menopause before age 40). The FMR1 mutation is responsible for premature ovarian failure in 5% of women with this diagnosis. Among carriers of the premutation, about a quarter develop this condition. It affects not only the general reproductive possibilities, but also the selection of the stimulation protocol for ART, as it often causes a poor ovarian response to stimulation. Interestingly, according to Genetico data, although poor ovarian response to stimulation affects the number of embryos produced per cycle, it does not lead to an increase in the proportion of aneuploid embryos. nine0003

2. Fragile X tremor/ataxia (FXTAS). This condition develops more often in men: when the premutation is carried by a man, it manifests itself in 33% of cases, and when the premutation is carried by a woman - only in 5-10%. FXTAS syndrome begins to manifest in old age. There is a tremor, a wobbly gait, speech may suffer.

The diagnostic method used in the Genetico laboratory is based on the use of a polymerase chain reaction with a special set of primers, which allows not only to detect normal, premutational and mutational states, but also to accurately determine the number of repeats in cases where they are less than 200. This diagnostic allows you to identify Fragile X syndrome at the molecular level, as well as to assess the likelihood of having a child with this syndrome and the possibility of the patient developing disorders associated with an increased number of repeats in the FMR1 gene. Such diagnostics also allows detection of the presence of AGG repeats among CGG repeats. It is believed that AGG regions that interrupt a long sequence of CGG repeats confer DNA stability and reduce the risk of an increase in the number of repeats in the next generation. nine0003

A genetic test that determines the number of repeats in the FMR1 gene is recommended primarily for women with premature ovarian failure syndrome or with identified non-random inactivation of the X chromosome (indirect sign), families with sons with intellectual disabilities. Also analysis of the state of the FMR1 gene is required:

1) women with reproductive problems or fertility disorders associated with increased levels of follicle-stimulating hormone (FSH)

2) Patients with intellectual disability and their relatives

3) Those with a family history of Fragile X Syndrome or mental retardation without a definite diagnosis FMR1

5) patients with late onset tremors and cerebellar ataxia (disorders in muscle coordination due to damage to the brain systems that control muscle movement).

If an asymptomatic carrier of a mutation in the FMR1 gene is detected in a woman, the use of donor oocytes or preimplantation genetic diagnosis (PGD) may be recommended in order to exclude the possibility of the syndrome in a child. It is also important to correctly assess the risk of having a sick child in the case of a premutational state of the FMR1 gene in future parents. In this case, according to the results of the test, it is recommended to consult a geneticist.

Author: Ochir Migyaev

Genetico laboratory intern

People X. Fragile X Syndrome

Have you met someone with Down syndrome in your life? Probably yes. What about fragile X syndrome? Most likely, too, yes, you just did not know about it. According to statistics, about 1 in 4,000 men and 1 in 8,000 women are carriers of this syndrome. It is also the second most common, after Down syndrome, genetic cause of mental retardation and the most common monogenetic cause of autism. nine0003

It seems we already know very well that a person with autism is not a slightly ridiculous "rain man" or a brilliant programmer who simply does not understand jokes. And it seems that we got used to the word "autism" pretty quickly, and some are even familiar with the term ASD. But what does this very autistic spectrum imply, what does it include? And what causes autism? The scientist who answered this question would receive all the Nobel Prizes and all honorary orders. But there is no such scientist and there will not be, because autism is not one specific disease with one specific cause, it is many causes, often genetic. nine0003

Fragile X Syndrome is a very specific condition and a very specific diagnosis that can be confirmed by one specific test. And in some countries, for example, there is a diagnostic standard according to which all boys with autism are given this analysis. And it also happens that the analysis for the carriage of a premutation (it can lead to a complete mutation) is done to women who have difficulty getting pregnant or who have experienced early menopause.

Why are we so new to this state? Maybe because this syndrome does not manifest such a characteristic phenotype as Down's syndrome? Or maybe because autism and mental retardation seem to be more serious problems than other clinical manifestations of the syndrome, of which there are many and which should also be monitored? Fragile X Syndrome, on the other hand, is much loved by gene therapy scientists, because the breakdown that causes this mutation is a convenient target for testing and experimentation, which is carried out in search of a cure for conditions that cause autism. nine0003

Inheritance and development of the syndrome depends on sex, since the FMR1 gene that causes this disease is located on the X chromosome. Men have only one X chromosome, which they receive from their mother. Therefore, if the mother is a carrier of the syndrome and has passed on a “fragile” chromosome to her son, the disease will manifest itself in him. Women have two X chromosomes, but only one of them is active. Therefore, in the case of inactivation of this “fragile” X chromosome, the disease may not manifest itself clinically or lead to the development of the disease only in a certain percentage of cases. A man with a fragile X chromosome can pass it on to all of his daughters, but not to any of his sons. A woman can pass it on to both sons and daughters with equal probability. nine0003

Behavioral characteristics may or may not include Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), Autism and Autistic Behavior, Social Anxiety, Hand Clapping, Difficulty Making Eye Contact, Sensory Disorders and an increased risk of aggression.

Most boys with Fragile X Syndrome have significant intellectual disabilities ranging from mild learning disabilities to more severe problems. nine0003

Physical features of post-pubertal males include large ears, a long face, overly extensible skin, and enlarged testicles (called macroorchidism). Involvement of the connective tissue in the pathological process leads to such disorders as otitis, flat feet, gothic palate, pathological flexibility of the fingers and hypermobility of the joints. No individual will present all the signs at once, and some symptoms, such as a long face and macroorchidism, are more common in men after puberty. nine0003

It happens that a person with fragile X syndrome does not have the classic signs of autism, but there are separate manifestations such as fixed interests or difficulties with routine violations. Interestingly, people with fragile X syndrome are very sociable and friendly, have excellent imitation skills, have good visual and long-term memory, love to help others; These are people with a great sense of humor. Their high sensitivity helps and hinders them at the same time, since, on the one hand, they are very empathic, on the other hand, they are very sensitive to the bad mood of others or a conflict situation, even a potential one or nothing to do with them. nine0003

Symptoms observed in men may also occur in women. However, women often have less pronounced intellectual disabilities, as well as moderate behavioral and physical disabilities.

But still, about a third of women diagnosed with the syndrome are significantly behind in mental development. The rest may have mild or moderate learning disabilities, emotional/mental problems, general restlessness and/or social anxiety. A small percentage of women who carry a complete FMR1 mutation, which causes the syndrome, do not have clear signs of the disease - intellectual, behavioral or physical impairment. In these women, the syndrome is often only discovered after the disease has been diagnosed in another family member. nine0003

Why diagnose at all if there is no specific treatment? In order to warn the rest of the family, in order to be able to plan a pregnancy and in order to know that a woman, in principle, may have difficulty planning a pregnancy if she has a premutational status. The premutation status itself is a condition that can also be accompanied by certain disorders. In old age, men may develop tremor/ataxia syndrome (FXTAS) - tremors, wobbly gait, and speech may suffer. Women may experience what is known as primary ovarian failure (FXPOI) (decrease in ovarian reserve and menopause before age 40). Among carriers of the premutation, about a quarter develop this condition. It affects not only the general reproductive possibilities, but also often turns out to be the cause of a poor response of the ovaries to stimulation. A good neurologist and gynecologist must be aware that their patient has this diagnosis. nine0003

If there is no specific treatment, this does not mean that there are no specific methods and standards of behavioral or pedagogical intervention that will help parents, and representatives of the helping professions, and teachers, and, of course, the carriers of the syndrome themselves.

Finally, in order to know what to follow and what to do is absolutely useless and which will take a lot of time and money. To know why to go to a neurologist (in order to exclude epilepsy, which is a companion of this disease, but not in order to prescribe something to improve blood circulation), and why to an ophthalmologist (weak muscle tone can cause strabismus), when a psychiatrist is needed (in case neither the parent nor the child can cope with the aggression and anxiety of the child), when a cardiologist (disturbances in the processes in the connective tissue can cause heart pathologies), and when an orthopedist (to tell you if you need insoles or better to do sports). nine0003

Find more information about the syndrome and get to know the community of parents and specialists here:

1. Fragile X Syndrome Support Association website: https://fragilexsyndrome.ru/
2. Youtube channel "People X": www.youtube.com/channel/UCMK-uxopVlbuYYSIO2av1ug
3. Introductory video about the syndrome: www.youtube.com/watch?v=370yeMDV90s
4. Instagram: www.

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