Fragile x gene
Fragile X syndrome: MedlinePlus Genetics
Description
Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females.
Affected individuals usually have delayed development of speech and language by age 2. Most males with fragile X syndrome have mild to moderate intellectual disability, while about one-third of affected females are intellectually disabled. Children with fragile X syndrome may also have anxiety and hyperactive behavior such as fidgeting or impulsive actions. They may have attention deficit disorder (ADD), which includes an impaired ability to maintain attention and difficulty focusing on specific tasks. About one-third of individuals with fragile X syndrome have features of autism spectrum disorder that affect communication and social interaction. Seizures occur in about 15 percent of males and about 5 percent of females with fragile X syndrome.
Most males and about half of females with fragile X syndrome have characteristic physical features that become more apparent with age. These features include a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles (macroorchidism) after puberty.
Frequency
Fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females.
Causes
Mutations in the FMR1 gene cause fragile X syndrome. The FMR1 gene provides instructions for making a protein called FMRP. This protein helps regulate the production of other proteins and plays a role in the development of synapses, which are specialized connections between nerve cells. Synapses are critical for relaying nerve impulses.
Nearly all cases of fragile X syndrome are caused by a mutation in which a DNA segment, known as the CGG triplet repeat, is expanded within the FMR1 gene. Normally, this DNA segment is repeated from 5 to about 40 times.
In people with fragile X syndrome, however, the CGG segment is repeated more than 200 times. The abnormally expanded CGG segment turns off (silences) the FMR1 gene, which prevents the gene from producing FMRP. Loss or a shortage (deficiency) of this protein disrupts nervous system functions and leads to the signs and symptoms of fragile X syndrome.
Males and females with 55 to 200 repeats of the CGG segment are said to have an FMR1 gene premutation. Most people with this premutation are intellectually normal. In some cases, however, individuals with a premutation have lower than normal amounts of FMRP. As a result, they may have mild versions of the physical features seen in fragile X syndrome (such as prominent ears) and may experience emotional problems such as anxiety or depression. Some children with an FMR1 premutation may have learning disabilities or autistic-like behavior. The premutation is also associated with an increased risk of disorders called fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS).
Inheritance
Fragile X syndrome is inherited in an X-linked dominant pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. (The Y chromosome is the other sex chromosome.) The inheritance is dominant if one copy of the altered gene in each cell is sufficient to cause the condition. X-linked dominant means that in females (who have two X chromosomes), a mutation in one of the two copies of a gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of a gene in each cell causes the disorder. In most cases, males experience more severe symptoms of the disorder than females.
In women, the FMR1 gene premutation on the X chromosome can expand to more than 200 CGG repeats in cells that develop into eggs. This means that women with the premutation have an increased risk of having a child with fragile X syndrome.
By contrast, the premutation in men does not expand to more than 200 repeats as it is passed to the next generation. Men pass the premutation only to their daughters. Their sons receive a Y chromosome, which does not include the FMR1 gene.
Other Names for This Condition
- Fra(X) syndrome
- FRAXA syndrome
- FXS
- Marker X syndrome
- Martin-Bell syndrome
- X-linked mental retardation and macroorchidism
Additional Information & Resources
Genetic Testing Information
- Genetic Testing Registry: Fragile X syndrome
Genetic and Rare Diseases Information Center
- Fragile X syndrome
Patient Support and Advocacy Resources
- Disease InfoSearch
- National Organization for Rare Disorders (NORD)
Research Studies from ClinicalTrials.gov
- ClinicalTrials.gov
Catalog of Genes and Diseases from OMIM
- FMRP TRANSLATIONAL REGULATOR 1
Scientific Articles on PubMed
- PubMed
References
- Cornish KM, Turk J, Wilding J, Sudhalter V, Munir F, Kooy F, Hagerman R.
Annotation: Deconstructing the attention deficit in fragile X syndrome: a developmental neuropsychological approach. J Child Psychol Psychiatry. 2004 Sep;45(6):1042-53. doi: 10.1111/j.1469-7610.2004.t01-1-00297.x. Citation on PubMed - Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB Jr, Moine H, Kooy RF, Tassone F, Gantois I, Sonenberg N, Mandel JL, Hagerman PJ. Fragile X syndrome. Nat Rev Dis Primers. 2017 Sep 29;3:17065. doi: 10.1038/nrdp.2017.65. Citation on PubMed
- Hunter JE, Berry-Kravis E, Hipp H, Todd PK. FMR1 Disorders. 1998 Jun 16 [updated 2019 Nov 21]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK1384/ Citation on PubMed
- Jacquemont S, Hagerman RJ, Hagerman PJ, Leehey MA. Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1.
Lancet Neurol. 2007 Jan;6(1):45-55. doi: 10.1016/S1474-4422(06)70676-7. Citation on PubMed - Koukoui SD, Chaudhuri A. Neuroanatomical, molecular genetic, and behavioral correlates of fragile X syndrome. Brain Res Rev. 2007 Jan;53(1):27-38. doi: 10.1016/j.brainresrev.2006.06.001. Epub 2006 Jul 17. Citation on PubMed
- Salcedo-Arellano MJ, Dufour B, McLennan Y, Martinez-Cerdeno V, Hagerman R. Fragile X syndrome and associated disorders: Clinical aspects and pathology. Neurobiol Dis. 2020 Mar;136:104740. doi: 10.1016/j.nbd.2020.104740. Epub 2020 Jan 10. Citation on PubMed or Free article on PubMed Central
- Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005 Oct;7(8):584-7. doi: 10.1097/01.gim.0000182468.22666.dd. Citation on PubMed or Free article on PubMed Central
- Sullivan SD, Welt C, Sherman S. FMR1 and the continuum of primary ovarian insufficiency.
Semin Reprod Med. 2011 Jul;29(4):299-307. doi: 10.1055/s-0031-1280915. Epub 2011 Oct 3. Citation on PubMed - Terracciano A, Chiurazzi P, Neri G. Fragile X syndrome. Am J Med Genet C Semin Med Genet. 2005 Aug 15;137C(1):32-7. doi: 10.1002/ajmg.c.30062. Citation on PubMed
- Van Esch H. The Fragile X premutation: new insights and clinical consequences. Eur J Med Genet. 2006 Jan-Feb;49(1):1-8. doi: 10.1016/j.ejmg.2005.11.001. Epub 2005 Dec 5. Citation on PubMed
- Willemsen R, Oostra BA, Bassell GJ, Dictenberg J. The fragile X syndrome: from molecular genetics to neurobiology. Ment Retard Dev Disabil Res Rev. 2004;10(1):60-7. doi: 10.1002/mrdd.20010. Citation on PubMed
Fragile X 101 | The Three Fragile X Disorders
Skip to contentFragile X 101Dan Whiting2022-11-02T12:35:00-04:00
What is Fragile X Syndrome?
Fragile X syndrome (FXS) is caused by a mutation of a single gene — FMR1 — on the X chromosome and is inherited genetically, often unknowingly.
Everyone has the FMR1 gene on their X chromosome, but when a mutation occurs, it can cause intellectual disability, behavioral and learning challenges, and various physical characteristics. There is no cure, but therapies, interventions, and medications are often prescribed to treat behavioral symptoms like anxiety, aggression, and ADHD.
Also see our Knowledge Center↗
FRAGILE X 101
A Guide for the Newly Diagnosed and Those Already Living with Fragile X
This guide helps answer questions about common physical, cognitive, and behavioral issues. You’ll also learn how Fragile X is inherited, the various treatment options available, how females are affected vs. males, and the support you can receive from the NFXF.
GET YOUR FREE COPY OF FRAGILE X 101Female carriers have a 50% chance of passing the mutation to each of her children, while males will pass it to all of his daughters (and and none of his sons).
Though Fragile X syndrome occurs in both genders, males are more frequently affected than females, and generally with greater severity. In fact, some females may not experience any of the behavioral, cognitive, or physical features that appear more widely in males.
Exactly why males are more often and more severely affected is unknown. But it’s believed to be due to the fact that females have two X chromosomes and males have only one — can a damaged FMR1 gene on one X chromosome be compensated for by a healthy FMR1 gene on the other? Because males have only one X, if they receive a damaged FMR1 gene, it’s the only one they have.
Life Expectancy
The life span for people with FXS is not affected because there are usually no life-threatening health concerns associated with the condition.
Prevalence
There have been a number of studies aimed at determining the prevalence of FXS in males and females. Studies have been undertaken both in the “special needs” population and the general population.
The agreed upon prevalence of FXS:
- Males — approximately 1 in 4,000 to 1 in 7,000
- Females — approximately 1 in 6,000 to 1 in 11,000
Have you had a new Fragile X diagnosis in your family?
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Signs & Symptoms
In Males
Physical features
No one individual will have all the features of FXS, and some features, such as a long face and macroorchidism, are more common after puberty. Some of the features are due to poor connective tissue, such as flexible joints, flat feet, and high arched palate.
Physical features may include:
- Large ears
- Long face
- Soft skin
- Flexible joints — particularly fingers, wrists, elbows
- Low muscle tone
- Flat feet
- High arched palate
- Large testicles (called “macroorchidism”) in post-pubertal males
Behavioral characteristics
Behavioral characteristics may include:
- Sensory processing challenges (sensitive fabrics or clothing, loud noises, crowds, food textures, etc.
) - Hand-flapping, hand-biting
- Poor eye contact
- ADHD (attention deficit/hyperactive disorder)
- Anxiety
- Autism spectrum disorders
- Increased risk for aggression
- Sleep disorders
Cognitive Abilities
- Cognitive abilities in FXS include a range from mild learning disabilities to more severe intellectual disabilities. The majority of males with Fragile X syndrome demonstrate moderate intellectual disability.
- Speech and language delay
- Motor delay (late crawling, walking, toileting)
Medical Issues
Medical issues may include:
- Ear infections (also often due to poor connective tissue)
- Strabismus (crossed eyes)
- Seizures
Disposition
Disposition characteristics often include:
- Very social and friendly
- Excellent imitation skills
- Strong visual and long-term memory
- Especially nice, likes to help others
- Wonderful sense of humor
In Females
Behavioral characteristics
Behavioral characteristics seen in males can also be seen in females, though females often have a milder presentation of the syndrome’s behavioral, physical, and connective tissue features.
Cognitive Abilities
About one-third of females with FXS have no to very mild learning disabilities, about a third have mild learning disabilities, and a third have moderate to significant intellectual disabilities.
Additional issues sometimes seen are:
- Emotional and mental health issues
- General anxiety
- Social anxiety
A small percentage of females who have the full mutation of the FMR1 gene that causes FXS will have no apparent signs of the condition — intellectual, behavioral, or physical. These females are often identified only after another family member has been diagnosed.
The 3 Main Fragile X Disorders
Full mutation of the FMR1 gene (> 200 CGG repeats)
1. Fragile X Syndrome
Symptoms include intellectual disability, behavioral and learning challenges, and various physical characteristics. Males are more frequently affected, and generally with greater severity.
Premutation of the FMR1 gene (55–200 CGG repeats)
Traditionally, a carrier of a genetic mutation is defined as a person who inherits an altered form of a gene but shows no effects of that mutation.
However, in Fragile X this definition does not exactly fit as carriers of a Fragile X premutation are at risk to develop FXTAS and FXPOI.
2. FXTAS — Fragile X-Associated Tremor/Ataxia Syndrome
Premutation carriers of an FMR1 gene mutation can have no apparent signs of a Fragile X disorder, and may or may not develop FXTAS (pronounced: FAKS-taz), which usually occurs in male premutation carriers after age 50, with symptoms — including balance, tremor, and memory problems — worsening with age.
LEARN MORE
3. FXPOI — Fragile X-Associated Primary Ovarian Insufficiency
Premutation carriers of an FMR1 gene mutation can have no apparent signs of a Fragile X disorder, and may or may not develop FXPOI (pronounced: FAKS-poi), which usually occurs in female premutation carriers after age 40, and refers to a spectrum of impaired ovarian functions that can include infertility and early menopause.
LEARN MORE
Genetics & Inheritance
Fragile X-associated disorders include a wide range of physical, intellectual, and behavioral symptoms that can affect family members in many different ways.
These conditions are passed down in families through expansions of the FMR1 gene. Even for genetics professionals, FMR1 inheritance is complex and confusing, so it’s no surprise that families often have questions about the genetics of Fragile X. We start with some background on genetics and chromosomes …
GENETICS AND INHERITANCE
Testing & Diagnosis
Who should be tested, lab tests for Fragile X including testing costs and reporting time, and other tests for children with developmental delay.
TESTING AND DIAGNOSIS
Premutation Carriers
When you or a family member are told you are a “carrier” for a Fragile X mutation, many questions arise.
PREMUTATION CARRIERS
More from the Fragile X Info Series
Fragile X Info Series flyers are designed to be easily printable on home and office printers. We created them so you can distribute them as needed, whether it’s for a neighbor, students at school, your own reference, or you work at a clinic and want to share information with new families.
Whatever the cause, they are meant to be informative and shareable.
Understanding Fragile X
Australian professor predicts the total extinction of men - RBC
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Australian professor Jenny Graves predicts the total extinction of men. According to a scientist from the University of Canberra, flaws in the structure of the male genome will destroy the stronger sex, writes the Daily Mail.
Photo: Depositphotos
An Australian geneticist recalls that women have two sex X chromosomes, each containing over 1,000 genes. Males have one X chromosome and one Y chromosome, the latter containing fewer than 100 genes.
The problem is that the Y-chromosome is fragile - over hundreds of millions of years of evolution, it was destroyed, losing genes. Meanwhile, this chromosome contains the SRY gene, which is important for males, which determines the male sex of the organism.
Women have two sex X chromosomes, and in case of damage they can "repair" each other by exchanging genes, the scientist notes. In men, the X- and Y-chromosome remain alone, without a "partner".
Therefore, the more fragile Y chromosome with fewer genes is destroyed beyond repair.
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"This is very bad news for all men," notes D. Graves. The professor predicts that in about 5 million years, both the Y chromosome and men will disappear without a trace.
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At the same time, the scientist draws attention: if the Y-chromosome completely disappears, the remaining X-chromosome can take over the functions of the missing "girlfriend". This will lead to the emergence of a new species of people, the professor believes. D. Graves notes that the process of destruction of the Y-chromosome has already started in some human populations isolated from the world.
Meanwhile, Professor Chris Mason of University College London is more optimistic. The scientist believes that in the 5 million years that the Australian geneticist assigned the male chromosome, medicine will surely find a way to save the doomed genes.
Australia
ᐈ Analysis: DNA diagnostics of Martin-Bell syndrome in Kiev, prices role in the emergence and development of neural connections, learning and memorization. The so-called "fragility" of the X chromosome is manifested in the fact that the chromosome looks atypical with special coloring, as if one piece has separated, although physically it remains intact. Clinical analysis to determine the genetic predisposition to Martin-Bell syndrome is extremely important. 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. In healthy people, the number of repeats in this gene ranges from 5 to 54. If there are more than 200 repeats, as a medical indicator of high accuracy, 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.
The premutational state is the number of CGG repeats from 55 to 200. In this number of repeats, the disease in humans does not manifest in a typical form, but the more repeats in this gene in the carrier, the more likely that as a result, her or his children the number of repetitions will be more than 200 and the disease will manifest itself. 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 uneven in terms of the probability of occurrence of the 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. Timely testing helps to determine the propensity for the occurrence of fragile X syndrome.
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.
Inheritance and development of the disease depends on sex, since the FMR1 gene is located on the X chromosome. A comprehensive examination with its characteristic symptoms will help establish a possible diagnosis. Males have only one X chromosome, which they get from their mother. Women have two X chromosomes, but only one of them is active. Therefore, the presence of one X-chromosome with a mutant FMR1 gene detected in the biological material of the study may not manifest itself clinically in case of inactivation of the “fragile” chromosome or lead to the development of the disease in 30-50% of cases. A person with a fragile X chromosome can pass it on to all of 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 the same probability.
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. Having the necessary experience of specialists, our clinic provides an opportunity for a qualitative passage of this study. Fragile X-associated tremor/ataxia (FXTAS) most often develops in men: when a man carries a premutation, it manifests itself in 33% of cases, and when a woman carries a premutation, it occurs only in 5-10%. FXTAS syndrome begins to manifest in old age. There is a tremor, a wobbly gait, speech may suffer. Molecular analysis of DNA is performed to detect an increased number of CGG repeats.
The diagnosis of MBS can be manifested by:
- developmental delay;
- hyperactivity, attention deficit disorder;
- craniofacial dimorphism;
- joint hypermobility;
- mitral valve prolapse;
- macroorchidism;
- muscle hypotension;
- chest deformity;
- convulsive syndrome.
DNA diagnostics for Martin-Bell syndrome or fragile X chromosome is intended to set:
- developmental delay;
- for suspected fragile X syndrome;
- for cognitive and neuropsychiatric disorders;
- with early detection of the disease in relatives;
- for family planning;
- women with premature ovarian failure syndrome or identified non-random X-chromosome inactivation;
- women with reproductive problems or fertility problems associated with elevated levels of follicle stimulating hormone (FSH).
If an asymptomatic FMR1 mutation is detected in a woman, the use of donor oocytes or preimplantation genetic diagnosis (PGD) may be recommended to rule out the possibility of the syndrome in the child. The price for the study is indicated on the website. 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.
