Fragile X syndrome
Encyclopedia
Fragile X syndrome Martin–Bell syndrome, or Escalante's syndrome (more commonly used in South American countries), is a genetic
syndrome
that is the most commonly known single-gene cause of autism
and the most common inherited cause of intellectual disability. It results in a spectrum of characteristic physical and intellectual limitations and emotional and behavioral features which range from severe to mild in manifestation.
The syndrome is associated with the expansion of a single trinucleotide gene sequence (CGG) on the X-chromosome
, and results in a failure to express the protein coded by the FMR1
gene, which is required for normal neural development. There are four generally accepted states of the chromosome region involved in Fragile X syndrome which relate to the length of the repeated CGG sequence; Normal (6-50 CGG repeats)(not affected by the syndrome) , Premutation (59-200 CGG repeats)(occasionally affected in later years with the development of Fragile X associated tremor/ataxia syndrome), and Full Mutation (more than 200 CGG repeats)(affected).
J. Purdon Martin and Julia Bell
in 1943, described a pedigree of X-linked mental disability, without considering the macroorchidism
(larger testicles). In 1969 Herbert Lubs first sighted an unusual "marker X chromosome" in association with mental disability. In 1970 Frederick Hecht coined the term "fragile site".
Renpenning's syndrome
is not synonymous with the syndrome. In Renpenning's syndrome, there is no fragile site on the X-chromosome. Renpenning's cases have short stature, moderate microcephaly
, and neurological (brain) disorders.
Aside from intellectual disability, prominent characteristics of the syndrome include an elongated face, large or protruding ears, flat feet, larger testes (macroorchidism
), and low muscle tone. Speech may include cluttered speech
or nervous speech. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness, limited eye contact, memory problems, and difficulty with face encoding.
Some individuals with the fragile X syndrome also meet the diagnostic criteria for autism
. Most females who have the syndrome experience symptoms to a lesser degree because of their second X-chromosome; however, they can develop symptoms just as severe as their male counterparts. While full mutation males tend to present with severe intellectual disability, the symptoms of full mutation females run the gamut of minimally affected to severe intellectual disability, which may explain why females are underdiagnosed relative to males.
In short, similarities between X-linked recessive inheritance and fragile X are:
A difference is that females may also have clinical symptoms, although this is also the case with other conditions classed as x-linked recessive e.g. Haemophilia, due to X-inactivation
.
, including gaze aversion, prolonged time to commence social interaction, and challenges forming peer relationships. Social anxiety in individuals with FXS is related to challenges with face encoding. Face encoding is the ability to recognize a face that one has seen before.
Individuals with FXS show decreased activation in the prefrontal regions of the brain. These regions are associated with social cognition
. A child with FXS is likely to have hyperactivity, anxiety, and social deficits. Individuals with fragile X-associated tremor/ataxia syndrome (FXTAS) are likely to experience dementia
, mood and/or anxiety disorders. Males with the FMR1 premutation and clinical evidence of FXTAS were found to have increased occurrence of somatization
, obsessive–compulsive disorder, interpersonal sensitivity, depression, phobic anxiety and psychoticism
.
Females with FXS show a high frequency of avoidant behavior, mood disorder, and habit disorder. Females are significantly more withdrawn and depressed as compared to normal individuals. The size of DNA insertion was related to IQ, severity of attention problems, and withdrawal symptoms. Females with FXS are most vulnerable to social anxiety, social avoidance, withdrawal, and depression, so special attention should be paid.
Mental age is positively correlated and autistic behavior is negatively correlated with sadness in a particular study. The results shows that there are different behavioral profiles for young children than there are for older aged children which implies that temperament and problem behaviors are not rooted in early temperament.
regression analysis. However, in a premutation individual, CGG length is only significantly correlated with the central executive, not with either phonological memory or visual–spatial memory.
. Premutation is the stage where the CGG sequence in the FMR-1 gene expands to contain between 54 and 230 repeats. There is also a decrease in measures of executive cognitive functioning, working memory and information processing speed. The relative weaknesses observed in performance IQ can be partly attributed to slowed motor performance as a result of intention tremor. Children with FXS have an intellectual learning rate which is 2.2 times slower than unaffected children.
There is overlap of behavioral and clinical symptomology between autism and FXS. The commonalities include social and communication skills, though the degree to which these two syndromes share the processes and stages of development and medical causes for the disease (etiology
) is not known. Research has shown that phenotype ‘commonalities’ reflected different developmental pathways that diverge over time and across syndromes.
Using this information will permit early and specialized interventions. These earlier interventions will allow for optimal development and show educational, clinical, and adaptive benefits in the patient. When both autism and FXS are present a severe language deficit and lower IQ is observed as compared to children with only FXS.
Perseveration
is a common communicative and behavioral characteristic in FXS. Children with FXS may repeat a certain ordinary activity over and over. In speech, the trend is not only in repeating the same phrase but also talking about the same subject continually. Cluttered speech and self-talk are commonly seen. Self-talk includes talking with oneself using different tones and pitches.
Ophthalmologic problems include strabismus
(lazy eye). This requires early identification to avoid amblyopia
. Surgery and/or patching are usually necessary to treat strabismus if diagnosed early. Refractive errors in patients with fragile X are also common.
According to a study of patients with fragile X premutation undergoing preimplantation genetic diagnosis
(PGD), there is a positive correlation between number of CGG repeats and estradiol
level, retrieved oocytes and two-pronuclear zygotes. Premutation carriers with <100 CGG repeats suffer from impaired ovarian response and decreased fertilization rate.
The fragile X abnormality is now directly determined by analysis of the number of CGG repeats and their methylation status using restriction endonuclease digestion and Southern blot
analysis.
Not everyone with fragile X syndrome has the same signs and symptoms. Even affected people in the same family don’t show the same symptoms. The signs and symptoms fall into six categories:
For 2% to 6% of all children diagnosed with autism, the cause is the Fragile X gene mutation. Approximately one-third of all children diagnosed with fragile X syndrome also have some degree of autism. Fragile X syndrome is the most common known single gene cause of autism.
From Dr. Randi Hagerman's statement to the United States House of Representatives Subcommittee on Health and Environment: "...Fragile X represents a portal through which we hope to view and treat a wide variety of other disorders of brain development and function. All children with autism...should be tested for Fragile X."
Genetic mouse models
of Fragile X syndrome have also been shown to have autistic-like behaviors.
caused by mutation
of the FMR1
gene
on the X-chromosome
. Mutation at that site is found in 1 out of about every 2000 male
s and 1 out of about every 259 female
s. (Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females.)
Normally, the FMR1
gene contains between 6–55 (29 in Robbins–Kumar pathology textbooks) repeats of the CGG codon (trinucleotide repeats
). In people with the fragile X syndrome, the FMR1 allele
has over 230–4000 repeats of this codon.
Expansion of the CGG repeating codon to such a degree results in a methylation
of that portion of the DNA
, effectively silencing the expression of the FMR1 protein
.
This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction of the X chromosome
which appears 'fragile' under the microscope at that point, a phenomenon that gave the syndrome its name.
Mutation of the FMR1 gene leads to the transcriptional silencing of the fragile X-mental retardation protein, FMRP. In normal individuals, FMRP is believed to regulate a substantial population of mRNA: FMRP plays important roles in learning and memory, and also appears to be involved in development of axon
s, formation of synapse
s, and the wiring and development of neural circuits.
.
Because males normally have only one copy of the X-chromosome, those males with significant trinucleotide expansion at the FMR1 locus are symptomatic. They are intellectually disabled and may show various physical features of the fragile X syndrome.
Females have two X-chromosomes and thus have an increased probability of having a working FMR1 allele
. Females carrying one X-chromosome with an expanded FMR1 gene can have some signs and symptoms of the disorder or be normal. Although the extra X-chromosome can serve as a backup, only one X-chromosome is active in each cell due to X-inactivation
.
Males with the fragile X cannot transmit it to any of their sons (since males contribute a Y-chromosome, not an X, to their male offspring), but will transmit the premutation to all of their daughters, as males contribute their X to all of their daughters. Males never transmit their full mutation (males with full mutations in their blood have premutations in their sperm), and expansion to full mutations never occurs through paternal transmission.
Females carrying one copy of the fragile X can transmit it to their sons or daughters; in this case each child has a 50% chance of inheriting the fragile X. Sons who receive the fragile X are at high risk of intellectual disability. Daughters who receive the fragile X may appear normal or they may be intellectually disabled, usually to a lesser degree than boys with the syndrome. The transmission of fragile X often increases with each passing generation. This seemingly anomalous pattern of inheritance is referred to as the Sherman paradox.
, and when necessary, treatment of physical abnormalities. Persons with the fragile X syndrome in their family histories are advised to seek genetic counseling
to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants.
assays, is of primary importance. Also being examined is the function the various domains of FMRP, an RNA-binding protein
, which is still relatively unknown. One hypothesis is that many symptoms are caused by unchecked activation of mGluR5
, a metabotropic glutamate receptor
, which was found in a 2007 study to contribute significantly to the pathogenesis of the disease; this suggests that mGluR5 blockers could be used to treat fragile X syndrome.
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
syndrome
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
that is the most commonly known single-gene cause of autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
and the most common inherited cause of intellectual disability. It results in a spectrum of characteristic physical and intellectual limitations and emotional and behavioral features which range from severe to mild in manifestation.
The syndrome is associated with the expansion of a single trinucleotide gene sequence (CGG) on the X-chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
, and results in a failure to express the protein coded by the FMR1
FMR1
FMR1 is a human gene that codes for a protein called fragile X mental retardation protein, or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function...
gene, which is required for normal neural development. There are four generally accepted states of the chromosome region involved in Fragile X syndrome which relate to the length of the repeated CGG sequence; Normal (6-50 CGG repeats)(not affected by the syndrome) , Premutation (59-200 CGG repeats)(occasionally affected in later years with the development of Fragile X associated tremor/ataxia syndrome), and Full Mutation (more than 200 CGG repeats)(affected).
J. Purdon Martin and Julia Bell
Julia Bell
Julia Bell was a pioneering English human geneticist. She attended Girton College in Cambridge and took the Mathematical Tripos exam in 1901. But because women could not officially receive degrees from Oxford or Cambridge, she was awarded a master's degree at Trinity College, Dublin for her work...
in 1943, described a pedigree of X-linked mental disability, without considering the macroorchidism
Macroorchidism
Macroorchidism is the medical term used to describe a genetic disorder found in males where a subject has abnormally large testes. The condition is commonly inherited in connection with fragile X syndrome, which is also the second most common genetic cause of mental disabilities...
(larger testicles). In 1969 Herbert Lubs first sighted an unusual "marker X chromosome" in association with mental disability. In 1970 Frederick Hecht coined the term "fragile site".
Renpenning's syndrome
Renpenning's syndrome
Renpenning's syndrome is a neurodevelopmental disorder recognised in males intellectual disability, mild growth retardation with examples in the testes and head, and a somewhat short stature...
is not synonymous with the syndrome. In Renpenning's syndrome, there is no fragile site on the X-chromosome. Renpenning's cases have short stature, moderate microcephaly
Microcephaly
Microcephaly is a neurodevelopmental disorder in which the circumference of the head is more than two standard deviations smaller than average for the person's age and sex. Microcephaly may be congenital or it may develop in the first few years of life...
, and neurological (brain) disorders.
Signs and symptoms
Macroorchidism
Macroorchidism is the medical term used to describe a genetic disorder found in males where a subject has abnormally large testes. The condition is commonly inherited in connection with fragile X syndrome, which is also the second most common genetic cause of mental disabilities...
), and low muscle tone. Speech may include cluttered speech
Cluttered speech
Cluttered speech is a common term for speech that becomes broken down, cluttered, or unintelligible due to a variety of reasons. Cluttered speech is often described as hurried, nervous, broken down, stuttering, stammering, and cluttering...
or nervous speech. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness, limited eye contact, memory problems, and difficulty with face encoding.
Some individuals with the fragile X syndrome also meet the diagnostic criteria for autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
. Most females who have the syndrome experience symptoms to a lesser degree because of their second X-chromosome; however, they can develop symptoms just as severe as their male counterparts. While full mutation males tend to present with severe intellectual disability, the symptoms of full mutation females run the gamut of minimally affected to severe intellectual disability, which may explain why females are underdiagnosed relative to males.
In short, similarities between X-linked recessive inheritance and fragile X are:
- Males are predominantly affected;
- Females (mothers) are obligatory carriers (i.e., are conclusively proven to be carriers) if a male child is affected, but not necessarily if female children are affected, as a female child with one fragile and one normal X-chromosome may have inherited the fragile chromosome from the father.
A difference is that females may also have clinical symptoms, although this is also the case with other conditions classed as x-linked recessive e.g. Haemophilia, due to X-inactivation
X-inactivation
X-inactivation is a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin...
.
Physical phenotype
- Prominent ears (one or both)
- Long face (vertical maxillary excess)
- High-arched palate (related to the above)
- Hyperextensible finger joints
- Double-jointed thumbs
- Flat feetFlat feetFlat feet is a formal reference to a medical condition in which the arch of the foot collapses, with the entire sole of the foot coming into complete or near-complete contact with the ground...
- soft skin
- Larger testes in men after puberty (postpubescent macroorchidismMacroorchidismMacroorchidism is the medical term used to describe a genetic disorder found in males where a subject has abnormally large testes. The condition is commonly inherited in connection with fragile X syndrome, which is also the second most common genetic cause of mental disabilities...
) - Low muscle tone
Social interaction
FXS is characterized by social anxietySocial anxiety
Social anxiety is anxiety about social situations, interactions with others, and being evaluated or scrutinized by other people...
, including gaze aversion, prolonged time to commence social interaction, and challenges forming peer relationships. Social anxiety in individuals with FXS is related to challenges with face encoding. Face encoding is the ability to recognize a face that one has seen before.
Individuals with FXS show decreased activation in the prefrontal regions of the brain. These regions are associated with social cognition
Social cognition
Social cognition is the encoding, storage, retrieval, and processing, in the brain, of information relating to conspecifics, or members of the same species. At one time social cognition referred specifically to an approach to social psychology in which these processes were studied according to the...
. A child with FXS is likely to have hyperactivity, anxiety, and social deficits. Individuals with fragile X-associated tremor/ataxia syndrome (FXTAS) are likely to experience dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
, mood and/or anxiety disorders. Males with the FMR1 premutation and clinical evidence of FXTAS were found to have increased occurrence of somatization
Somatization
Somatization is currently defined as "a tendency to experience and communicate somatic distress in response to psychosocial stress and to seek medical help for it".This can be, but not always, related to a psychological condition:...
, obsessive–compulsive disorder, interpersonal sensitivity, depression, phobic anxiety and psychoticism
Psychoticism
Psychoticism is one of the three traits used by the psychologist Hans Eysenck in his P-E-N model model of personality. Psychoticism refers to a personality pattern typified by aggressiveness and interpersonal hostility.High levels of this trait were believed by Eysenck to be linked to increased...
.
Females with FXS show a high frequency of avoidant behavior, mood disorder, and habit disorder. Females are significantly more withdrawn and depressed as compared to normal individuals. The size of DNA insertion was related to IQ, severity of attention problems, and withdrawal symptoms. Females with FXS are most vulnerable to social anxiety, social avoidance, withdrawal, and depression, so special attention should be paid.
Mental age is positively correlated and autistic behavior is negatively correlated with sadness in a particular study. The results shows that there are different behavioral profiles for young children than there are for older aged children which implies that temperament and problem behaviors are not rooted in early temperament.
Working memory
From their 40s onward, males with FXS begin developing progressively more severe problems in performing tasks that require the central executive of working memory. Working memory involves the temporary storage of information 'in mind', while processing the same or other information. Phonological memory (or verbal working memory) deteriorates with age in males, while visual-spatial memory is not found to be directly related to age. Males often experience an impairment in the functioning of the phonological loop. The CGG length is significantly correlated with central executive and the visual–spatial memory throughregression analysis. However, in a premutation individual, CGG length is only significantly correlated with the central executive, not with either phonological memory or visual–spatial memory.
Intellectual development
Current evidence shows that individuals with premutation have difficulties with mathematics, anxiety, attention, and/or executive functionsExecutive functions
The executive system is a theorized cognitive system in psychology that controls and manages other cognitive processes. It is responsible for processes that are sometimes referred to as the executive function, executive functions, supervisory attentional system, or cognitive control...
. Premutation is the stage where the CGG sequence in the FMR-1 gene expands to contain between 54 and 230 repeats. There is also a decrease in measures of executive cognitive functioning, working memory and information processing speed. The relative weaknesses observed in performance IQ can be partly attributed to slowed motor performance as a result of intention tremor. Children with FXS have an intellectual learning rate which is 2.2 times slower than unaffected children.
There is overlap of behavioral and clinical symptomology between autism and FXS. The commonalities include social and communication skills, though the degree to which these two syndromes share the processes and stages of development and medical causes for the disease (etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
) is not known. Research has shown that phenotype ‘commonalities’ reflected different developmental pathways that diverge over time and across syndromes.
Using this information will permit early and specialized interventions. These earlier interventions will allow for optimal development and show educational, clinical, and adaptive benefits in the patient. When both autism and FXS are present a severe language deficit and lower IQ is observed as compared to children with only FXS.
Hypersensitivity and repetitive behavior
Children with fragile X have very short attention spans, are hyperactive, and show hypersensitivity to visual, auditory, tactile, and olfactory stimuli. These children have difficulty in large crowds due to the loud noises and this can lead to tantrums due to hyperarousal. Children with FXS pull away from light touch and can find textures of materials to be irritating. Transitions from one location to another can be difficult for children with FXS. Behavioral therapy can be used to decrease the child’s sensitivity in some cases.Perseveration
Perseveration
Perseveration is the repetition of a particular response, such as a word, phrase, or gesture, despite the absence or cessation of a stimulus, usually caused by brain injury or other organic disorder. If an issue has been fully explored and discussed to a point of resolution, it is not uncommon for...
is a common communicative and behavioral characteristic in FXS. Children with FXS may repeat a certain ordinary activity over and over. In speech, the trend is not only in repeating the same phrase but also talking about the same subject continually. Cluttered speech and self-talk are commonly seen. Self-talk includes talking with oneself using different tones and pitches.
Visual orientation
Eye problems have not been found to develop in accordance with mental age in individuals with fragile X. But patients with the syndrome have showed delayed voluntary orienting. The group differences in reflexive orienting between individuals with Down and fragile X syndrome at the low mental age level reinforce the practice of separating etiologies and highlight the contribution of basic attentional processes in the study of people with mental limitations.Ophthalmologic problems include strabismus
Strabismus
Strabismus is a condition in which the eyes are not properly aligned with each other. It typically involves a lack of coordination between the extraocular muscles, which prevents bringing the gaze of each eye to the same point in space and preventing proper binocular vision, which may adversely...
(lazy eye). This requires early identification to avoid amblyopia
Amblyopia
Amblyopia, also known as lazy eye, is a disorder of the visual system that is characterized by a vision deficiency in an eye that is otherwise physically normal, or out of proportion to associated structural abnormalities of the eye...
. Surgery and/or patching are usually necessary to treat strabismus if diagnosed early. Refractive errors in patients with fragile X are also common.
Fertility
Females with in the premutation range (55-200 repeats) are at an increased risk for premature ovarian failure (premature menopause).According to a study of patients with fragile X premutation undergoing preimplantation genetic diagnosis
Preimplantation genetic diagnosis
In medicine and genetics pre-implantation genetic diagnosis refers to procedures that are performed on embryos prior to implantation, sometimes even on oocytes prior to fertilization. PGD is considered another way to prenatal diagnosis...
(PGD), there is a positive correlation between number of CGG repeats and estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
level, retrieved oocytes and two-pronuclear zygotes. Premutation carriers with <100 CGG repeats suffer from impaired ovarian response and decreased fertilization rate.
Diagnosis
Fragile X syndrome was originally diagnosed by culturing cells in a folate deficient medium and then assessing the cultures for X-chromosome "breakage" by cytogenetic analysis of the long arm of the X-chromosome (the appearance of a broken chromosome being caused by discontinuity of staining in the region of the trinucleotide repeat). This technique proved unreliable for both diagnosis and carrier testing.The fragile X abnormality is now directly determined by analysis of the number of CGG repeats and their methylation status using restriction endonuclease digestion and Southern blot
Southern blot
A Southern blot is a method routinely used in molecular biology for detection of a specific DNA sequence in DNA samples. Southern blotting combines transfer of electrophoresis-separated DNA fragments to a filter membrane and subsequent fragment detection by probe hybridization. The method is named...
analysis.
Not everyone with fragile X syndrome has the same signs and symptoms. Even affected people in the same family don’t show the same symptoms. The signs and symptoms fall into six categories:
- Intelligence and learning
- Physical
- Social and emotional
- Speech and language
- Sensory
- Disorders commonly associated or sharing features with Fragile X
Autism and Fragile X syndrome
Fragile X syndrome can cause a child to have autism or an Autism Spectrum Disorder (ASD) though not all children with fragile X syndrome have autism or an ASD.For 2% to 6% of all children diagnosed with autism, the cause is the Fragile X gene mutation. Approximately one-third of all children diagnosed with fragile X syndrome also have some degree of autism. Fragile X syndrome is the most common known single gene cause of autism.
From Dr. Randi Hagerman's statement to the United States House of Representatives Subcommittee on Health and Environment: "...Fragile X represents a portal through which we hope to view and treat a wide variety of other disorders of brain development and function. All children with autism...should be tested for Fragile X."
Genetic mouse models
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
of Fragile X syndrome have also been shown to have autistic-like behaviors.
Causes
Fragile X syndrome is a genetic disorderGenetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
caused by mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
of the FMR1
FMR1
FMR1 is a human gene that codes for a protein called fragile X mental retardation protein, or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function...
gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
on the X-chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
. Mutation at that site is found in 1 out of about every 2000 male
Male
Male refers to the biological sex of an organism, or part of an organism, which produces small mobile gametes, called spermatozoa. Each spermatozoon can fuse with a larger female gamete or ovum, in the process of fertilization...
s and 1 out of about every 259 female
Female
Female is the sex of an organism, or a part of an organism, which produces non-mobile ova .- Defining characteristics :The ova are defined as the larger gametes in a heterogamous reproduction system, while the smaller, usually motile gamete, the spermatozoon, is produced by the male...
s. (Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females.)
Normally, the FMR1
FMR1
FMR1 is a human gene that codes for a protein called fragile X mental retardation protein, or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function...
gene contains between 6–55 (29 in Robbins–Kumar pathology textbooks) repeats of the CGG codon (trinucleotide repeats
Trinucleotide repeat disorders
Trinucleotide repeat disorders are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation where trinucleotide repeats in certain genes exceeding the normal, stable, threshold, which differs per gene...
). In people with the fragile X syndrome, the FMR1 allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
has over 230–4000 repeats of this codon.
Expansion of the CGG repeating codon to such a degree results in a methylation
DNA methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring...
of that portion of the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, effectively silencing the expression of the FMR1 protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
.
This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction of the X chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
which appears 'fragile' under the microscope at that point, a phenomenon that gave the syndrome its name.
Mutation of the FMR1 gene leads to the transcriptional silencing of the fragile X-mental retardation protein, FMRP. In normal individuals, FMRP is believed to regulate a substantial population of mRNA: FMRP plays important roles in learning and memory, and also appears to be involved in development of axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
s, formation of synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s, and the wiring and development of neural circuits.
Transmission
Fragile X syndrome is an X-linked dominant condition with variable expressivity and possibly reduced penetrancePenetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
.
Because males normally have only one copy of the X-chromosome, those males with significant trinucleotide expansion at the FMR1 locus are symptomatic. They are intellectually disabled and may show various physical features of the fragile X syndrome.
Females have two X-chromosomes and thus have an increased probability of having a working FMR1 allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
. Females carrying one X-chromosome with an expanded FMR1 gene can have some signs and symptoms of the disorder or be normal. Although the extra X-chromosome can serve as a backup, only one X-chromosome is active in each cell due to X-inactivation
X-inactivation
X-inactivation is a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin...
.
Males with the fragile X cannot transmit it to any of their sons (since males contribute a Y-chromosome, not an X, to their male offspring), but will transmit the premutation to all of their daughters, as males contribute their X to all of their daughters. Males never transmit their full mutation (males with full mutations in their blood have premutations in their sperm), and expansion to full mutations never occurs through paternal transmission.
Females carrying one copy of the fragile X can transmit it to their sons or daughters; in this case each child has a 50% chance of inheriting the fragile X. Sons who receive the fragile X are at high risk of intellectual disability. Daughters who receive the fragile X may appear normal or they may be intellectually disabled, usually to a lesser degree than boys with the syndrome. The transmission of fragile X often increases with each passing generation. This seemingly anomalous pattern of inheritance is referred to as the Sherman paradox.
Treatment
Although several medications have been proposed to treat fragile X syndrome, none of them are supported by good evidence. While there is no current cure for the syndrome, there is hope that further understanding of its underlying causes would lead to new therapies. Currently, the syndrome can be treated through behavioral therapy, special educationSpecial education
Special education is the education of students with special needs in a way that addresses the students' individual differences and needs. Ideally, this process involves the individually planned and systematically monitored arrangement of teaching procedures, adapted equipment and materials,...
, and when necessary, treatment of physical abnormalities. Persons with the fragile X syndrome in their family histories are advised to seek genetic counseling
Genetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants.
Research
Recent studies have focused on a number of critical areas. The role of FMRP's RNA partners, many of which have now been validated through in vitroIn vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
assays, is of primary importance. Also being examined is the function the various domains of FMRP, an RNA-binding protein
RNA-binding protein
RNA-binding proteins are proteins that bind to RNA. They bind to either double-strand or single-strand RNAs through RNA recognition motif . RNA-binding proteins may regulate the translation of RNA, and post-transcriptional events, such as RNA splicing, editing.They are cytoplasmic and nuclear...
, which is still relatively unknown. One hypothesis is that many symptoms are caused by unchecked activation of mGluR5
Metabotropic glutamate receptor 5
Metabotropic glutamate receptor 5 is a protein that in humans is encoded by the GRM5 gene.- Function :The amino acid L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors...
, a metabotropic glutamate receptor
Metabotropic glutamate receptor
The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs...
, which was found in a 2007 study to contribute significantly to the pathogenesis of the disease; this suggests that mGluR5 blockers could be used to treat fragile X syndrome.
External links
- CDC’s National Center on Birth Defects and Developmental Disabilities
- FraXA.org – The Fragile X Research Foundation
- Fragilex.org.uk – The United Kingdom National Fragile X charity
- FragileX.org The National Fragile X Foundation (US) – Support, Awareness, Education, Research and Advocacy since 1984
- FragileX.org.au – Fragile X Association of Australia – charity – news, forums, support, information, clinics
- The Colorado Fragile X Consortium
- Gene Reviews
- Closely linked to Nicolaides-Baraitser syndromeNicolaides-Baraitser syndromeNicolaides-Baraitser syndrome is a rare condition which has only been reported in 23 cases worldwide. NBS is a distinct condition and well recognizable once the symptoms have been identified, and has probably been underdiagnosed until now....