Fragile X syndrome, or
Martin-Bell syndrome, is a
geneticA genetic disorder is an illness caused by abnormalities in genes or chromosomes. While some diseases, such as cancer, are due in part to a genetic disorders, they can also be caused by environmental factors. Most disorders are quite rare and affect one person in every several thousands or millions...
syndromeIn medicine and psychology, the term syndrome refers to the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one feature alerts the physician to the presence of the others...
which results in a spectrum of characteristic physical, intellectual, emotional and behavioural 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 chromosomeThe X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals . It is a part of the XY sex-determination system and X0 sex-determination system...
, and results in a failure to express the
FMR1FMR1 is a human gene that codes for a protein called fragile X mental retardation protein, or FMRP. This protein is normally made in many tissues, especially in the brain and testes...
protein 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 (29-31 CGG repeats) (not affected by the syndrome), Premutation (55-200 CGG repeats)(not affected by the syndrome), Full Mutation (more than 200 CGG repeats)(affected), and Intermediate or Gray Zone Alleles (40 - 60 repeats).
Martin and Bell in 1943, described a pedigree of X-linked mental disability, without considering the macroorchidism (larger testicles). In 1969 Chris and Weesam 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
microcephalyMicrocephaly 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.
Escalante's syndrome is synonymous with the fragile X syndrome. This term has been used in Brazil and other South American countries.
Causes
The fragile X syndrome is a
genetic disorderA genetic disorder is an illness caused by abnormalities in genes or chromosomes. While some diseases, such as cancer, are due in part to a genetic disorders, they can also be caused by environmental factors. Most disorders are quite rare and affect one person in every several thousands or millions...
caused by
mutationIn biology, a mutation is a randomly derived change to the nucleotide sequence of the genetic material of an organism.Mutations can be caused by copying errors in the genetic material during cell division, or by exposure to mutagens , or can be induced by the organism itself, by cellular processes...
of the
FMR1FMR1 is a human gene that codes for a protein called fragile X mental retardation protein, or FMRP. This protein is normally made in many tissues, especially in the brain and testes...
geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
on the
X chromosomeThe X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals . 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
maleMale refers to the 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
femaleFemale is the sex of an organism, or a part of an organism, which produces 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 4000 females.)
Normally, the
FMR1FMR1 is a human gene that codes for a protein called fragile X mental retardation protein, or FMRP. This protein is normally made in many tissues, especially in the brain and testes...
gene contains between 6-55 (29 in Robbins-Kumar pathology textbooks) repeats of the CGG codon (
trinucleotide repeatsTrinucleotide repeat disorders are a set of genetic disorders caused by trinucleotide repeats in certain genes exceeding the normal, stable, threshold, which differs per gene...
). In people with the fragile X syndrome, the FMR1
alleleAn allele is one of a series of different forms of a gene. The word is a short form of allelomorph , which was used in the early days of genetics to describe variant forms of a gene detected as different phenotypes...
has over 230-4000 repeats of this codon.
Expansion of the CGG repeating codon to such a degree results in a
methylationDNA methylation is a type of chemical modification of DNA that can be inherited and subsequently removed without changing the original DNA sequence...
of that portion of the
DNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms and some viruses. The main role of DNA molecules is the long-term storage of information...
, effectively silencing the expression of the FMR1
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
.
This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction of the X
chromosomeA chromosome is an organized structure of DNA and protein that is 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...
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
axonAn axon or nerve fiber is a long, slender projectionof a nerve cell, or neuron, that conducts electrical impulsesaway from the neuron's cell body or soma....
s, formation of synapses, and the wiring and development of neural circuits.
Transmission of the fragile X
Technically, fragile X syndrome is an X-linked dominant condition with reduced penetrance.
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 double the chance of having a working FMR1
alleleAn allele is one of a series of different forms of a gene. The word is a short form of allelomorph , which was used in the early days of genetics to describe variant forms of a gene detected as different phenotypes...
. 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-inactivationX-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 it to all of their daughters, as males contribute their X to all of their daughters.
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.
Symptoms
Aside from intellectual disability, prominent characteristics of the syndrome include an elongated face, large or protruding ears, flat feet, larger testicles in men (
macroorchidismMacroorchidism 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 retardation...
), and low muscle tone. Speech may include
cluttered speechCluttered 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. Most females who have the syndrome experience symptoms to a lesser degree because of their second X-chromosome, however they can develop just as severe symptoms. 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.
Differences are:
- Females may also have clinical symptoms.
Physical Phenotype
- Prominent ears
- Long face (vertical maxillary excess)
- High-arched palate (related to the above)
- Hyperextensible finger joints
- Double-jointed thumbs
- Flat feet
- Soft skin
- Larger testicles in men (macroorchidism)
- Low muscle tone
Social Interaction
FXS is characterized by
social anxietySocial anxiety is a term used to describe an experience of anxiety regarding social situations, interactions with others and being evaluated or scrutinized by other people. It occurs early in childhood as a normal part of the development of social functioning, but may go unnoticed until adolescence...
, 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 someone’s 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 cognitionSocial cognition is the study of how people process social information, especially its encoding, storage, retrieval, and application to social situations. Social cognition’s focus on information processing has many affinities with its sister discipline, cognitive psychology...
. A child with FXS is likely to have
hyperactivityHyperactivity can be described as a physical state in which a person is abnormally and easily excitable or exuberant. Strong emotional reactions, impulsive behavior, and sometimes a short span of attention are also typical for a hyperactive person. Some individuals may show these characteristics...
, anxiety, and social deficits.
Individuals with fragile X-associated tremor/ataxia syndrome (FXTAS) are likely to experience
dementiaDementia is a serious cognitive disorder. It may be static, the result of a unique global brain injury or progressive, resulting in long-term decline in cognitive function due to damage or disease in the body 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
somatizationSomatization 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 such as:...
, obsessive–compulsive disorder, interpersonal sensitivity, depression, phobic anxiety and
psychoticismPsychoticism is one of the three traits used by the psychologist Hans Eysenck in his P-E-N model model of personality....
.
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 then 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 through
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.
Intellectual development
Current evidence shows that individuals with premutation have difficulties with mathematics, anxiety, attention, and/or
executive functionsThe executive system is a theorized cognitive system in psychology that controls and manages other cognitive processes. It is also referred to as the executive function, executive functions, supervisory attentional system, or cognitive control.The concept is used by psychologists and...
. 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. It should be emphasized that 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 (
etiologyEtiology 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,
hyperactivityHyperactivity can be described as a physical state in which a person is abnormally and easily excitable or exuberant. Strong emotional reactions, impulsive behavior, and sometimes a short span of attention are also typical for a hyperactive person. Some individuals may show these characteristics...
and also show hypersensitivity to visual, auditory, tactile, and olfactory stimuli. These children have difficulty in large crowds due to the loud noises as they 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 improve the child’s sensitivity in some cases.
PerseverationPerseveration is the uncontrollable 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...
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 retardation.
Ophthalmologic problems include
strabismusStrabismus is a condition in which the eyes are not properly aligned with each other...
(lazy eye). This requires early identification to avoid
amblyopiaAmblyopia, otherwise known as lazy eye, is a disorder of the visual system that is characterized by poor or indistinct vision in an eye that is otherwise physically normal, or out of proportion to associated structural abnormalities...
. Surgery and/or patching are usually necessary to treat strabismus if diagnosed early. Refractive errors in patients with fragile X are also common.
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. 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 blotA 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
Treatment and current 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 vitroA procedure performed in vitro is performed not in a living organism but in a controlled environment, such as in a test tube or Petri dish...
assays, is of primary importance. Also being examined is the function the various domains of FMRP, an
RNA-binding proteinRNA-binding proteins are typically cytoplasmic and nuclear proteins that associate with double-strand or single-strand RNAs through RNA recognition motif...
, which is still relatively unknown. One hypothesis is that many symptoms are caused by unchecked activation of
mGluR5Metabotropic glutamate receptor 5 is a protein that in humans is encoded by the GRM5 gene.-Ligands:In addition to the orthosteric site at least two distinct allosteric binding sites exist on the mGluR5...
, a
metabotropic glutamate receptorThe metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor which 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.
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 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,...
, medication, and when necessary, treatment of physical abnormalities. Persons with the fragile X syndrome in their family histories are advised to seek
genetic counselingGenetic counseling 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 in order to prevent, avoid...
to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants.
External links