Fragile-X syndrome
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Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles. About a third of those affected have features of
autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
such as problems with social interactions and delayed speech. Hyperactivity is common, and seizures occur in about 10%. Males are usually more affected than females. This disorder and finding of Fragile X syndrome has an
X-linked dominant inheritance X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome. As an inheritance pattern, it is less common than the X-linked recessive type. ...
. It is typically caused by an expansion of the CGG triplet repeat within the '' FMR1'' (fragile X messenger ribonucleoprotein 1) gene on the X chromosome. This results in silencing (
methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
) of this part of the gene and a deficiency of the resultant protein (FMRP), which is required for the normal development of connections between neurons. Diagnosis requires
genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
to determine the number of CGG repeats in the ''FMR1'' gene. Normally, there are between 5 and 40 repeats; fragile X syndrome occurs with more than 200. A premutation is said to be present when the gene has between 55 and 200 repeats; women with a premutation have an increased risk of having an affected child. Testing for premutation carriers may allow for
genetic counseling Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease; t ...
. There is no cure. Early intervention is recommended, as it provides the most opportunity for developing a full range of skills. These interventions may include special education,
speech therapy Speech is a human vocal communication using language. Each language uses phonetic combinations of vowel and consonant sounds that form the sound of its words (that is, all English words sound different from all French words, even if they are th ...
,
physical therapy Physical therapy (PT), also known as physiotherapy, is one of the allied health professions. It is provided by physical therapists who promote, maintain, or restore health through physical examination, diagnosis, management, prognosis, patient ...
, or
behavioral therapy Behaviour therapy or behavioural psychotherapy is a broad term referring to clinical psychotherapy that uses techniques derived from behaviourism and/or cognitive psychology. It looks at specific, learned behaviours and how the environment, or oth ...
. Medications may be used to treat associated seizures, mood problems, aggressive behavior, or
ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...
. Fragile X syndrome is estimated to occur in 1.4 per 10,000 males and 0.9 per 10,000 females.


Signs and symptoms

Most young children do not show any physical signs of FXS. It is not until puberty that physical features of FXS begin to develop. Aside from intellectual disability, prominent characteristics of the syndrome may include an elongated face, large or
protruding ear Prominent ear, otapostasis or bat ear is an abnormally protruding human ear. It may be unilateral or bilateral. The concha is large with poorly developed antihelix and scapha. It is the result of malformation of cartilage during primitive ear deve ...
s, flat feet, larger testes ( macroorchidism), and
low muscle tone Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...
. Recurrent
otitis media Otitis media is a group of inflammatory diseases of the middle ear. One of the two main types is acute otitis media (AOM), an infection of rapid onset that usually presents with ear pain. In young children this may result in pulling at the ear, ...
(middle ear infection) and sinusitis is common during early childhood. Speech may be cluttered or nervous. 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 fragile X syndrome also meet the diagnostic criteria for
autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
. Males with a full mutation display virtually complete penetrance and will therefore almost always display symptoms of FXS, while females with a full mutation generally display a penetrance of about 50% as a result of having a second, normal X chromosome. Females with FXS may have symptoms ranging from mild to severe, although they are generally less affected than males.


Physical phenotype

* Large,
protruding ears Prominent ear, otapostasis or bat ear is an abnormally protruding human ear. It may be unilateral or bilateral. The concha is large with poorly developed antihelix and scapha. It is the result of malformation of cartilage during primitive ear deve ...
(both) * Long face (
vertical maxillary excess A jaw abnormality is a disorder in the formation, shape and/or size of the jaw. In general abnormalities arise within the jaw when there is a disturbance or fault in the fusion of the mandibular processes. The mandible in particular has the most d ...
) *
High-arched palate A high-arched palate (also termed high-vaulted palate) is where the palate is unusually high and narrow. It is usually a congenital developmental feature that results from the failure of the palatal shelves to fuse correctly in development, the sa ...
(related to the above) * Hyperextensible finger joints * Hyperextensible thumbs ('double-jointed') * Flat feet * Soft skin * Postpubescent macroorchidism (large testicles in men after puberty) * Hypotonia (low muscle tone)


Intellectual development

Individuals with FXS may present anywhere on a continuum from learning disabilities in the context of a normal intelligence quotient (IQ) to severe intellectual disability, with an average IQ of 40 in males who have complete silencing of the ''FMR1'' gene. Females, who tend to be less affected, generally have an IQ which is normal or borderline with learning difficulties. The main difficulties in individuals with FXS are with working and short-term memory, executive function, visual memory, visual-spatial relationships, and mathematics, with verbal abilities being relatively unaffected. Data on intellectual development in FXS are limited. However, there is some evidence that standardized IQ decreases over time in the majority of cases, apparently as a result of slowed intellectual development. A longitudinal study looking at pairs of siblings where one child was affected and the other was not found that affected children had an intellectual learning rate which was 55% slower than unaffected children. Individuals with FXS often demonstrated language and communicative problems. This may be related to muscle function of the mouth and frontal-lobe deficits.


Autism

Fragile X syndrome co-occurs with autism in many cases and is a suspected genetic cause of the autism in these cases. This finding has resulted in screening for FMR1 mutation to be considered mandatory in children diagnosed with autism. Of those with fragile X syndrome, prevalence of concurrent autism spectrum disorder (ASD) has been estimated to be between 15 and 60%, with the variation due to differences in diagnostic methods and the high frequency of autistic features in individuals with fragile X syndrome not meeting the DSM criteria for an ASD. Although individuals with FXS have difficulties in forming friendships, those with FXS and ASD characteristically also have difficulties with reciprocal conversation with their peers. Social withdrawal behaviors, including avoidance and indifference, appear to be the best predictors of ASD in FXS, with avoidance appearing to be correlated more with social anxiety while indifference was more strongly correlated to ASD. When both autism and FXS are present, a greater language deficit and lower IQ is observed as compared to children with only FXS.Hagerman, Randi J., and Paul J. Hagerman. ''Fragile X syndrome: diagnosis, treatment, and research''. 3, illustrated ed. Baltimore, MD: JHU P, 2002. Genetic mouse models of FXS have also been shown to have autistic-like behaviors.


Social interaction

FXS is characterized by social anxiety, including poor eye contact, gaze aversion, prolonged time to commence social interaction, and challenges forming peer relationships. Social anxiety is one of the most common features associated with FXS, with up to 75% of males in one series characterized as having excessive shyness and 50% having panic attacks. Social anxiety in individuals with FXS is related to challenges with face encoding, the ability to recognize a face that one has seen before. It appears that individuals with FXS are interested in social interaction and display greater empathy than groups with other causes of intellectual disability, but display anxiety and withdrawal when placed in unfamiliar situations with unfamiliar people. This may range from mild social withdrawal, which is predominantly associated with shyness, to severe social withdrawal, which may be associated with co-existing autism spectrum disorder. Females with FXS frequently display shyness, social anxiety and social avoidance or withdrawal. In addition, premutation in females has been found to be associated with social anxiety. Female individuals with FXS show decreased activation in the prefrontal regions of the brain.


Mental health

Attention deficit hyperactivity disorder (ADHD) is found in the majority of males with FXS and 30% of females, making it the most common psychiatric diagnosis in those with FXS. Children with fragile X have very short attention spans, are hyperactive, and show hypersensitivity to visual, auditory, tactile, and
olfactory The sense of smell, or olfaction, is the special sense through which smells (or odors) are perceived. The sense of smell has many functions, including detecting desirable foods, hazards, and pheromones, and plays a role in taste. In humans, it ...
stimuli. These children have difficulty in large crowds due to the loud noises and this can lead to tantrums due to hyperarousal. Hyperactivity and disruptive behavior peak in the preschool years and then gradually decline with age, although inattentive symptoms are generally lifelong. Aside from the characteristic social phobia features, a range of other anxiety symptoms are very commonly associated with FXS, with symptoms typically spanning a number of psychiatric diagnoses but not fulfilling any of the criteria in full. 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. Behaviors such as hand flapping and biting, as well as aggression, can be an expression of anxiety. 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 Intrapersonal communication is the process by which an individual communicates within themselves, acting as both sender and receiver of messages, and encompasses the use of unspoken words to consciously engage in self-talk and inner speech. Intr ...
are commonly seen. Self-talk includes talking with oneself using different tones and pitches. Although only a minority of FXS cases will meet the criteria for obsessive–compulsive disorder (OCD), a significant majority will have symptoms of obsession. However, as individuals with FXS generally find these behaviors pleasurable, unlike individuals with OCD, they are more frequently referred to as stereotypic behaviors. Mood symptoms in individuals with FXS rarely meet diagnostic criteria for a major mood disorder as they are typically not of sustained duration. Instead, these are usually transient and related to stressors, and may involve labile (fluctuating) mood, irritability, self-injury and aggression. Individuals with
fragile X-associated tremor/ataxia syndrome Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder most frequently seen in male premutation carriers of Fragile X syndrome (FXS) over the age of 50. The main clinical features of FXTAS include problems o ...
(FXTAS) are likely to experience combinations of dementia, mood, and
anxiety disorder Anxiety disorders are a cluster of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal function are significantly impaired. Anxiety may cause physi ...
s. 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.


Vision

Ophthalmologic problems include strabismus. This requires early identification to avoid
amblyopia Amblyopia, also called lazy eye, is a disorder of sight in which the brain fails to fully process input from one eye and over time favors the other eye. It results in decreased vision in an eye that typically appears normal in other aspects. Amb ...
. Surgery or patching are usually necessary to treat strabismus if diagnosed early. Refractive errors in patients with FXS are also common.


Neurology

Individuals with FXS are at a higher risk of developing seizures, with rates between 10% and 40% reported in the literature. In larger study populations the frequency varies between 13% and 18%, consistent with a recent survey of caregivers which found that 14% of males and 6% of females experienced seizures. The seizures tend to be
partial Partial may refer to: Mathematics * Partial derivative, derivative with respect to one of several variables of a function, with the other variables held constant ** ∂, a symbol that can denote a partial derivative, sometimes pronounced "partial ...
, are generally not frequent, and are amenable to treatment with medication. Individuals who are carriers of premutation alleles are at risk for developing
fragile X-associated tremor/ataxia syndrome Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder most frequently seen in male premutation carriers of Fragile X syndrome (FXS) over the age of 50. The main clinical features of FXTAS include problems o ...
(FXTAS), a progressive neurodegenerative disease. It is seen in approximately half of male carriers over the age of 70, while penetrance in females is lower. Typically, onset of
tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...
occurs in the sixth decade of life, with subsequent progression to ataxia (loss of coordination) and gradual cognitive decline.


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. However, in a premutation individual, CGG length is only significantly correlated with the central executive, not with either phonological memory or visual–spatial memory.


Fertility

About 20% of women who are carriers for the fragile X premutation are affected by fragile X-related primary ovarian insufficiency (FXPOI), which is defined as early menopause, which is menopause occurring before 40 ayears of age (average age at menopause is 51 years old in the US). The number of CGG repeats correlates with penetrance and age of onset, but it is not a linear relationship. However premature menopause is more common in premutation carriers than in women with the full mutation, and the highest risk for FXPOI is observed in women with between 70-100 repeats the risk of FXPOI.
Fragile X-associated primary ovarian insufficiency Fragile X-associated Primary Ovarian Insufficiency (FXPOI) is the most common genetic cause of premature ovarian failure in women with a normal karyotype 46, XX. The expansion of a CGG repeat in the 5' untranslated region of the ''FMR1'' gene f ...
(FXPOI) is one of three Fragile X-associated Disorders (FXD) caused by changes in the FMR1 gene. FXPOI affects female premutation carriers, of which is caused by the FMR1 gene, when their ovaries are not functioning properly. Women with FXPOI may exhibit changes in menstrual cycles and have changes in hormone levels but not be considered menopausal. Women with FXPOI still have the chance to get pregnant in about 10% of cases, because their ovaries occasionally release viable eggs through "escape" ovulation.
FMRP ''FMR1'' (Fragile X Messenger Ribonucleoprotein 1) is a human gene that codes for a protein called ''fragile X messenger ribonucleoprotein'', or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development ...
is a chromatin-binding protein that functions in the
DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
response. FMRP also occupies sites on
meiotic Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately res ...
chromosomes and regulates the dynamics of the DNA damage response machinery during
spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...
.


Causes

Fragile X syndrome is a genetic disorder which occurs as a result of a mutation of the ''Fragile X Messenger Ribonucleoprotein 1'' (''FMR1'') gene on the X chromosome, most commonly an increase in the number of CGG trinucleotide repeats in the
5' untranslated region The 5′ untranslated region (also known as 5′ UTR, leader sequence, transcript leader, or leader RNA) is the region of a messenger RNA (mRNA) that is directly Upstream and downstream (DNA), upstream from the initiation codon. This region is im ...
of ''FMR1''. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females. Although this accounts for over 98% of cases, FXS can also occur as a result of point mutations affecting ''FMR1''. In unaffected individuals, the ''FMR1'' gene contains 5–44 repeats of the sequence CGG, most commonly 29 or 30 repeats. Between 45 and 54 repeats is considered a "grey zone", with a premutation allele generally considered to be between 55 and 200 repeats in length. Individuals with fragile X syndrome have a full mutation of the ''FMR1'' allele, with over 200 CGG repeats. In these individuals with a repeat expansion greater than 200, there is
methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
of the CGG repeat expansion and ''FMR1'' promoter, leading to the silencing of the ''FMR1'' gene and a lack of its product. This methylation of ''FMR1'' 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. One study found that FMR1 silencing is mediated by the FMR1 mRNA. The FMR1 mRNA contains the transcribed CGG-repeat tract as part of the 5' untranslated region, which hybridizes to the complementary CGG-repeat portion of the FMR1 gene to form an RNA·DNA duplex. A subset of people with intellectual disability and symptoms resembling fragile X syndrome are found to have point mutations in ''FMR1.'' This subset lacked the CGG repeat expansion in ''FMR1'' traditionally associated with fragile x syndrome.


Inheritance

Fragile X syndrome has traditionally been considered an X-linked dominant condition with variable expressivity and possibly reduced penetrance. However, due to
genetic anticipation In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase in the severity of ...
and X-inactivation in females, the inheritance of Fragile X syndrome does not follow the usual pattern of X-linked dominant inheritance, and some scholars have suggested discontinuing labeling X-linked disorders as dominant or recessive. Females with full FMR1 mutations may have a milder phenotype than males due to variability in X-inactivation. Before the ''FMR1'' gene was discovered, analysis of pedigrees showed the presence of male carriers who were asymptomatic, with their grandchildren affected by the condition at a higher rate than their siblings suggesting that
genetic anticipation In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase in the severity of ...
was occurring. This tendency for future generations to be affected at a higher frequency became known as the
Sherman paradox The Sherman paradox was a term used to describe the anomalous pattern of inheritance found in fragile X syndrome. The phenomenon is also referred to as anticipation or dynamic mutation. Background The paradox was named in the late 1980s after A ...
after its description in 1985. Due to this, male children often have a greater degree of symptoms than their mothers. The explanation for this phenomenon is that male carriers pass on their premutation to all of their daughters, with the length of the ''FMR1'' CGG repeat typically not increasing during meiosis, the cell division that is required to produce sperm. Incidentally, males with a full mutation only pass on premutations to their daughters. However, females with a full mutation are able to pass this full mutation on, so theoretically there is a 50% chance that a child will be affected. In addition, the length of the CGG repeat frequently does increase during meiosis in female premutation carriers due to instability and so, depending on the length of their premutation, they may pass on a full mutation to their children who will then be affected. Repeat expansion is considered to be a consequence of
strand slippage Slipped strand mispairing (SSM), (also known as replication slippage), is a mutation process which occurs during DNA replication. It involves denaturation and displacement of the DNA strands, resulting in mispairing of the complementary bases. ...
either during DNA replication or DNA repair synthesis.


Pathophysiology

FMRP is found throughout the body, but in highest concentrations within the brain and testes. It appears to be primarily responsible for selectively binding to around 4% of mRNA in mammalian brains and transporting it out of the cell nucleus and to the
synapses In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...
of
neurons A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
. Most of these mRNA targets have been found to be located in the dendrites of neurons, and brain tissue from humans with FXS and mouse models shows abnormal dendritic spines, which are required to increase contact with other neurons. The subsequent abnormalities in the formation and function of synapses and development of neural circuits result in impaired neuroplasticity, an integral part of memory and learning. Connectome changes have long been suspected to be involved in the sensory pathophysiology and most recently a range of circuit alterations have been shown, involving structurally increased local connectivity and functionally decreased long-range connectivity. In addition, FMRP has been implicated in several signalling pathways that are being targeted by a number of drugs undergoing clinical trials. The group 1 metabotropic glutamate receptor (mGluR) pathway, which includes
mGluR1 The glutamate receptor, metabotropic 1, also known as GRM1, is a human gene which encodes the metabotropic glutamate receptor 1 (mGluR1) protein. Function L-glutamate is the major excitatory neurotransmitter in the central nervous system and ...
and
mGluR5 Metabotropic glutamate receptor 5 is an excitatory Gq-coupled G protein-coupled receptor predominantly expressed on the postsynaptic sites of neurons. In humans, it is encoded by the ''GRM5'' gene. Function The amino acid L- glutamate is the ...
, is involved in mGluR-dependent
long term depression In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depend ...
(LTD) and
long term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neuron ...
(LTP), both of which are important mechanisms in learning. The lack of FMRP, which represses mRNA production and thereby protein synthesis, leads to exaggerated LTD. FMRP also appears to affect
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
pathways in the prefrontal cortex which is believed to result in the attention deficit, hyperactivity and impulse control problems associated with FXS. The downregulation of GABA pathways, which serve an inhibitory function and are involved in learning and memory, may be a factor in the anxiety symptoms which are commonly seen in FXS.


Diagnosis

Cytogenetic analysis for fragile X syndrome was first available in the late 1970s when diagnosis of the syndrome and carrier status could be determined by culturing cells in a folate deficient medium and then assessing for "
fragile site A chromosomal fragile site is a specific heritable point on a chromosome that tends to form a gap or constriction and may tend to break when the cell is exposed to partial replication stress. Based on their frequency, fragile sites are classified ...
s" (discontinuity of staining in the region of the trinucleotide repeat) on the long arm of the X chromosome. This technique proved unreliable, however, as the fragile site was often seen in less than 40% of an individual's cells. This was not as much of a problem in males, but in female carriers, where the fragile site could generally only be seen in 10% of cells, the mutation often could not be visualised. Since the 1990s, more sensitive molecular techniques have been used to determine carrier status. The fragile X abnormality is now directly determined by analysis of the number of CGG repeats using polymerase chain reaction (PCR) and methylation status using
Southern blot A Southern blot is a method 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 detecti ...
analysis. By determining the number of CGG repeats on the X chromosome, this method allows for more accurate assessment of risk for premutation carriers in terms of their own risk of fragile X associated syndromes, as well as their risk of having affected children. Because this method only tests for expansion of the CGG repeat, individuals with FXS due to missense mutations or deletions involving ''FMR1'' will not be diagnosed using this test and should therefore undergo sequencing of the FMR1 gene if there is clinical suspicion of FXS. Prenatal testing with
chorionic villus sampling Chorionic villus sampling (CVS), sometimes called "chorionic ''villous'' sampling" (as "villous" is the adjectival form of the word "villus"), is a form of prenatal diagnosis done to determine chromosomal or genetic disorders in the fetus. It ent ...
or amniocentesis allows diagnosis of FMR1 mutation while the fetus is in utero and appears to be reliable. Early diagnosis of fragile X syndrome or carrier status is important for providing early intervention in children or fetuses with the syndrome, and allowing genetic counselling with regards to the potential for a couple's future children to be affected. Most parents notice delays in speech and language skills, difficulties in social and emotional domains as well as sensitivity levels in certain situations with their children.


Management

There is no cure for the underlying defects of FXS. Management of FXS may include
speech therapy Speech is a human vocal communication using language. Each language uses phonetic combinations of vowel and consonant sounds that form the sound of its words (that is, all English words sound different from all French words, even if they are th ...
,
behavioral therapy Behaviour therapy or behavioural psychotherapy is a broad term referring to clinical psychotherapy that uses techniques derived from behaviourism and/or cognitive psychology. It looks at specific, learned behaviours and how the environment, or oth ...
,
occupational therapy Occupational therapy (OT) is a global healthcare profession. It involves the use of assessment and intervention to develop, recover, or maintain the meaningful activities, or ''occupations'', of individuals, groups, or communities. The field of ...
, special education, or individualised educational plans, and, when necessary, treatment of physical abnormalities. Persons with fragile X syndrome in their family histories are advised to seek
genetic counseling Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease; t ...
to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants.


Medication

Current trends in treating the disorder include medications for symptom-based treatments that aim to minimize the secondary characteristics associated with the disorder. If an individual is diagnosed with FXS, genetic counseling for testing family members at risk for carrying the full mutation or premutation is a critical first-step. Due to a higher prevalence of FXS in boys, the most commonly used medications are stimulants that target hyperactivity, impulsivity, and attentional problems. For co-morbid disorders with FXS, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are utilized to treat the underlying anxiety, obsessive-compulsive behaviors, and mood disorders. Following antidepressants, antipsychotics such as risperidone and quetiapine are used to treat high rates of self-injurious, aggressive and aberrant behaviors in this population (Bailey Jr et al., 2012). Anticonvulsants are another set of pharmacological treatments used to control seizures as well as mood swings in 13%–18% of individuals with FXS. Drugs targeting the mGluR5 (metabotropic glutamate receptors) that are linked with synaptic plasticity are especially beneficial for targeted symptoms of FXS. Lithium is also currently being used in clinical trials with humans, showing significant improvements in behavioral functioning, adaptive behavior, and verbal memory. Few studies suggested using folic acid, but more researches are needed due to the low quality of that evidence. Alongside pharmacological treatments, environmental influences such as home environment and parental abilities as well as behavioral interventions such as speech therapy, sensory integration, etc. all factor in together to promote adaptive functioning for individuals with FXS. While metformin may reduce body weight in persons with fragile X syndrome, it is uncertain whether it improves neurological or psychiatric symptoms. Current pharmacological treatment centers on managing problem behaviors and psychiatric symptoms associated with FXS. However, as there has been very little research done in this specific population, the evidence to support the use of these medications in individuals with FXS is poor.
ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...
, which affects the majority of boys and 30% of girls with FXS, is frequently treated using
stimulants Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
. However, the use of stimulants in the fragile X population is associated with a greater frequency of adverse events including increased anxiety, irritability and mood lability. Anxiety, as well as mood and obsessive-compulsive symptoms, may be treated using
SSRIs Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs increase the extracellul ...
, although these can also aggravate hyperactivity and cause disinhibited behavior. Atypical antipsychotics can be used to stabilise mood and control aggression, especially in those with comorbid ASD. However, monitoring is required for metabolic side effects including weight gain and diabetes, as well as movement disorders related to
extrapyramidal side effects Extrapyramidal symptoms (EPS) are symptoms that are archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they are also known as extrapyramidal side ...
such as tardive dyskinesia. Individuals with coexisting seizure disorder may require treatment with
anticonvulsants Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...
.


Prognosis

A 2013 review stated that life expectancy for FXS was 12 years lower than the general population and that the causes of death were similar to those found for the general population.


Research

Fragile X syndrome is the most "translated" human neurodevelopmental disorder under study. Hence, research into the etiology of FXS has given rise to many attempts at drug discovery. The increased understanding of the molecular mechanisms of disease in FXS has led to the development of therapies targeting the affected pathways. Evidence from mouse models shows that mGluR5
antagonists An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
(blockers) can rescue dendritic spine abnormalities and seizures, as well as cognitive and behavioral problems, and may show promise in the treatment of FXS. Two new drugs, AFQ-056 (
mavoglurant Mavoglurant (developmental code name AFQ-056) is an experimental drug candidate for the treatment of fragile X syndrome and other conditions which has been discontinued. It exerts its effect as an receptor antagonist, antagonist of the metabotrop ...
) and dipraglurant, as well as the repurposed drug
fenobam Fenobam is an imidazole derivative developed by McNeil Laboratories in the late 1970s as a novel anxiolytic drug with an at-the-time-unidentified molecular target in the brain. Subsequently, it was determined that fenobam acts as a potent and se ...
are currently undergoing human trials for the treatment of FXS. There is also early evidence for the efficacy of
arbaclofen Arbaclofen placarbil ( , also known as XP19986) is a prodrug of ''R''-baclofen. Arbaclofen placarbil possesses more favorable pharmacokinetic profile than baclofen, with less fluctuations in plasma drug levels. It was being developed as a potent ...
, a GABAB agonist, in improving social withdrawal in individuals with FXS and ASD. In addition, there is evidence from mouse models that minocycline, an antibiotic used for the treatment of acne, rescues abnormalities of the dendrites. An open trial in humans has shown promising results, although there is currently no evidence from
controlled trials Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dieta ...
to support its use. The first complete DNA sequence of the repeat expansion in someone with the full mutation was generated by scientists in 2012 using
SMRT sequencing Single-molecule real-time (SMRT) sequencing is a parallelized single molecule DNA sequencing method. Single-molecule real-time sequencing utilizes a zero-mode waveguide (ZMW). A single DNA polymerase enzyme is affixed at the bottom of a ZMW with a ...
.


History

In 1943, British neurologist
James Purdon Martin James Purdon Martin (1893–1984) was a British neurologist. Biography After education at the Royal Belfast Academical Institution, J. Purdon Martin matriculated in 1912 at Queen's University Belfast and graduated there in with BA in 1915 an ...
and British geneticist
Julia Bell Julia Bell (28 January 1879 – 26 April 1979) was a pioneering English human geneticist.Greta Jones, 'Bell, Julia (1879–1979)', ''Oxford Dictionary of National Biography'', Oxford University Press, Sept 2004; online edn, Jan 200accessed 10 M ...
described a pedigree of X-linked intellectual disability, without considering the macroorchidism (larger testicles). In 1969, Herbert Lubs first sighted an unusual "marker X chromosome" in association with intellectual disability. In 1970, Frederick Hecht coined the term "fragile site". And, in 1985, Felix F. de la Cruz outlined extensively the physical, psychological, and cytogenetic characteristics of those with the condition in addition to prospects for therapy. Continued advocacy later won him an honour through the FRAXA Research Foundation in December 1998.


References


External links


CDC’s National Center on Birth Defects and Developmental Disabilities

Gene Reviews
{{Authority control Genetics of autism Intellectual disability Rare syndromes Syndromes affecting the eye Syndromes affecting the nervous system Syndromes with craniofacial abnormalities Trinucleotide repeat disorders X-linked dominant disorders Neurogenetic disorders Wikipedia medicine articles ready to translate Autism spectrum disorders