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  • Fragile X syndrome, also known as MartinBell syndrome, or Escalante's syndrome, is a genetic

  • syndrome that is the most widespread single-gene cause of autism and inherited cause of intellectual

  • disability especially among boys. It results in a spectrum of intellectual disabilities

  • ranging from mild to severe as well as physical characteristics such as an elongated face,

  • large or protruding ears, and large testes, and behavioral characteristics such as stereotypic

  • movements, and social anxiety. Fragile X syndrome is associated with the

  • expansion of the CGG trinucleotide repeat affecting the Fragile X mental retardation

  • 1 gene on the X chromosome, resulting in a failure to express the fragile X mental retardation

  • protein, which is required for normal neural development. Depending on the length of the

  • CGG repeat, an allele may be classified as normal, a premutation, or full mutation. A

  • definitive diagnosis of fragile X syndrome is made through genetic testing to determine

  • the number of CGG repeats. Testing for premutation carriers can also be carried out to allow

  • for genetic counseling. The first complete DNA sequence of the repeat expansion in someone

  • with the full mutation was generated by scientists in 2012 using SMRT sequencing.

  • There is currently no drug treatment that has shown benefit specifically for fragile

  • X syndrome. However, medications are commonly used to treat symptoms of attention deficit

  • and hyperactivity, anxiety, and aggression. Supportive management is important in optimizing

  • functioning in individuals with fragile X syndrome, and may involve speech therapy,

  • occupational therapy, and individualized educational and behavioral programs.

  • Signs and symptoms

  • Aside from intellectual disability, prominent characteristics of the syndrome may include

  • an elongated face, large or protruding ears, flat feet, larger testes, and low muscle tone.

  • Recurrent otitis media and sinusitis is common during early childhood. Speech may be cluttered

  • or nervous. Behavioral characteristics may include stereotypic movements 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. 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

  • Long face High-arched palate

  • Hyperextensible finger joints Hyperextensible thumbs

  • Flat feet Soft skin

  • Postpubescent macroorchidism Hypotonia

  • Intellectual development Individuals with FXS may present anywhere

  • on a continuum from learning disabilities in the context of a normal intelligence quotient

  • 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 spared.

  • 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.

  • When both autism and FXS are present, a greater language deficit and lower IQ is observed

  • as compared to children with only FXS. Autism

  • Fragile X syndrome co-occurs with autism in about 5% of 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 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 severe ASD. When both autism and FXS are

  • present, a greater language deficit and lower IQ is observed as compared to children with

  • only FXS. 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. The size of DNA insertion is related to severity

  • of attention problems and withdrawal symptoms. Individuals with FXS show decreased activation

  • in the prefrontal regions of the brain. These regions are associated with social cognition.

  • Psychiatric Attention deficit hyperactivity disorder is

  • found in the majority of males with FXS and 30% of females, making it the most common

  • psychiatric diagnosis in those with FXS. 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. Behaviors such as hand flapping and biting, as well as aggression, can be an expression

  • of anxiety. Although only a minority will meet the criteria for obsessive-compulsive

  • disorder, a significant majority will feature obsessive-type symptoms. 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 mood, irritability, self-injury and aggression.

  • Individuals with fragile X-associated tremor/ataxia syndrome are likely to experience combinations

  • of dementia, mood, and anxiety disorders. Males with the FMR1 premutation and clinical

  • evidence of FXTAS were found to have increased occurrence of somatization, obsessivecompulsive

  • disorder, interpersonal sensitivity, depression, phobic anxiety, and psychoticism.

  • 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 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.

  • Vision Ophthalmologic problems include strabismus.

  • This requires early identification to avoid amblyopia. Surgery or patching are usually

  • necessary to treat strabismus if diagnosed early. Refractive errors in patients with

  • FXS are also common. Neurological

  • 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, 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, 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 occurs in the sixth decade of life, with subsequent progression to ataxia

  • 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 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 visualspatial memory. However, in a premutation individual,

  • CGG length is only significantly correlated with the central executive, not with either

  • phonological memory or visualspatial memory. Fertility

  • About 20% of women who are carriers for the fragile X premutation are affected by fragile

  • X-related primary ovarian insufficiency, which is defined as menopause before the age of

  • 40. The number of CGG repeats correlates with penetrance and age of onset. However, it is

  • interesting to note that premature menopause is more common in premutation carriers than

  • in women with the full mutation, and for premutations with more than 100 repeats the risk of FXPOI

  • begins to decrease. Causes

  • Fragile X syndrome is a genetic disorder which occurs as a result of a mutation of the fragile

  • X mental retardation 1 gene on the X chromosome, most commonly an increase in the number of

  • CGG trinucleotide repeats in the 5' untranslated region 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 CGG codon, 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 repeats of the CGG codon. In these individuals with

  • a repeat expansion greater than 200, there is methylation 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. Transmission

  • Fragile X syndrome has traditionally been considered an X-linked dominant condition

  • with variable expressivity and possibly reduced penetrance. However, due to genetic anticipation