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, obsessive–compulsive

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 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, 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

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 was occurring. This tendency

for future generations to be affected at a higher frequency became known as the Sherman

paradox after its description in 1985. 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.

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 of neurons. 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. 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 pathway, which includes mGluR1 and mGluR5,

is involved in mGluR-dependent long term depression and long term potentiation, 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