Fragile X syndrome, also known as Martin–Bell 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, 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
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 sites" 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 and methylation status using Southern blot 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 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.
Management Pharmacological
Due to the fact that there are no current treatments or cures for the underlying defects
of FXS, it is even more critical for medical science to innovate new and efficacious pharmacological
treatments as well as targeted behavioral interventions.
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 are utilized to treat the underlying anxiety,
obsessive-compulsive behaviors, and mood disorders. Following antidepressants, antipsychotics
such as Risperdal and Seroquel are used to treat high rates of self-injurious, aggressive
and aberrant behaviors in this population. Anticonvulsants are another set of pharmacological
treatments used to control seizures as well as mood swings in 13%-18% of individuals suffering
from FXS. Drugs targeting the mGluR5 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. 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. Despite the presence of many medications used
to treat the secondary behavioral phenotype of FXS, medical scientists and policy makers
need to work closely together in order to generate not only good science through efficacious
treatments but also for increasing the available knowledge bank on molecular therapies and
FXS through clinical trials of more known disorders such as ADHD and autism. Due to
FXS individuals falling on a spectrum of cognitive deficits, planned educational curricula can
be facilitated in order to manage better cognitive functioning for these individuals. It is important
to understand the implications targeted treatments can have on not only the individuals with
FXS, but also the clinicians and parents in close contact with these individuals, resulting
in early diagnosing and screening matched with optimal targeted interventions.
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. While there is no current cure for the syndrome, there is hope that
further understanding of its underlying causes will lead to new therapies.
ADHD, which affects the majority of boys and 30% of girls with FXS, is frequently treated
using stimulants. 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, 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 such as tardive dyskinesia. Individuals with coexisting seizure disorder may require
treatment with anticonvulsants. Non-pharmacological
Management of FXS may include speech therapy, behavioral therapy, sensory integration occupational
therapy, 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 to assess the likelihood of having children who are affected, and how
severe any impairments may be in affected descendants.
Research 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 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 and dipraglurant, as
well as the repurposed drug fenobam are currently undergoing human trials for the treatment
of FXS. There is also early evidence for the efficacy of arbaclofen, 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
to support its use. History
In 1943, J. Purdon Martin and Julia Bell described a pedigree of X-linked mental disability,
without considering the macroorchidism. In 1969, Herbert Lubs first sighted an unusual
"marker X chromosome" in association with mental disability. In 1970, Frederick Hecht
coined the term "fragile site". References
External links CDC’s National Center on Birth Defects and
Developmental Disabilities Fraxa.org – The Fragile X Research Foundation
Fragilex.org.uk – The United Kingdom National Fragile X charity
FragileX.org The National Fragile X Foundation – Support, Awareness, Education, Research
and Advocacy since 1984 FragileX.org.au – Fragile X Association
of Australia – charity – news, forums, support, information, clinics
The Colorado Fragile X Consortium Gene Reviews
Closely linked to Nicolaides-Baraitser syndrome