| Fragile X syndrome | |
|---|---|
| Other names | Martin-Bell syndrome, Escalante syndrome |
 | |
| Boy with fragile X syndrome | |
| Specialty | Medical genetics, pediatrics, psychiatry |
| Symptoms | Intellectual disability, long and narrow face, large ears, flexible fingers, large testicles |
| Complications | Autism features, seizures |
| Usual onset | Noticeable by age 2 |
| Duration | Lifelong |
| Causes | Genetic (X-linked dominant) |
| Diagnostic method | Genetic testing |
| Treatment | Supportive care, early interventions |
| Frequency | 1 in 4,000 (males), 1 in 8,000 (females) |
Fragile X syndrome (FXS) is a genetic disorder. Symptoms often include mild to moderate intellectual disability. The average IQ in males is under 55, while about two thirds of 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 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.
Fragile X syndrome is inherited in an X-linked dominant pattern. Women with a premutation have an increased risk of having an affected child. It is typically due to an expansion of the CGG triplet repeat within the Fragile X mental retardation 1 (FMR1) gene on the X chromosome. This results in not enough of the fragile X mental retardation protein (FMRP), which is required for the normal development of connections between neurons. Diagnosis requires genetic testing to determine the number of CGG repeats in the FMR1 gene. Normal is between 5 and 40 repeats, fragile X syndrome occurs with more than 200, and a premutation is said to be present when an intermediate number of repeats occurs. Testing for premutation carriers may allow for genetic counseling.
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, physical therapy, or behavioral therapy. Medications may be used to treat associated seizures, mood problems, aggressive behavior, or ADHD. Fragile X syndrome is estimated to occur in 1.4 in 10,000 males and 0.9 in 10,000 females.
Signs and symptoms
Prominent characteristics of the syndrome include an elongated face, large or protruding ears, and low muscle tone.
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 ears, flat feet, larger testes (macroorchidism), and low muscle tone. Recurrent otitis media (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.
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 (both)
- Long face (vertical maxillary excess)
- High-arched palate (related to the above)
- Hyperextensible finger joints
- Hyperextensible ('double-jointed') thumbs
- 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 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 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 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.
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 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 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 (FXTAS) 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.
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.
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, 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 (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 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 menopause before the age of 40. The number of CGG repeats correlates with penetrance and age of onset. However 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.
Fragile X-associated primary ovarian insufficiency (FXPOI) is one of
three Fragile X-associated Disorders (FXD) caused by changes in the FMR1
gene. FXPOI affects female premutation carriers of Fragile X syndrome,
which is caused by the FMR1 gene, when their ovaries are not functioning
properly. Women with FXPOI may develop menopause-like symptoms but they
are not actually menopausal. Women with FXPOI can still get pregnant in
some cases because their ovaries occasionally release viable eggs.
FMRP is a chromatin-binding protein that functions in the DNA damage response. FMRP also occupies sites on meiotic chromosomes and regulates the dynamics of the DNA damage response machinery during spermatogenesis.
Causes
Location of FMR1 gene on the X chromosome.
Fragile X syndrome is a genetic disorder which occurs as a result of a mutation of the fragile X mental retardation 1 (FMR1) 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 sequence CGG, most commonly 29 or 30 repeats. Between 45-54 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 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 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. 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 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 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. 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 and mGluR5, is involved in mGluR-dependent long term depression (LTD) and long term potentiation (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
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" (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 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. 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, 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.
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 suffering from 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, 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.
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 neurodevelopmental disorder under study.
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
(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) 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.
The first complete DNA sequence of the repeat expansion in
someone with the full mutation was generated by scientists in 2012 using
SMRT sequencing.
History
In 1943, James Purdon Martin and Julia Bell described a pedigree of X-linked mental disability, without considering the macroorchidism (larger testicles). 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". And, in 1985, Felix F. de la Cruz
outlined extensively the physical, psychological, and cytogenic
characteristics of those afflicted in addition to prospects for therapy. Continued advocacy later won him an honour through the FRAXA Research Foundation in December 1998.
