Fragile X syndrome is a genetic disorder, which is due to a mutation
in the X-linked FMR1 gene that causes a range of developmental problems
including learning disabilities and cognitive impairment or intellectual
disability. Males with fragile X syndrome almost always exhibit mental
retardation, usually in the moderate range, and often have characteristic
physical features and behaviour. Since the mutation is X-linked, males are more
severely affected than females.
Prevalence:
In general population Fragile X syndrome occurs in
approximately 1 in 4,000 (1:4000) males and 1 in 8,000 (1:8000) females.
1.
Physical features
The physical features include a
long and narrow face (elongated face), large and protruding ears,
flexible fingers, flat feet, macroorchidism
(large testicles) and low muscle tone (hypotonia). During
early childhood, recurrent otitis media (middle ear
infection) and sinusitis is common. 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. 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.
2.
Intellectual development:
Studies show that Individuals with
Fragile X syndrome have low IQ level, with an average IQ of 40 in males who
have complete silencing of the FMR1 gene but in case of females, who are less
vulnerable to FXS, 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, visual-spatial
relationships, visual memory, verbal abilities being relatively spared,
executive function and low mathematics ability.
3.
Autism:
Most of the time Fragile X
syndrome co-occurs with autism in many cases and FXS is a suspected genetic
cause of the autism in these cases. Prevalence of concurrent autism spectrum
disorder (ASD) in individual with FXS has been estimated to be between 15 and
60%.
In different studies, genetic
mouse models of FXS have also been shown to have autistic-like behaviours.
4.
Social interaction:
Social anxiety is one of the most
common features associated with FXS. 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 in individuals with FXS is
related to challenges with face encoding i.e. the ability to recognize a face
that one has seen before. Females with FXS frequently display shyness, social
anxiety and social avoidance or withdrawal.
5.
Mental health:
The most common psychiatric diagnosis
in those with FXS is the “Attention deficit hyperactivity disorder”
(ADHD). Children with fragile X have very short attention spans,
are hyperactive, and show hypersensitivity to visual,
auditory, tactile, and olfactory stimuli.
The other common communicative and
behavioural characteristic in FXS is Perseveration. Children with
FXS may repeat a certain ordinary activity over and over. In speech, repetition
of the same phrase, also talking about the same subject continually, cluttered
speech and self-talk are commonly seen. Self-talk generally includes chatting
with oneself using different tones and pitches.
Fragile X-associated
tremor/ataxia syndrome (FXTAS) is characterized by problems with
movement and thinking ability (cognition). FXTAS is a late-onset disorder,
usually occurring after age 50, and its signs and symptoms worsen with age.
This condition affects males more frequently and severely than females.
Affected individuals have areas of damage in the part of the brain that
controls movement (the cerebellum) and in a type of brain tissue known as white
matter, which can be seen with magnetic resonance imaging (MRI). The
characteristic features of FXTAS are intention tremor, which is trembling or
shaking of a limb when trying to perform a voluntary movement such as reaching
for an object, and problems with coordination and balance (ataxia).
6.
Neurology:
Several studies reported that individuals
with FXS are at a higher risk of developing seizures, with rates
between 10% and 40%. In larger study populations the frequency varies between
13% and 18%, recent studies also found that 14% of males and 6% of females
experienced seizures.
7.
Working memory
Males with FXS begin developing
progressively more severe problems at the age of 40 onwards in performing tasks
that require the central executive of working memory. The working memory implicates
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.
Studies shows that 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.
8.
Fertility
In female who are carriers for the
fragile X premutation about 20% of them are affected by fragile X-related
primary ovarian insufficiency (FXPOI), which could defined as menopause before
the age of 40.
Molecular basis of Fragile X syndrome
Fragile X mental retardation 1
(FMR 1) gene gives rise to a family of disorders when its non-coding CGG-repeat
element is expanded to either the premutation range (55–200 CGG repeats) or the
full mutation range (>200 CGG repeats). Alleles that have 45–54 CGG repeats
are labeled as the “gray zone” because instability in transmission to the next
generation is common. The molecular basis of the syndrome is usually an
expansion of a repetitive CGG triplet sequence located in the 5’-untranslated
region (5’-UTR) of FMR1 gene. Rarely, FXS results from other molecular
alterations (such as point mutations or deletions) within FMR1 gene. The
CGG repeat element is polymorphic, varying from 6 to 44 repeats in the normal
range, from 45 to 54 repeats in the gray zone, and from 55 to 200 repeats in
the premutation range. For alleles below the gray zone, CGG repeat is
generally stable in parent-to-offspring transmissions. However, CGG elements in
the premutation range become increasingly unstable with increasing repeat
number, and alleles exceeding 59 CGG repeats can expand to a full mutation in a
single generation, almost exclusively by transmission from mother to son. The
expansion of the number of repeats above a threshold of approximately 200
repeats, results in hypermethylation of FMR 1 promoter region and a lack of
gene expression which fail to express FMRP protein, this allele is termed as
full mutation. The premutation is relatively common in the general
population, present in approximately 1 in 130 to 250 women and 1 in 250 to 810
males. The full mutation is less common at approximately 1 per 2,500 to 1 per
4,000. Mothers who bring their children into the clinic are usually without
apparent clinical involvement cognitively, although anxiety and depression are
common. Variation in FMR1 CGG repeat size is a useful biomarker of various
types of risk that could affect parents, as it defines differences between
“healthy” and “affected” and between full mutation and premutation carriers.
Pattern of Inheritance
Fragile X syndrome is inherited in
an X-linked dominant pattern. A condition is considered X-linked if the mutated
gene that causes the disorder is located on the X chromosome, one of the two
sex chromosomes. The Y chromosome is the other sex chromosome. The inheritance
is dominant if one copy of the altered gene in each cell is sufficient to cause
the condition. X-linked dominant means that in females who have two X
chromosomes, a mutation in one of the two copies of a gene in each cell is
sufficient to cause the disorder. In males who have only one X chromosome, a
mutation in the only copy of a gene in each cell causes the disorder. In most
cases, males experience more severe symptoms of the disorder than females.
Pathophysiology of Fragile X syndrome
Synaptic plasticity:
The Fragile X mental retardation
protein (FMRP) has a diverse array of functions throughout different areas of
the neuron; however these functions have not been fully characterized. FMRP has
been suggested to play roles in nucleocytoplasmic shuttling of mRNA, dendritic
mRNA localization, and synaptic protein synthesis. FMRP is found throughout the
human body. It is reported that brain and testes have the highest
concentrations of FMRP. 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.
Group 1 metabotropic glutamate
receptor (mGluR) signaling has been implicated in playing an important role in
FMRP-dependent synaptic plasticity. Post-synaptic mGluR stimulation results in
the up-regulation of protein synthesis through a second messenger system. A
role for mGluR in synaptic plasticity is further evidenced by the observation
of dendritic spine elongation following mGluR stimulation. Furthermore, mGluR
activation results in the synthesis of FMRP near synapses. The produced FMRP
associates with polyribosomal complexes after mGluR stimulation, proposing the
involvement of fragile X mental retardation protein in the process of
translation. This further advocates a role for FMRP in synaptic protein
synthesis and the growth of synaptic connections. The loss of FMRP results in
an abnormal dendritic spine phenotype.
Effect of FMRP on dopamine
pathway:
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.
Effect of FMRP on GABA pathway:
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 of Fragile X syndrome
FXS can be diagnosed by testing a
person’s DNA from blood. Diagnosis of FMR1 mutation while the
fetus is in the uterus could be performed with chorionic villus sampling
or amniocentesis. The following techniques are used for the
diagnosis of Fragile X syndrome:
Culturing cells in a folate
deficient medium:
This is was of the oldest technique to
diagnose FXS. This technique is very unreliable and not used now a days.
Through this technique FXS 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.
PCR and Southern blotting:
Fragile X genotyping can be done
by direct PCR amplification of the CGG trinucleotide repeats region or by
southern analysis. In most cases both methods are used to complement the
results. Full mutations usually cannot be identified by PCR and southern
analysis is the preferred method to distinguish full mutations.
Single-molecule real-time
sequencing (SMRT)
Single-molecule real-time
sequencing (SMRT) is a single molecule DNA sequencing method. Because the above
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.
Commercial Kit for the
diagnosis of Fragile X syndrome
1.
CpG WIZ® Fragile X Amplification Kit (Catalogue
No. S7807; Merckmillipore)
2.
AmplideX® mPCR FMR1 (Asuragen
Genetics)
3.
Fragile X GScanTM V2 6-FAM Kit; 1 Kit (Catalogue
No. 40-2004-15FM; Genelink)
Management of Fragile X syndrome
Therapy
There is no cure yet for the 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.
Medication
Present trends in treating the FXS
include medications for symptom-based treatments that aim to minimize the
secondary characteristics associated with the disorder.
For co-morbid disorders with FXS,
antidepressants such as selective serotonin reuptake inhibitors (SSRIs)
are utilized to treat the underlying anxiety, obsessive-compulsive behaviours,
and mood disorders. Following antidepressants, antipsychotics
such as risperidone and quetiapine are used to
treat high rates of self-injurious, aggressive and aberrant behaviours. Anticonvulsants
are another set of pharmacological treatments used to control seizures as well
as mood swings. 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 behavioural
functioning, adaptive behaviour, and verbal memory. Few studies also suggested
using folic acid.
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 behaviour.
Current Clinical trials and Research
Evidence from mouse models shows
that mGluR5 antagonists (blockers) can rescue dendritic spine abnormalities and
seizures, as well as cognitive and behavioural 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.
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