Introduction
Fragile X syndrome is the most common inherited cause of intellectual disability and the leading single-gene cause of autism spectrum disorder. However, it is still considered a rare condition. Estimates indicate Fragile X syndrome affects approximately 1 in 4000 males and 1 in 8000 females. However, the condition is underdiagnosed, especially in females, so true prevalence may be higher. About 1 in 260 women and 1 in 800 men are estimated to be carriers of premutation alleles. Regarding incidence, about 1 in 3600 males and 1 in 4000 to 6000 females are born with Fragile X syndrome each year. The condition seems to affect all geographic, ethnic and racial groups equally. However, founder effects have been observed in certain populations like people of Ashkenazi Jewish descent, with higher carrier frequencies of 1 in 100. Overall, while individually rare, Fragile X syndrome collectively impacts a significant number of individuals and families across the globe. This article, thus, serves to shed light and raise awareness on this serious condition, specifically diving into the causes, symptoms, diagnosis, treatment and future research in Fragile X Syndrome.
Causes
Fragile X syndrome is a genetic condition caused by a mutation in the FMR1 gene on the X chromosome. It is the most common inherited cause of intellectual disability and autism spectrum disorder. The underlying cause of Fragile X syndrome is the abnormal expansion of a CGG triplet repeat sequence in the 5’ untranslated region of the FMR1 gene.
In unaffected individuals, the FMR1 gene has 5-44 CGG repeats. In those with Fragile X syndrome, the CGG triplet repeats expand to over 200 copies. This abnormal expansion leads to hypermethylation and silencing of the FMR1 gene, resulting in reduced or absent production of the FMRP protein which is essential for typical brain development and function.
The expansion of the CGG repeats occurs due to errors during DNA replication and recombination. The repeats tend to be unstable and can expand across generations. For example, a premutation allele with 55-200 CGG repeats may expand to a full mutation in one generation if inherited from the mother. This is because the FMR1 gene is on the X chromosome and only the mother passes on her X chromosome.
The likelihood of expansion depends on the number of existing CGG repeats and is higher with increasing repeat length. Full mutation alleles with over 200 CGG repeats are stable and do not change in size between generations. However, premutation alleles are at risk of further expansion.
Figure 1: Structure of FMR1 Gene
How does FMRP Protein deficiency cause the Fragile X syndrome?
Firstly, in terms of protein synthesis regulation, FMRP normally binds to around 4% of mRNA in the brain to stall translation. Without FMRP, excessive protein synthesis occurs which disrupts synaptic signalling pathways. There is unchecked activity of the metabotropic glutamate receptor 5 (mGluR5) pathway, which is involved in synaptic plasticity.
Secondly, synapse formation, FMRP is required for appropriate development of axons and dendrites as well as maturation of synapses through pruning. Dendritic spines appear long and thin due to overproduction combined with lack of maturation. There are also alterations in the balance of excitatory and inhibitory synapses. Overall, neural networks end up with faulty wiring and immature connections.
Next, for synaptic plasticity, FMRP facilitates long-term depression by regulating protein synthesis in response to mGluR5 stimulation. Without this synthesis control, long-term depression is impaired. This affects the ability to weaken synaptic connections, impacting learning and memory mechanisms. Alterations in long-term potentiation may also occur.
Additionally, in mRNA transport, FMRP interacts with motor proteins like kinesin to transport mRNA cargo to synapses. This localised translation of proteins is critical for synaptic plasticity. Lack of FMRP severely impairs mRNA transport along dendrites and axons.
Finally, FMRP helps transmit signals within neurons and enables proper responses to neurotransmitters like glutamate and GABA as well as hormones like oxytocin. Absence of FMRP affects neuronal excitability and communication.
Figure 2: The multiple functions of FMRP
Symptoms
Intellectual disability in Fragile X syndrome ranges from mild to severe, with IQ typically between 40-70. Affected individuals have impairments in memory, attention, visual-spatial abilities, mathematical reasoning, spoken language, reading, writing, and other academic skills. Speech and language delays are common - first words often occur after 24 months. Speech may involve repetitive phrases, incorrect grammar, and challenges with conversational turn-taking.
Behavioural and emotional symptoms include hyperactivity, attention deficits, anxiety, mood instability, poor eye contact, hand flapping, hand biting, and tactile defensiveness. Autism spectrum disorder, featuring social problems and repetitive behaviours, occurs in 30-60% of males and 20% of females with Fragile X. Up to 70% meet ADHD criteria. About 30% experience seizures, often starting in childhood.
Physical features may include a long, narrow face with large, protruding ears, flat feet, soft skin, flexible joints, and low muscle tone. After puberty, males develop enlarged testicles called macroorchidism. Girls may have irregular periods. A small percentage have heart defects like mitral valve prolapse.
Recurrent ear infections, gastrointestinal issues like reflux, and sleep apnea are more prevalent. About 15% are also impacted by strabismus or lazy eye. Fine motor skills like writing may be delayed.
Females with Fragile X tend to have milder intellectual disability and less autism but more emotional problems like anxiety, depression and withdrawal. Symptoms worsen with age due to reduced FMRP levels.
Figure 3: Summary of the common physical features of Fragile X Syndrome
Diagnosis
The gold standard for diagnosis is DNA analysis of the FMR1 gene, typically using PCR techniques. This determines the number of CGG trinucleotide repeats present. Normal alleles have up to 44 repeats. Premutation alleles have 45-200 repeats. Full mutation alleles have over 200 repeats. Males with over 200 repeats and methylated FMR1 gene are diagnosed with Fragile X syndrome.
PCR analysis can be performed on DNA extracted from peripheral blood samples or buccal swabs. Both leukocyte DNA and buccal cell DNA give accurate genotyping results. Quantitative PCR methods allow precise sizing of longer premutation and full mutation alleles. Southern blot analysis can also be used to visualise methylation status and repeat length.
If clinical features suggest Fragile X, genetic testing is recommended even if intellectual disability has other identified causes. Testing of parents and siblings helps determine if mutations were inherited or arose de novo. Prenatal diagnosis through chorionic villus sampling or amniocentesis is available for known carrier mothers.
A multidisciplinary evaluation team should assess developmental level, adaptive behaviour, physical and neurological status to determine support needs post-diagnosis. Family genetic counselling helps interpret results and recurrence risks. For females with full mutations, FMRP testing in blood samples determines X chromosome activation status. Around 25% of women have little FMRP due to preferential activation of the unaffected X.
Early diagnosis is crucial for implementing early interventions. However, testing children is suggested only if results will impact medical management since intellectual disability is currently untreatable. Predictive testing of minors is discouraged. Improved therapies and community support help those affected live productive and fulfilling lives.
Treatment
As Fragile X syndrome has no cure, management involves multimodal therapies and supports. Early intervention in infancy and toddlerhood is crucial and focuses on cognitive, motor, speech/language, sensory, and behavioural development. Physical therapy aids low muscle tone and coordination. Occupational therapy improves fine motor abilities and daily living skills. Speech therapy develops communication and social interaction. ABA therapy reduces problem behaviours.
During school years, an IEP outlines educational accommodations like one-on-one aides, small class sizes, and adaptive technologies. Social skills training is beneficial. Medications include stimulants like methylphenidate for ADHD, antidepressants for anxiety/OCD, and antipsychotics for aggression in some cases.
In adulthood, group homes, sheltered workshops, job coaches, and day programs provide care and vocational support. However, some adults can live semi-independently and maintain employment with assistance. Relationships and parenting classes are helpful for family planning.
Caregiver counselling and respite services provide ongoing family support. Regular developmental monitoring is key, along with treatment of medical issues like seizures, sleep apnea, and GI problems. Assistive devices aid communication and daily tasks. Some patients may benefit from virtual reality and biofeedback therapy.
While Fragile X has no cure, research on targeted treatments continues. Early behavioural interventions combined with lifelong tailored supports and services can greatly improve outcomes for individuals with Fragile X syndrome.
Future Research
As Fragile X syndrome is caused by silencing of the FMR1 gene, significant research is focused on restoring expression of FMR1 and production of FMRP. One approach utilises chemical compounds that selectively demethylate FMR1 DNA, unsilencing the gene. In preclinical studies, drugs like 5-azadeoxycytidine have shown ability to reactivate FMR1 in patient cells. However, demethylating agents may have unintended effects on global gene expression. More targeted drugs are in development.
Gene therapy to deliver a functional FMR1 gene using viral vectors is also being explored. This could potentially restore localised FMRP expression in the CNS. However, challenges include achieving stable transgenic expression without adverse immune response. New non-viral CRISPR-associated gene delivery methods are in early stages.
Drugs targeting the mGluR5 glutamate receptor pathway are another avenue, as lack of FMRP exaggerates mGluR5 signalling. Antagonists like mavoglurant aim to reduce excessive protein synthesis in Fragile X. Early trials show some behavioural improvements.
FMRP modulates a number of synaptic pathways involved in protein translation, ion channels, and second messengers that could be drug targets. However, directly correcting underlying synaptic and circuitry abnormalities remains challenging.
Advanced gene editing techniques may eventually allow selective correction of the expanded CGG repeat mutation while leaving FMR1 gene function intact. However, this ideal treatment is still far from clinical use.
While current management remains supportive, scientists are making strides in unravelling FMRP’s mechanisms of action in the brain. This knowledge combined with rapid drug development and gene therapy tool maturation brings increasing hope that targeted Fragile X treatments are on the horizon.
Recently, peptides / peptidomimetics have been hypothesised as another therapeutic means to restore the FMRP-CYFIP1 deficiency. However, more research is necessary to reinforce this hypothesis, through, for example, creating 3D Structures capable of illustrating and predicting the interactions of FMRP with other interacting proteins.
Conclusion
In conclusion, Fragile X syndrome is a devastating genetic condition that steals away intellectual abilities and emotional stability from birth. This heartbreaking disorder arises from mutations in the FMR1 gene that repress production of the vital FMRP protein in the brain. The absence of this protein tragically disrupts neuronal development, leading to moderate to severe intellectual disability, autism spectrum challenges, crippling anxiety, unpredictable mood swings, and physical differences. While currently no cure exists to rescue individuals from these struggles, early diagnosis and intervention provides a ray of hope by maximising their potential through supportive education and therapy. Ongoing research also inspires optimism that in the future, FMR1 gene function may be restored and intellectual disability prevented. In the meantime, with compassionate medical care and devotion from families and support staff, those affected by Fragile X syndrome can live fulfilled lives. Increased awareness and research funding is still desperately needed to drive breakthroughs in treating this heart-wrenching disorder. Though the road is long, the promise of hope remains for the day affected individuals can be liberated from this syndrome’s imprisonment.
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