Fragile X Syndrome

Fragile X syndrome (FXS) is a genetic disorder associated with abnormal methylation of the FMR1 gene on the X chromosome. FXS is one of the most common genetic causes of intellectual disability and is also related to autism spectrum disorder (ASD). The prevalence of FXS is estimated to be 1/4000 in males and 1/8000 in females. The clinical manifestations of FXS include intellectual impairment, learning difficulties, social problems, behavioral issues, facial features, physical abnormalities, and more. Diagnosis of FXS mainly relies on molecular genetic methods, such as polymerase chain reaction (PCR) and Southern blotting. Currently, there is no curative treatment for FXS, but various measures can be taken to improve the quality of life of patients, such as pharmacological treatment, behavioral intervention, educational support, and others.

Clinical Features

The clinical manifestations of FXS vary depending on the gender, age, and genotype of the patients. The most common and prominent feature of FXS is intellectual impairment, which ranges from mild to severe and is more pronounced in males than in females. The average IQ of FXS patients is between 50 and 70, and about 80% of males and 30% of females have an IQ below 70. FXS patients also experience learning difficulties in various domains, such as language, reading, writing, and mathematics. They often require special education and individualized instruction to meet their needs.

Another major aspect of FXS is social impairment, which manifests as shyness, anxiety, avoidance, and autism-like behaviors. Approximately 30-50% of FXS patients also meet the diagnostic criteria for ASD, characterized by impaired social communication and interaction, and restricted and repetitive behaviors. FXS patients also exhibit behavioral problems, such as hyperactivity, impulsivity, inattention, mood swings, aggression, and self-injury. These problems may be related to abnormalities in neurotransmitters, such as glutamate, serotonin, dopamine, and GABA, in the brains of FXS patients.

Clinical features of FXS. Fig.1 Clinical features of FXS. (Hagerman RJ, 2017)

Clinical Diagnosis and Treatment Methods

The diagnosis of FXS is primarily based on molecular genetic methods, which detect the number and methylation status of CGG repeats in the FMR1 gene. The normal range of CGG repeats in the FMR1 gene is between 5 and 44, while FXS patients have more than 200 CGG repeats. The excessive number of CGG repeats leads to the methylation and silencing of the FMR1 gene, resulting in reduced or absent expression of the FMR1 protein (FMRP). FMRP is an RNA-binding protein involved in synaptic plasticity and cognitive function, and its deficiency causes the clinical features of FXS. PCR and Southern blotting are common methods for detecting the number and methylation status of CGG repeats, where PCR is suitable for samples with fewer than 200 CGG repeats, and Southern blotting is suitable for samples with more than 200 CGG repeats.

The treatment of FXS is currently symptomatic and supportive, as there is no cure for the disorder. Depending on the different symptoms of FXS patients, various types of drugs can be used, such as antidepressants, anti-anxiety drugs, antipsychotics, antiepileptics, stimulants, and others. Moreover, some drugs are under investigation, aiming to restore the function of FMRP or modulate its downstream signaling pathways. In addition to pharmacological treatment, behavioral intervention can also help FXS patients improve their social skills, emotional regulation, self-control, and other aspects. Behavioral intervention includes behavioral therapy, cognitive therapy, social skills training, and others. Furthermore, educational support is also essential for FXS patients, who need special education and individualized instruction according to their personality and ability. Educational support should cover basic skills such as language, reading, writing, and mathematics, as well as practical skills such as life skills and vocational skills.

Conclusion

Fragile X syndrome (FXS) is a genetic disorder associated with abnormal methylation of the FMR1 gene on the X chromosome, which causes reduced or absent expression of the FMR1 protein (FMRP). FXS is one of the most common genetic causes of intellectual disability and is also related to autism spectrum disorder (ASD). FXS patients exhibit various clinical manifestations, such as intellectual impairment, learning difficulties, social problems, behavioral issues, facial features, physical abnormalities, and more. The diagnosis of FXS mainly relies on molecular genetic methods, such as PCR and Southern blotting, which detect the number and methylation status of CGG repeats in the FMR1 gene. Currently, FXS has no curative treatment, but various measures can be taken to improve the quality of life for patients, such as pharmacological treatment, behavioral intervention, educational support, and others.

References

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