Introduction:
Fragile X syndrome (FXS) is a genetic disorder that causes a variety of developmental issues such as learning impairments and cognitive impairment. It is caused by a mutation in the FMR1 gene, which is responsible for producing a protein called fragile X mental retardation protein (FMRP). This protein plays a critical role in the development and function of the brain, and a deficiency of FMRP can lead to the symptoms associated with FXS.
FXS, also known as Martin-Bell syndrome, is a non-Mendelian trinucleotide repeat disease. FXS is the most common monogenic cause of autism spectrum disorder and the most common inherited cause of mild to severe intellectual disability (ASD).
Frequency:
Fragile X syndrome (FXS) is the most commonly known cause of inherited intellectual disability and is also the most common inherited cause of autism. It is estimated to affect about 1 in 4,000 males and 1 in 8,000 females worldwide. The prevalence of FXS may be higher in certain populations, and the condition is more common in males than in females.
It’s important to note that the prevalence of FXS can vary widely and may be underestimated in some populations. This is because the symptoms of FXS can be mild and may go undiagnosed or be misdiagnosed as another condition. Additionally, some people with FXS may not have any obvious physical characteristics that would suggest the condition.
Causes:
Fragile X syndrome (FXS) is caused by a mutation in the FMR1 gene, which is located on the X chromosome. The FMR1 gene is responsible for producing a protein called fragile X mental retardation protein (FMRP). This protein plays a critical role in the development and function of the brain, and a deficiency of FMRP can lead to the symptoms associated with FXS.
There are two types of mutations that can cause FXS: a full mutation and a premutation.
- A full mutation is a change in the DNA sequence of the FMR1 gene that results in a complete loss of FMRP production. This type of mutation is more severe and typically leads to more severe symptoms of FXS.
- A premutation is a small change in the DNA sequence of the FMR1 gene that does not completely shut off FMRP production. A premutation is not typically associated with FXS, but it can increase the risk of developing FXS in the future. If a premutation is passed down from one generation to the next, it can expand to a full mutation and cause FXS in the next generation.
Inheritance of FXS follows an X-linked dominant pattern, which means that males are more likely to be affected by the condition than females. Females have two copies of the X chromosome, so if one copy has the mutation, the other copy can compensate for the deficiency of FMRP. Males, on the other hand, have only one X chromosome, so if they inherit the mutated copy, they will be affected by the condition.
Diagnosis:
There are several tests available to diagnose Fragile X syndrome (FXS). The most common and accurate method is genetic testing, which involves analyzing a person’s DNA to look for a mutation in the FMR1 gene. In addition to genetic testing, a healthcare provider may also perform a physical examination and review a person’s medical history to help diagnose FXS. This may include looking for physical characteristics associated with FXS, such as a long, narrow face and large ears, as well as a history of developmental delays or learning disabilities.
There are two types of genetic tests for FXS:
Full gene sequencing
This test looks at the entire FMR1 gene to identify any mutations. It is the most accurate test for diagnosing FXS, but it can be expensive and may not be covered by insurance.
Fragile X DNA amplification test
This test uses a technique called polymerase chain reaction (PCR) to amplify and analyse a specific region of the FMR1 gene. It is less expensive and quicker than full gene sequencing, but it is not as accurate and may not identify all mutations.
Accurate risk assessments for FXS are made possible by counting the CGG repeats on the X chromosome, which also offers information on reproductive alternatives for FXS families.
It’s important to note that a test that solely counts the amount of CGG repeats will miss less than 1% of FXS cases that are caused by deletions or missense mutations in the FMR1 gene.
Potential “nonCGG repeat” causes of FXS could be found using both the FMR1 gene’s sequencing and a direct measurement of the FMRP protein level.
Treatment:
There is no cure for Fragile X syndrome (FXS), but treatment can help manage the symptoms and improve quality of life. Treatment may include a combination of medications, therapy, and educational and behavioural interventions. The specific treatment plan will depend on the individual’s needs and may be adjusted over time as the person’s symptoms and needs change.
Medications
Medications may be used to help manage the symptoms of FXS, such as hyperactivity, impulsivity, and anxiety.
Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), may be helpful in reducing anxiety and improving social interactions in people with FXS.
Stimulants, such as methylphenidate (Ritalin), may be helpful in improving attention and reducing hyperactivity in people with FXS.
Other medications, such as anti-seizure medications and antipsychotics, may be used in some cases to help manage specific symptoms.
Therapy
- Therapy can help people with FXS improve communication and social skills, manage behaviour, and develop coping strategies.
- Speech therapy can help improve language skills and communication.
- Occupational therapy can help improve fine motor skills and daily living skills.
- Physical therapy can help improve gross motor skills and coordination.
- Behavioural therapy can help manage problem behaviours and improve social skills.
Educational and behavioural interventions
Educational interventions, such as special education or early intervention programs, can help children with FXS learn and develop at their own pace.
Behavioural interventions, such as positive reinforcement and structured routines, can help manage problem behaviours and improve social skills.
Prevention:
- Prenatal testing: If there is a family history of FXS or if a couple is planning to have children and one of them has a premutation (a small change in the DNA sequence of the FMR1 gene), prenatal testing can be done to determine if the fetus is affected by FXS. This can allow parents to make informed decisions about their pregnancy and prepare for the birth of a child with FXS.
- Early diagnosis: If FXS is suspected based on physical characteristics or a family history of the condition, genetic testing can be done to confirm the diagnosis. Early diagnosis of FXS allows for early intervention, which can improve outcomes and quality of life for individuals with FXS.
- Treatment: Treatment for FXS can help manage the symptoms and improve quality of life. This may include medications, therapy, and educational and behavioural interventions. A comprehensive treatment plan can help individuals with FXS reach their full potential and live fulfilling lives.
References:
- Stone, W.L., Basit, H. and Los, E., 2017. Fragile X Syndrome.
- Sheridan SD, Theriault KM, Reis SA, Zhou F, Madison JM, Daheron L, Loring JF, Haggarty SJ. Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. PLoS One. 2011;6(10): e26203.
- Crawford DC, Acuna JM, Sherman SL. FMR1 and the fragile X syndrome: human genome epidemiology review. Genet Med. 2001; 3:359–371.
- https://fragilex.org/