Fragile X Syndrome 101

By Linya Thng

Fragile X syndrome (FXS) is commonly known as the monogenic leading cause of inherited intellectual disability and is also linked to other psychiatric and neurologic disorders such as autism (Mila et al., 2018). FXS is an X-linked condition caused by a triplet expansion involving the inhibition of FMR1 gene expression. The gene product, fragile X mental retardation protein (FMRP) plays an imperative role in the regulation of mRNA metabolism in the brain and thus controls the expression of key molecules involved in receptor signaling pathways. In terms of frequency, males are usually more severely affected by this disorder compared to females due to them lacking a second X chromosome (Bagni et al., 2012). Currently in the status quo, there is no available cure for FXS. The understanding of FMR1/FMRP function paves a pathway for future treatment designs with massive potential of combating monogenic diseases. This article aims to provide a comprehensive overview of FXS and its contributing gene/protein.

FXS is a cognitive disorder caused by the transcriptional silencing of the FMR1 gene. The absence of the associated FMRP gene product results in the dysregulation of various genes which generates a phenotype consisting of a spectrum of autism disorders. Phenotypical features associated with FXS include elongated faces, large ears, prominent jaw and hyperextensible fingers. The FMR1 gene is a FMRP encoding gene commonly found in the brain, which plays an essential role in normal cognitive development and female reproductive functions. FMRP, the protein FMR1 encodes for, is suggested to be a contributing factor to the regulation of synaptic plasticity which is crucial for learning and memory. Based on previous studies of the FMR1 Mus musculus (614 amino acids) model, FMRP was characterized as a translational repressor and the absence of FMRP triggers increased protein synthesis. This alteration in protein levels contributes to the generalized FXS phenotype.

FMR1 is characterized by the presence of polymorphic CGG triplet sequence in the 5’ UTR located within the 4.4 kb of FMR1 transcript. FXS is the prototype of the unstable expansion within this triplet sequence. Four main types of alleles arise from the triplet variability: (1) Normal-, (2) Intermediate-, (3) Premutation (PM)-, and (4) Full- mutation (FM) alleles. The generation of the four alleles is dependent on the degree of CGG triplet expansion and the levels of FMR1 mRNA transcription and translation (Bagni et al., 2012). The level of FMRP directly correlates with IQ. In normal alleles, the repeat length is variable in the human population, ranging from 5 to 55 repeats. However, the repeat can become unstable upon maternal transmission, resulting in an expansion in the offspring. Expansions ranging from 55 to 200 repeats give rise to PM alleles. PM carrier females with expansion exceeding 200 repeats would generate FM alleles that induce hypermethylation and a consequent deficiency of FMRP – FM alleles initiates transcriptional silencing of the FMR1 gene. Affected individuals with a deletion of FMR1 or a FM allele that is fully methylated results in the absence of FMRP and hence FXS, a developmental disorder associated with autism, intellectual disability and specific physical features.

To date, existing treatments such as integration therapies help minimize the symptoms of this condition, however, there is no available cure for FXS. The risk of having an offspring with FXS is dependent on the sex and phenotype of the carrier parent. As stated previously, FXS is associated with a variable clinical phenotype and autism spectrum disorders can be observed. However, diagnosis of FXS cannot be dependent on the clinical description as oftentimes these physical features may be mild or absent. Therefore, FXS diagnosis methods are based on FMR1 DNA testing which are performed on patients. For detection of FMR1 mutation in the developing fetus, a prenatal test is performed on pregnant women with an FMR1 PM or FM allele. The tests can be categorized into amniocentesis and chorionic villus. Prenatal diagnosis utilizes analysis of Southern blotting and PCR samples of either chorionic villi or amniotic fluid of the mother (Xunclà et al., 2010). Current parameters offer symptoms-based management of FXS that consists of a dual approach of therapeutic services with psychopharmacologic treatment of symptoms. Depending on the clinical phenotype and behaviors displayed by each individual, medications can either be stimulants, selective serotonin reuptake inhibitors (SSRIs), or atypical antipsychotic agents. The search for FXS targeted treatments is still ongoing.

As we enter a new age of advanced technology, the tremendous progress invested in gaining more insights on the pathophysiology of FXS emerges as a cornerstone in the development of various targeted therapies. In addition to the ultimate goal of enhancing targeted treatments, research on FXS are vital to strengthening synaptic connections and improving the quality of patients’ lives. Alongside existing FXS stem cell models, the ongoing search for advanced targeted treatments offers potential to reverse cognitive and behavioral deficits associated with this disorder. Stem cell therapies and gene editing may potentially play a key role in diagnosing FXS early in its course. These advancements in FXS medications will not only subside the symptoms in individuals with FXS, but also promote more independent functioning in individuals’ daily lives.

References:

Mila, M., Alvarez‐Mora, M. I., Madrigal, I. & Rodriguez‐Revenga, L. (2018) Fragile X syndrome: An overview and update of the FMR1 gene. Clinical Genetics. 93 (2), 197-205. Available from: doi: 10.1111/cge.13075. [Accessed: 4th November 2020]

Bagni, C., Tassone, F., Neri, G. & Hagerman, R. (2012) Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. The Journal of Clinical Investigation. 122 (12), 4314-4322. Available from: doi: 10.1172/jci63141. [Accessed:4th November 2020]

Xunclà, M., Badenas, C., Domínguez, M., Rodríguez-Revenga, L., Madrigal, I., Jiménez, L., Soler, A., Borrell, A., Sánchez, A. & Milà, M. (2010) Fragile X syndrome prenatal diagnosis: parental attitudes and reproductive responses. Reproductive Biomedicine Online. 21 (4), 560-565. Available from: doi: 10.1016/j.rbmo.2010.05.015.

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