Fragile X syndrome

Abstract

Fragile X Syndrome (FXS) is a genetic disease due to a CGG trinucleotide expansion, named full mutation (greater than 200 CGG repeats), in the fragile X mental retardation 1 gene locus Xq27.3; which leads to an hypermethylated region in the gene promoter therefore silencing it and lowering the expression levels of the fragile X mental retardation 1, a protein involved in synaptic plasticity and maturation. Individuals with FXS present with intellectual disability, autism, hyperactivity, long face, large or prominent ears and macroorchidism at puberty and thereafter. Most of the young children with FXS will present with language delay, sensory hyper arousal and anxiety. Girls are less affected than boys, only 25% have intellectual disability. Given the genomic features of the syndrome, there are patients with a number of triplet repeats between 55 and 200, known as premutation carriers. Most carriers have a normal IQ but some have developmental problems. The diagnosis of FXS has evolved from karyotype with special culture medium, to molecular techniques that are more sensitive and specific including PCR and Southern Blot. During the last decade, the advances in the knowledge of FXS, has led to the development of investigations on pharmaceutical management or targeted treatments for FXS. Minocycline and sertraline have shown efficacy in children.

Keywords: Fragile X Mental Retardation Protein; Fragile X Syndrome; Genetic Counselling; Therapeutics; intellectual disability.

Figure 1.. Description of the typical phenotypic characteristics of Fragile X Syndrome.

Figure 2.. Use of molecular techniques for Fragile X Syndrome (SXF) diagnosis.

Figure 3.. Therapeutic targets and FXS physiopathogenesis. In a neuron with a normal range of CGG repeats in the FMR1 gene, there is a euchromatin structural conformation which allows the entry of transcription machinery, due to the acetylation of histones H3 and H4. This conformation allows the normal production of the FMRP, protein that inhibits mRNA translation of some neuronal proteins as Neuroligin, NMDA Receptor (NMDAR), AMPA Receptor (AMPAR) and mGluR5 receptor among others. The expansion above 200 repeats leads to the detection of the CpG islands by DNA Methyl-transferases (DNMT) that add methyl groups to the cytosines of the CGG sequence and the promoter which silences the gene. This methylated cytosines are recognized by the MeCP2 which attracts and activates Histone Deacetylases (HDAC) that cleaves acetyl groups from histones H3 and H4 near the affected segment thus condensing the chromatin. Together, this changes silence the gene allowing the excessive production of neuronal proteins causing neuronal hyperexcitability, spinal dysmorphogenesis and successive clinical manifestations. 5-azadC is a drug that inhibits the DNMT preventing cytosine methylation. TSA, butyrate and 4-phenylbutyrate inhibit the HDAC therefore acting synergically with 5-azadC. Valproic acid seems to reactivate silenced genes but its mechanism has not been yet described. Inhibitors of mGluR5 allows to reduce its hyperexcitation, produced by its overproduction, and the consequences it carries.