Fragile X syndrome

Abstract

Fragile X syndrome, an X-linked dominant disorder with reduced penetrance, is associated with intellectual and emotional disabilities ranging from learning problems to mental retardation, and mood instability to autism. It is most often caused by the transcriptional silencing of the FMR1 gene, due to an expansion of a CGG repeat found in the 5'-untranslated region. The FMR1 gene product, FMRP, is a selective RNA-binding protein that negatively regulates local protein synthesis in neuronal dendrites. In its absence, the transcripts normally regulated by FMRP are over translated. The resulting over abundance of certain proteins results in reduced synaptic strength due to AMPA receptor trafficking abnormalities that lead, at least in part, to the fragile X phenotype.

Figure 1

Four allelic classes of the FMR1 gene in humans. For each allele, the size of the CGG repeat in the 5′-UTR of FMR1 is indicated in blue at the left of the gene schematic. The level of transcription is indicated by the width of the arrow beneath each allele class. Increased transcription is associated with premutation alleles, whereas full mutations are hypermethylated, as indicated by the red hashmarks, and transcriptionally silent. Despite the ACMG definition, the smallest premutation allele known to expand to the full mutation in a single generation had 59 repeats.

Figure 2

Facial features of fragile X syndrome. As illustrated by the photographs of four children with FXS, the facies associated with this syndrome are subtle. They can include a long, thin face, and prominent ears that often project away from the head, and a prominent forehead.