Fragile X syndrome

Last revised by Travis Fahrenhorst-Jones on 7 Jun 2023

Fragile X syndrome is the most common inherited cause of cognitive disability and is the result of a mutation in the fragile X messenger ribonucleoprotein 1 (FMR1) gene. 

Although the degree of cognitive disability is typically more severe in males with fragile X syndrome, females can also be affected. The estimated frequency of fragile X syndrome is 1/4000 males and 1/7000 females 3

Affected individuals demonstrate a variety of cognitive disabilities and physical changes 3.

The underlying genetic abnormality is an expansion of a trinucleotide repeat (CGG) in the 5` untranslated region fragile X messenger ribonucleoprotein 1 (FMR1) gene that encodes for the fragile X messenger ribonucleoprotein (FMRP) 1-3. This repeat is inherently unstable and can result in an expansion of the repeat during maternal transmission 3

Based on the number of repeats FMR1 genes can be divided into three groups that correlate with phenotype 1-3.

  • 5-54 repeats: normal population

  • 55-200 repeats: premutation

  • >200 repeats: fragile X syndrome

When 55-200 repeats are present there are excessive levels of FMR1 mRNA transcription but despite this, the actual levels of FMRP are reduced 3. Generally, most premutation carriers are phenotypically normal, however, approximately 25% demonstrate some subtle physical changes 2. Emotional difficulties are also reported 2. Specific sex-dependent phenotypic manifestations are also encountered: 

Once more than 200 repeats are present a cascade of events takes place resulting in the eventual methylation of the promoter region of the FMR1 gene which in turn silences the gene resulting in a lack of FMRP and resultant fragile X syndrome 2,3.

Imaging will depend on the specific manifestations of the syndrome in an individual (see above). 

At this time there are no accepted gene therapies or FMRP replacement therapies available, although both approaches are being researched. 

Management is therefore targetted at the various manifestations of fragile X syndrome. 

Previously named "fragile X mental retardation 1" gene, the gene responsible for fragile X syndrome was renamed in 2021 by the European Fragile X Network to "fragile X messenger ribonucleoprotein 1" 5. This was to remove the stigmatising language associated with the previous naming of the gene.

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