Fragile X Syndrome and Premutation Disorders

Abstract

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability (ID) and the most common known single-gene cause of autism spectrum disorders (ASDs). It is caused by a trinucleotide repeat (CGG) expansion at the 5′ noncoding region of the Fragile X messenger ribonucleoprotein 1 gene (FMR1) gene located on the long arm of the X chromosome at band Xq27.3. The full mutation (>200 CGG repeats) causes hypermethylation and silencing of the gene, leading to a loss of the gene product, FMR1 protein (FMRP). The resulting phenotype is complex and consists of cognitive impairments, difficulties with emotional and behavioral regulation, and physical features secondary to loose connective tissue including prominent ears and hyperextensible finger joints as well as large testicles at the time of puberty.

However, smaller expansions (between 55 and 200 repeats) called the premutation have normal or close-to-normal levels of FMRP, which leads to phenotypic features caused by a different molecular mechanism, specifically increased transcription of FMR1 mRNA. The higher the CGG repeat number within the premutation range the greater the elevation of mRNA leading to RNA toxicity involving sequestration of proteins important for neuronal function and mitochondrial deficits. The clinical problems associated with the premutation include the fragile X-associated tremor ataxia syndrome (FXTAS), the fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) that are discussed at length in the second part of this chapter. Lastly the development of targeted treatments for FXS and premutation disorders are discussed which have the potential to reverse the neurobiological abnormalities associated with these disorders.