Fragile X-associated disorders

Abstract

Fragile X-Associated Disorders Fragile X syndrome (FXS), also known as Martin-Bell syndrome, is the most common inherited cause of intellectual disability (ID), and it is the most common known single-gene cause of autism or autism spectrum disorders (ASDs). It is caused by a trinucleotide repeat (CGG) expansion at the 5′ noncoding region of the fragile X mental retardation 1 (FMR1) gene located on the long arm of the X chromosome at band Xq27.3. Large expansions (>200 CGG repeats) cause hypermethylation and silencing of the gene, leading to a loss of the gene product, fragile X mental retardation protein (FMRP). The resulting phenotype is complex and consists of cognitive impairments, difficulties with emotional and behavioral regulation, and certain physical characteristics as well, all elaborated upon later in this chapter. However, even smaller expansions (between 55 and 200 repeats) within the premutation range with normal or close-to-normal levels of FMRP can also result in clinical complications of its own. This is due in large part to the increased transcription of FMR1 mRNA seen in premutation carriers, which can be toxic to cells, particularly neurons and astrocytes. The resulting premutation-associated disorders are discussed at length in the second part of this chapter. Finally, pharmacological interventions that are still being studied are discussed. These pharmaceuticals, including mGluR5 antagonists and GABA agonists, seek to restore the imbalance of neurotransmission in FXS and have led to some promising preliminary results in mitigating or even reversing the neurobiological abnormalities caused by the loss of FMRP.