The neurobiology of the Prader-Willi phenotype of fragile X syndrome

Abstract

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism, caused by a CGG expansion to greater than 200 repeats in the promoter region of FMR1 on the bottom of the X chromosome. A subgroup of individuals with FXS experience hyperphagia, lack of satiation after meals and severe obesity, this subgroup is referred to have the Prader-Willi phenotype of FXS. Prader-Willi syndrome is one of the most common genetic severe obesity disorders known and it is caused by the lack of the paternal 15q11-13 region. Affected individuals suffer from hyperphagia, lack of satiation, intellectual disability, and behavioral problems. Children with fragile X syndrome Prader-Willi phenotye and those with Prader Willi syndrome have clinical and molecular similarities reviewed here which will impact new treatment options for both disorders.

Keywords: Autism; FMR1 gene; Fragile X syndrome (FXS); Growth hormone; Hyperphagia; IGF-1; Prader-Willi phenotype.

Figure 1.

11 year old with FXS and PWP, showing severe obesity, small hands and mild facial dysmorphic features

Figure 2.

Suggested mechanism of action of GH. GH stimulates the liver to release IGF-1, which activates CREB, and this increases FMRP in neurons. The increase of FMRP leads to increased GABAergic input to some areas of the brain.

Figure 3.

Mechanism of action of metformin. Metformin decreases protein synthesis and insulin signaling (IS) via the AMPK/Akt/mTOR pathway, it also inhibits the lipid and sterol biosynthetic pathways