ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Mol Genet Genomic Med. 2019;7(11):e956. doi: 10.1002/mgg3.956

Short summary: Nine boys with Fragile X syndrome (FXS), aged between 2 to 7 years old, received off-label treatment with metformin for at least 3 months. Language development and behaviour improved in the majority of children. A controlled trial of metformin in very young children with FXS, whose brains are in a critical developmental window, is needed.

Comment: Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability, affecting about 1 in 2500 to 5000 males, and 1 in 4000 to 6000 females. The physical features of FXS include a long face, prominent ears, hyperextensible finger joints and macro-orchidism in males. Overweight and obesity are common in FXS for 3 main reasons. Firstly, overeating is commonly associated with anxiety and obsessive-compulsive behaviours. Secondly is the common use of atypical antipsychotics. Thirdly, in about 10% of those affected, the Prader-Willi phenotype (PWP) of FXS is found. The FXS-PWP is associated with hyperphagia, morbid obesity, delayed puberty, and lowered cytoplasmic FMRP interacting protein CYFIP1 (OMIM: 606322) expression.¹ Treatment with metformin led to clinical improvements in eating behaviours and weight loss in those with and without FXS-PWP, and is now recommended for the treatment of obesity in FXS.

Metformin administration in a knockout mouse model of FXS reduced the high testicular weights and improved several behavioural phenotypes.² A controlled trial of metformin for individuals with FXS aged 6–25 years is ongoing. However, evidence suggests the existence of a critical period of development during which targeted interventions may have significant and durable effects on the developmental trajectory and outcomes in FXS. That was the rationale in the current study for the treatment of metformin in young children aged 2–7 years.

References:

1. Muzar Z, Lozano R, Kolevzon A, et al. The neurobiology of the Prader-Willi phenotype of fragile X syndrome. Intractable Rare Dis Res 2016;5(4):255–61. doi: 10.5582/irdr.2016.01082 [published Online First: 2016/12/03].

2. Gantois I, Khoutorsky A, Popic J,et al. Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nat Med 2017;23(6):674–77. doi: 10.1038/nm.4335 [published Online First: 2017/05/16].