Abigail Lauren Riley

Background: Fragile X Syndrome, commonly referred to as ‘FXS”, is due to a CGG trinucleotide expansion repeat resulting in hypermethylation and subsequent inactivation of the Fragile X Messenger Ribonucleoprotein 1 (FMR1)^1,2. FMR1 regulates mGluR5, a G protein coupled receptor that is involved in plasticity². Definitive diagnosis of FXS is made through PCR/Southern Blotting and the pathology is marked by a level of intellectual disability among a litany of other comorbid diagnosis². Due to the lack of cure in FXS, polypharmacy is the mainstay in treatment in order to manage the associated cognitive and behavioral disorders- one of these medications includes Metformin⁷. Metformin is typically used as a blood-glucose lowering drug in Type 2 Diabetes, and is regularly used in FXS patients with a comorbid diagnosis of obesity, but it has been seen to modulate reduction of problematic behaviors such as irritability, aggressiveness, and social evasion, identifying itself as a possible therapeutic option to eliminate polypharmacy³.

Objective: In this narrative analysis, the potential effects of Metformin in eliminating the polypharmacy associated with the diagnosis of Fragile X syndrome was investigated.

Search Methods: An online search utilizing the PubMed database was conducted from 2018-2024 using the following keywords: “Fragile X Syndrome”, “FXS”, “polypharmacy”, and “Metformin”.

Results: Studies reveal that FMRP knockout is correlated with plasticity and synaptic formation, and KO mice models demonstrate this by exposing memory and cognitive deficits⁵. FMRP KO is shown to allow for increased signaling in the mGluR5 pathways, activating mTORC1 ultimately resulting in hyperphosphorylation of AKT and Rk². After treatment with Metformin, there was Akt/ERK independent normalization of protein synthesis resulting in rescue of neurodevelopmental abnormalities⁵. Off-label studies in human patients with a prior diagnosis of FXS reveal that rescue of these neurodevelopmental abnormalities through Metformin can be measured utilizing the biomarkers matrix metalloproteinase 9 (MMP9), hexokinase 1 (HK1), and RAS¹. Results indicate that HK1 and MMP9 have positive association with normalization on the Clinical Global Impression Scale (CGI), which allows clinicians to analyze a patient’s illness improvement relative to baseline state, and RAS predicts body mass index (BMI) normalization when treated with Metformin¹. Studies have also revealed that treatment with Metformin normalizes categories such as lethargy, stereotypy, irritability, and social responsiveness in individuals with FXS when measured on the Aberrant Behavior Checklist (ABC), which also measures treatment effects in patients^6,7. Adverse events were documented in normoglycemic individuals to ensure Metformin was a safe medication to be utilized and found that no adverse events were shown to occur in patients with FXS and no comorbid diagnosis of obesity or diabetes⁴.

Conclusions: Studies have found that utilization of Metformin in individuals diagnosed with Fragile X Syndrome provides a safe alternative in treating a multitude of the symptoms associated with the pathology of the disease^4,6,7. Additionally, Metformin works by inhibiting overactive protein synthesis in a Akt/ERK independent manner, indicating that a pharmaceutical intervention targeting phosphorylation could potentially yield enhanced outcomes in managing cognitive and behavioral impairments⁵.

Works Cited:

1. Jasoliya M, Bowling H, Petrasic IC, et al. Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome. Brain Sci. 2020;10(6):361. Published 2020 Jun 10. doi:10.3390/brainsci10060361
2. Protic DD, Aishworiya R, Salcedo-Arellano MJ, et al. Fragile X Syndrome: From Molecular Aspect to Clinical Treatment. Int J Mol Sci. 2022;23(4):1935. Published 2022 Feb 9. doi:10.3390/ijms23041935
3. Salcedo-Arellano MJ, Hagerman RJ, Martínez-Cerdeño V. Fragile X syndrome: clinical presentation, pathology and treatment. Síndrome X frágil: presentación clínica, patología y tratamiento. Gac Med Mex. 2020;156(1):60-66. doi:10.24875/GMM.19005275
4. Proteau-Lemieux M, Lacroix A, Galarneau L, Corbin F, Lepage JF, Çaku A. The safety and efficacy of metformin in fragile X syndrome: An open-label study. Prog Neuropsychopharmacol Biol Psychiatry. 2021;110:110307. doi:10.1016/j.pnpbp.2021.110307
5. Utami KH, Yusof NABM, Kwa JE, Peteri UK, Castrén ML, Pouladi MA. Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment. Mol Autism. 2020;11(1):41. Published 2020 May 27. doi:10.1186/s13229-020-00350-5
6. Biag HMB, Potter LA, Wilkins V, et al. Metformin treatment in young children with fragile X syndrome. Mol Genet Genomic Med. 2019;7(11):e956. doi:10.1002/mgg3.956
7. Dy ABC, Tassone F, Eldeeb M, Salcedo-Arellano MJ, Tartaglia N, Hagerman R. Metformin as targeted treatment in fragile X syndrome. Clin Genet. 2018;93(2):216-222. doi:10.1111/cge.13039