Alexis Dominguez

Background: Fragile X Syndrome (FXS) is a nucleotide repeat disorder that results in the loss of function of the Fragile X messenger ribonucleoprotein (FMR1) gene on chromosome Xq27.3.¹ The prevalence of FXS is approximately one in 5,000 males and one in 4,000 to 8,000 females.¹  Repetition of CGG triplets and methylation of the promoter result in silencing of the promoter leading to silencing of the FMRP protein.¹  The FMRP protein is involved in synaptic connections where it binds to ribosomes and controls translation of specific messenger RNAs.^1,4  Without the binding of FMRP, alterations in the synaptic connectivity occur and there is decreased GABA and GABA receptor synthesis.⁴ The absence of FMRP carries multiple clinical manifestations such as ADHD, Autism, anxiety, aggressiveness, intellectual disability, language deficit, and sleep disturbances.¹

Objective: Approximately 31-77% of patients with FXS report having severe sleep disturbances and this may negatively impact neuropsychological and behavioral functioning within this group. If the role of sleep in FXS can be determined, hypnotic treatment for sleep may help regulate behavioral outcomes early on.

Search Methods: An online search in PubMed database was conducted from 2019-2024 using the following keywords: “Fragile X Syndrome”, “Polysomnographic”, “Electroencephalography”, and “hypnotic treatment”.

Results: Polysomnographic data with 24 hour EEG recordings collected in children with Fragile X Syndrome and typically developing children showed statistically significant different values in sleep macrostructure parameters such as total time in bed, total sleep time, awakenings per hour, and arousal index in both NREM and REM.¹  This study also found that within FXS children alone, there were statistically significant differences found in their sleep partial time, total sleeping time, and stage 3 sleep.¹ Given that data has shown sleep abnormalities in FXS, researchers sought to determine exactly how sleep was affecting behavior by sleep restricting mice and measuring behavioral phenotypes. In one study, FMR1 knock out (KO) mice were either able to sleep normally, sleep restricted (woken up every 3 hours), or sleep stressed (woken up every 15 minutes).² Although sleep restrictions actually improved certain behaviors, it was concluded that overall sleep is playing a role in FXS behavioral outcomes and that further research needs to be conducted to determine the exact etiology.²  Hypnotic treatment was hypothesized to restore sleep macrostructure. ML297 is a G-protein gated inwardly rectifying potassium channel that is coupled to GABA receptors. When administered to FMRI KO mice, ML297 restored NREM sleep time.⁴ Lastly, Gaboxadol, an anti-insomnia GABA agonist, was hypothesized to improve behavioral outcomes in FXS. When administered to FMRI KO mice at a dosage of 0.5 mg/kg, behavioral measurements of anxiety, hyperactivity, and aggressiveness were improved.⁵

Conclusions: There is a high prevalence of patients with FXS that have sleep-related disturbances. Early detection with polysomnographic data and EEGs may provide opportunity to regulate behavioral outcomes in early stages. Gaba agonists appear promising for regulating sleep macrostructure (ML297 agonist) and behavioral manifestations (gaboxadol) in mouse models; specifically, 0.5mg/kg of Gaboxadol. Future studies are needed to assess this medication class in human clinical trials in FXS.

Works Cited:

1. Carotenuto M, Roccella M, Pisani F, et al. Polysomnographic Findings in Fragile X Syndrome Children with EEG Abnormalities. Behav Neurol. 2019;2019:5202808. Published 2019 Dec 3. doi:10.1155/2019/5202808.
2. Saré RM, Song A, Levine M, et al. Behavioral and Molecular Consequences of Chronic Sleep Restriction During Development in Fragile X Mice. Front Neurosci. 2022;16:834890. Published 2022 Jun 27. doi:10.3389/fnins.2022.834890.
3. Saré RM, Lemons A, Smith CB. Effects of Treatment With Hypnotics on Reduced Sleep Duration and Behavior Abnormalities in a Mouse Model of Fragile X Syndrome. Front Neurosci. 2022;16:811528. Published 2022 Jun 2. doi:10.3389/fnins.2022.811528.
4. Cogram P, Deacon RMJ, Warner-Schmidt JL, von Schimmelmann MJ, Abrahams BS, During MJ. Gaboxadol Normalizes Behavioral Abnormalities in a Mouse Model of Fragile X Syndrome. Front Behav Neurosci. 2019;13:141. Published 2019 Jun 25. doi:10.3389/fnbeh.2019.00141.
5. Martinez JD, Wilson LG, Brancaleone WP, et al. Hypnotic treatment reverses NREM sleep disruption and EEG desynchronization in a mouse model of Fragile X syndrome to rescue memory consolidation deficits. Preprint. bioRxiv. 2023;2023.07.14.549070. Published 2023 Jul 18. doi:10.1101/2023.07.14.549070
6. 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.
7. Kenny A, Wright D, Stanfield AC. EEG as a translational biomarker and outcome measure in fragile X syndrome. Transl Psychiatry. 2022;12(1):34. Published 2022 Jan 24. doi:10.1038/s41398-022-01796-2.
8. 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.