Metformin treatment in young children with fragile X syndrome

Abstract

BackgroundMetformin is a drug commonly used in individuals with type 2 diabetes, obesity, and impaired glucose tolerance. It has a strong safety profile in both children and adults. Studies utilizing the Drosophila model and knock out mouse model of fragile X syndrome (FXS) have found metformin to rescue memory, social novelty deficits, and neuroanatomical abnormalities. These studies provided preliminary evidence that metformin could be used as a targeted treatment for the cognitive and behavioral problems associated with FXS. Previously, a case series of children and adults with FXS treated with metformin demonstrated improvements in irritability, social responsiveness, language, and hyperactivity.MethodsHere, we present nine children with FXS between 2 and 7 years of age who were treated clinically with metformin and monitored for behavioral and metabolic changes.ResultsParent reports and developmental testing before and after metformin are presented. There were improvements in language development and behavior (such as lethargy and stereotypy) in most of the patients.ConclusionThese results support the need for a controlled trial of metformin in children with FXS under 7 years old whose brains are in a critical developmental window and thus may experience a greater degree of clinical benefit from metformin.

Expressive language sampling as a source of outcome measures for treatment studies in fragile X syndrome: feasibility, practice effects, test-retest reliability, and construct validity

“…ELS has several potential advantages compared to typical norm-referenced standardized tests [30], such as the Receptive and Expressive subscales of the Mullen Early Scales [37], the Peabody Picture Vocabulary Test-4th edition [38], the Preschool Language Scale-5 [39], the Clinical Evaluation of Language Fundamentals [40], and the Comprehensive Assessment of Spoken Language [41], all of which have been used in clinical trials for FXS [42][43][44][45]. First, ELS interactive contexts are more closely aligned with performance in real-world contexts, and thus, performance is more likely to be generalizable to activities that are functional and meaningful for the individual [46].…”

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

“…Neurotransmission is fundamental for brain functions, and defects in neurotransmission are implicated in many neurological disorders, such as AD, FXS, depression and so on. Met has been suggested to be effective in these disorders [ 8 , 9 , 10 , 29 , 30 ]. Although Met exerts its glucose level-lowering effects in the peripheral system, it has been reported that Met can cross the brain–blood barrier rapidly [ 31 ].…”

“…In a fragile X syndrome (FXS) mouse model, Met treatment ameliorated social deficit, repetitive behavior and abnormal dendritic spine morphology and exaggerated long-term depression (LTD) [ 7 ]. Furthermore, improvements in language and cognitive behaviors were observed in a small sample size of Met-treated FXS patients [ 8 , 9 , 10 ]. In some Alzheimer’s disease (AD) mice models, Met attenuated amyloid plaque deposition and improved learning and memory [ 11 , 12 , 13 , 14 ].…”

Metformin Ameliorates Lipopolysaccharide-Induced Depressive-Like Behaviors and Abnormal Glutamatergic Transmission

“…injection of metformin corrects core de cits, like social de cit, repetitive behavior, abnormal dendritic spine morphology and exaggerated long term depression (LTD) [43]. And there are language, cognitive and behavioral improvements in a small sample size of metformin treated FXS patients [44][45][46]. In an Alzheimer's disease (AD) mice model, metformin attenuates amyloid plaque deposition and spatial memory de cit [47].…”