PC1183: Use of Metformin in a Patient with Fragile X Syndrome and Additional Genetic Variants

Introduction: Fragile X syndrome (FXS) is caused by >200 CGG repeats in the promoter region of the fragile X mental retardation gene (FMR1) located at Xq27.3. While clinical characteristics may vary, most individuals have intellectual disability, speech/language delays, and behavioral disturbances including social anxiety, inattention, hyperactivity, impulsivity, and aggression. The presence of additional genetic variants is associated with a more severe phenotype in FXS patients. Metformin is being studied as a potential targeted treatment for individuals with FXS with studies showing improvements in language and behavior after metformin treatment. Here, we present a patient with FXS and additional genetic variants including gain at 8p11.23, and losses at Xp22.33 and Xp21.31 who exhibited improvements in language skills and a decrease in challenging behaviors after starting metformin.

Case Description: We describe our experience using metformin in an 11-year-old male with confirmed FXS and additional genetic variants identified on CGH array who presented for follow up at a Fragile X Research and Treatment Center. At the initial evaluation, he was reported to be speaking in short phrases, and exhibiting significant daily outbursts in school and at home. He was also very aggressive toward caregivers. At the follow-up visit seven months after starting metformin 500mg once daily, he was reported to be able to speak in 5–7-word sentences, communicate his desires, have back and forth conversations for two turns, and follow multi-step directions. Caregivers also noticed a substantial decrease in outbursts and aggression as behaviors only occurred occasionally. Caregivers reported receiving positive reports from school for the first time.

Discussion: Metformin is a biguanide anti-hyperglycemic medication utilized as first-line treatment for type 2 diabetes and weight loss. Animal studies in FXS have demonstrated an overactive insulin receptor and up-regulation of the mammalian target of rapamycin complex 1 (mTORC1) and mitogen activated protein kinase/extracellular signal-related kinases (MAPK/ERK) signaling pathways, as well as elevation of matrix metalloproteinase-9 (MMP-9) levels in the absence of fragile X mental retardation protein (FMRP), the protein produced by the FMR1 gene. Metformin has been shown to act as a strong inhibitor of the mTOR pathway and improve cognitive and social behaviors. Metformin has been shown to improve irritability, aggression, and social avoidance in individuals with FXS and anecdotal clinical evidence has suggested improvements in language and cognitive skills.

Conclusion: While metformin has been shown to improve language and cognitive abilities, and behaviors in individuals with FXS, we show that an individual with FXS and additional genetic variants can have improvements in language and cognitive abilities, and behavioral disturbances with metformin as well.