A Sweet Cure for Fragile X Syndrome?: Fragile X Syndrome and diabetes

A Sweet Cure for Fragile X Syndrome?: Fragile X Syndrome and diabetes

By: Shruthi Kandalai

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and most common genetic cause of autism spectrum disorder. This occurs when there are over 200 repeats on the FMR1 gene of the X chromosome, leading to excess FMR1 mRNA, which is neurotoxic. Men are most commonly affected as they have only one X chromosome. FXS presents with symptoms of cognitive impairment, sleep problems, increased risk of seizures, repetitive behaviors, physical abnormalities and those related to anxiety, OCD and ADHD. Women with this mutation on one X chromosome do not present with the same symptoms, but have an increased risk of ovarian insufficiency, cognitive deficits and neurodegenerative movement disorders. Currently, there are no drugs specifically approved to treat FXS. 

A 2017 paper used a Drosophila model of fragile X syndrome to study how it is related to insulin signaling. This model mutates Drosophila homolog dfmr1 and leads to behavioral and anatomical defects.

  • Insulin secretion in dfmr1 mutants was significantly increased. Reducing insulin secretion rescued both memory and circadian defects associated with mutant phenotype.
  • dfmr1 expression in insulin-producing cells of the brain was necessary for normal insulin release and insulin signaling.
    • The closest homologous human tissue to Drosophila insulin-producing cells of the brain are pancreatic beta cells. Beta cells do express FMR1, though its role has not yet been studied.
  • The use of metformin, a drug normally used to treat T2D, to normalize insulin also improved short-term and long-term memory in dfmr1 mutants.

Another 2017 paper used a knock-out mouse model of fragile X syndrome to similarly study if metformin may be used to rescue symptoms and overall phenotype. This model leads to behavioral changes similar to humans, including lack of social novelty, increased self-grooming (related to repetitive behaviors), seizures and hyperactivity. Metformin had the following effects:

  • Rescued mice of social deficit, with these mice preferring novel interactions
  • Normalized self-grooming behaviors, though prolonged exposure was necessary for this effect
  • Decreased seizure activity, but had no effect on hyperactivity
  • Corrected dendritic spine density and morphology in CA1 hippocampal pyramidal neurons

Following these results in model animals, a 2019 paper studied the effect of metformin treatment in nine boys between 2 and 7 years. 

  • Patients improved in receptive and expressive language, fine motor skills and some aberrant behavior (lethargy, stereotypy).
  • Seven patients saw a decrease in hyperactivity following treatment, though hyperactivity associated with FXS is also known to decrease over time. One patient had an increase in hyperactivity following metformin treatment.
  • One patient had a seizure one month after metformin treatment, though another patient showed improvements in seizure activity after treatment.

While this study was not double-blind or placebo-controlled, there are ongoing Canadian and American phase 2 and phase 3 clinical trials using metformin as a treatment for FXS.

The takeaway: Metformin, which is normally used as a T2D treatment, may also help treat fragile X syndrome, as based on data from model organisms and human trials. This may also suggest that similar pathways are involved in both disorders.

Sources: 

  • Klusek, J., LaFauci, G., Adayev, T., Brown, W. T., Tassone, F., & Roberts, J. E. (2017). Reduced vagal tone in women with the FMR1 premutation is associated with FMR1 mRNA but not depression or anxiety. Journal of Neurodevelopmental Disorders, 9(1). 
  • Monyak, R. E., Emerson, D., Schoenfeld, B. P., Zheng, X., Chambers, D. B., Rosenfelt, C., … Jongens, T. A. (2016). Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model. Molecular Psychiatry, 22(8), 1140–1148. 
  • Gantois, I., Khoutorsky, A., Popic, J., Aguilar-Valles, A., Freemantle, E., Cao, R., … Sonenberg, N. (2017). Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nature Medicine, 23(6), 674–677. 
  • Biag, H. M. B., Afzal, S., Rosvall, A., Salcedo‐Arellano, M. J., Rajaratnam, A., Manzano‐Nunez, R., … Hagerman, R. J. (2019). Metformin treatment in young children with fragile X syndrome. Molecular Genetics & Genomic Medicine, 7(11). 

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