One year of treatment with approved oral diabetes medicine, metformin, helped to improve the cognitive and behavior symptoms in two patients with fragile X syndrome, a study reports.
The study, “Cognitive and behavioral improvement in adults with fragile X syndrome treated with metformin‐two cases,” was published in the journal Molecular Genetics & Genomic Medicine.
Fragile X syndrome is an inherited rare disease that is caused by genetic mutations in the FMR1 gene, which prevent the normal production of the gene’s encoded protein.
Patients with this disease often have intellectual disabilities, with their intelligence quotient (IQ) scores declining during childhood and adolescence. They may experience social and behavior problems, such as attention‐deficit/hyperactivity disorder, anxiety, autism spectrum disorder, and aggression, as well as increased appetite and eating issues that lead to obesity.
Deficient levels of FMRP protein leads to enhanced activity of insulin receptors, along with other metabolic alterations, which suggests that interventions to reverse these effects could be beneficial for fragile X patients.
Previous studies showed that treatment with metformin was beneficial for mice with the disease, and improved their memory and circadian rhythm (daily sleep and awake patterns).
Metformin — marketed as Riomet and Glucophage, among other names — helps regulate the level of sugar in the blood and improves sensitivity to insulin. Given its therapeutic activities, it is an approved therapy widely used to manage type 2 diabetes.
In the study, researchers from the UC Davis Medical Investigation of Neurodevelopmental Disorders Institute in California tested the long-term effects of metformin, delivered at 1,000 milligrams (mg) twice a day, for one year in two male patients, 25 and 30 years old. Genetic analysis confirmed that both patients had mutations in the FMR1 gene, confirming their fragile X syndrome diagnoses.
The younger patient had autism and was also diagnosed with generalized anxiety disorder. First prescribed metformin at 22, he is currently taking 500 mg of metformin twice a day and 10 mg per day of simvastatin — used to lower the level of cholesterol in the blood.
The second patient was also diagnosed with anxiety and exhibited socially nervous behaviors, including panic attacks. He had severe limitations in language use, and communicated in short sentences and by mumbling. He had been on an extended-release formulation of metformin, taking 1,000 mg once a day for one year.
Both patients showed significant cognitive and behavioral improvements. After one year of treatment with metformin, test results revealed an increase in the patients’ IQ scores, from 53 to 57 in the younger patient and from 50 to 58 in the second patient.
Verbal and nonverbal IQ — the ability to analyze information and solve problems using visual or hands-on reasoning — were also improved in both patients. Non-verbal IQ increased from 50 to 52 in the younger patient and from 47 to 51 in the other. Verbal IQ went from 61 to 66 in the first patient, and from 58 to 68 in the second.
Treatment with metformin was shown to improve the patients’ visuospatial processing and knowledge of spatial relations, working memory, numeracy skills, and quantitative reasoning. They also improved their eating habits, and reached weights within the normal range for their ages. Their communication skills, social activities, and behavior improved as well.
“This is the first paper which describes individuals with fragile X syndrome who have shown an improvement in IQ scores after treatment with metformin,” the researchers wrote.
A randomized Phase 2/3 trial (NCT03479476), currently recruiting participants, is evaluating the safety and efficacy of a 12-week treatment with metformin against a placebo in patients, 6 to 25 years old, with fragile X syndrome. The trial’s primary objective (endpoint) is to evaluate metformin’s effects in patients’ language deficits. Researchers will also assess the impact of the treatment on behavior problems and obesity/excessive appetite.
Preliminary results of the trial are expected to be available in 2021. For more information about this trial, visit the study’s webpage here.