Fall Research Roundtable Summary

Hello and welcome to Science with Sandra!

This month I would like to share a brief summary of our Fall Research Roundtable which took place on October 24th. We had 23 participants and our special guest speakers Dr. Maoxue Tang and Dr. Valentina De Giorgis. It was a great opportunity to learn about their projects.

The first speaker of the day was Dr. Maoxue Tang. Dr. Tang is currently an Assistant Professor in the Department of Neurology at Columbia University Irving Medical Center. Before he joined the faculty position at Columbia, he completed his PhD studies at the Chinese Academy of Agricultural Science and his post-doc work was on gene therapy for Glut1 Deficiency with Dr. Darryl De Vivo at Columbia University. His current research is focusing on understanding the circuit, cellular and molecular mechanisms underlying the Glucose Transporter 1 Deficiency Syndrome, and his long-term goal is to develop viable treatments for patients suffering from Glut1 Deficiency.

The title of his talk was: “Cognitive dysfunction is also a feature of disease in Glut1 DS model mice”. Dr. Tang shared results from his experiments on brain microvasculature using a mouse model of Glut1 Deficiency.  Results from his studies indicate that brain microvasculature is affected in the absence of the Glut1 protein; in addition, endothelial tip cells in the thalamus are impaired in the absence of Glut1. Endothelial tip cells are leading cells at the tips of vascular sprouts that coordinate multiple processes during angiogenesis or blood vessel formation.

Tang, M 2021

The figure above is part of a publication from Dr. Tang and Dr. Monani. The pictures show microvasculature in the thalamus area of the brain. On the left side you can see the microvasculature of a healthy mouse and on the right side you can see microvasculature of a Glut1 deficient mouse. Red arrows point at tip cells. You can see how Glut1 deficient mice have impaired tip cells, lacking the extensions (lamellipodia) typically seen during cerebral angiogenesis. 

Experiments performed on Glut1 deficient mice using gene therapy based on an AAV9 vector with the Glut1 gene, resulted in improved brain microvasculature density compared to the untreated Glut1 deficient mice.

Dr. Tang has performed additional studies to understand the consequences of brain energy deficit in Glut1 deficient mice. These studies have shown that these mice have reduced levels of lactate, glucose, and glycogen in the brain, specifically in the thalamus and cortex area. Additionally, these mice have an increase in inflammation, as seen by an increase in activated astrocyte and microglia, as well as loss of neurons. Increased inflammation is seen in mice as young as 1 week old. 

Dr. Tang wanted to understand how all of these differences in the brain of Glut1 Deficient mice could impact learning and memory. In order to do this, he used different tests to evaluate these aspects. His results indicated that Glut1 deficient mice have impaired learning and memory. Finally, he observed that calcium activity was significantly increased in cortical pyramidal neurons of Glut1 deficient mice. Still more studies are needed to understand the implications of the calcium increase in cortical pyramidal neurons of Glut1 deficient mice, and he will be focusing on understanding this on future studies.

Our second speaker of the day was Dr. Valentina De Giorgis. Dr. De Giorgis is an Assistant Professor at Università degli studi di Pavia and a Pediatric neurologist at Fondazione Mondino, Istituto Neurologico Nazionale, in Pavia Italy. Her area of expertise is rare and complex epilepsies, Glut1 Deficiency syndrome and the treatment of drug-resistant epileptic encephalopathies. Dr. De Giorgis leads the Infancy and Adolescence Epileptology Center in Mondino hospital and coordinates the keto clinic for children and adults. In addition, Dr. De Giorgis is a member of the scientific advisory board of the GLUT1 and SCN2A Italian association. She is also a member of the International League against epilepsy task force for dietary therapies and a member of the European Reference Network on Rare and complex epilepsies.

The title of her talk was: “Ketonemia variability through menstrual cycle”. Dr. De Giorgis shared the results of her latest manuscript “Ketonemia variability through menstrual cycle in patients undergoing classic ketogenic diet” which focused on the results of her ongoing clinical study on the fluctuation and variability of ketone levels during the menstrual cycle. Dr. De Giorgis explained that variations on blood levels of ketone bodies during menstruation have not been systematically assessed yet, and it deserves special attention because of the hormonal and metabolic changes that occur during this period.

Dr. De Giorgis explained that this study is the first study aimed at observing the course of blood levels of ketone bodies during the menstrual cycle in patients with glut1 Deficiency and drug-resistant epilepsy undergoing the ketogenic diet. She also described that in addition to her interest to understand the variation of ketone bodies during menstruation because of the use of the diet for treatment of patients, there is another rationale for investigating changes in ketone bodies and glucose level during the menstrual cycle. First, during the luteal phase of the cycle there is a reduction in glucose uptake related to the action of progesterone and increased insulin resistance that have been documented. Furthermore, it has been suggested that interactions between seizures and menstrual cycle are possible, suggested by variations on seizure frequency according to the day, phase and ovulatory status of the menstrual cycle, this is called “catamenial epilepsy”. Whether a relevant variation of ketone blood levels would be documented, according to the clinical picture of the individual clinical picture, the keto-team might decide to modify the diet with a targeted intervention during menstrual cycle.

The study is a multicenter study aimed at investigating ketone bodies and glucose blood levels during the menstrual cycle in female patients with a diagnosis of Glut1 Deficiency or drug resistant epilepsy undergoing the Ketogenic diet therapy. The study is currently taking place at Mondino Foundation in Pavia, Italy, Ospedale dei Bambini V. Buzzi in Milan, and “Prof. Dr. Juan P. Garrahan” Hospital in Buenos Aires. The study is registered in clinicaltrials.gov, ID number  NCT05234411, Name: KETOMENS, Ketonemia through the menstrual cycle. 

The inclusion and exclusion criteria for the study is described below:

INCLUSION CRITERIA	EXCLUSION CRITERIA
Patients with drug resistant epilepsy or GLUT1DS	Patients who experienced secondary amenorrhea
Stable treatment with Classical Ketogenic Diet from at least 3 months	Patients who have irregular menstrual cycle
Regular menarche from at least 3 months	Pregnancy
Absence of recognized endocrinological problems/diseases

Participants are asked to:

– measure ketonemia and glycemia twice a day (before meals, morning and evening) for a period of three months, possibly everyday and at least 5 days per week

– compile a brief daily dietary diary to be checked by dietitians and clinical diary to be checked by neurologists/ epileptologists

The results of the publication focus on 6 patients who completed the trial, from which 3 were Glut1 Deficiency patients, and their age range was between 13 and 18 years of age.

The results of the study show that Glut1 Deficiency patients had increased fatigue during menstruation days, however they did not experience changes in seizures or movement disorder manifestations. In addition, all participants had a significantly higher value on glycemia levels during menstruation compared to the remaining days. Moreover, blood levels of ketone bodies were found to be lower during menstruation in 4 out of 6 patients. 

Finally, Dr. De Giorgis shared that further investigation needs to be done for this study, due to the low number of participants. She shared that the study is still open and they will share more information about a possible recruitment of patients around the world fulfilling the inclusion criteria. If interested please send an email to [email protected]

We thank our wonderful speakers Dr. Maoxue Tang and Dr. Valentina De Giorgis for taking the time to present their wonderful projects at our Research Roundtable, and for their interest and all  the work they are conducting to help our community!

Thank you for visiting our blog and please do not hesitate to contact me if you have any questions or concerns at [email protected].