Summaries: Recent Publications

Science Sandra

I would like to highlight a few new publications from scientists in our community. The first one is “ Head circumference in glucose transporter 1 deficiency syndrome: Normal for individuals, abnormal as a group” from Dr. Michel Willemsen’s team located in Radboud University Medical Center, Amalia Children’s hospital in Nijmegen, The Netherlands. In this manuscript, Dr. Willemsen and his team shared the results from an observational study among a large cohort of Dutch patients with GLUT1DS where they studied the prevalence of microcephaly. The aim of the study was to analyze all available data on head circumference of all patients with GLUT1DS known in their medical center. In conclusion, their studies found that microcephaly is less frequent in patients with GLUT1DS than generally thought. However, patients with GLUT1DS as a group have smaller head circumferences compared to the reference population, supporting a role for disturbed early brain development as part of the underlying disease mechanisms of GLUT1DS. 

The second publication I would like to highlight is from Dr. Karin Borges, who leads the neurological disorders and metabolism lab at the University of Queensland in Australia. The title of her publication is “ β-Hydroxybutyrate and Medium-Chain Fatty Acids are Metabolized by Different Cell Types in Mouse Cerebral Cortex Slices Neurochemical Research”. Here we are sharing a summary that Dr. Borges very kindly provided to us:

Medium chain triglycerides (MCT) are often added to ketogenic diets by people with epilepsy to control epileptic seizures. Beneficial metabolic and anti-seizure effects from MCT are thought to arise mostly from increased ketone body production. So far it has been unclear, to which extent there are any other metabolic benefits of MCT. In the intestines, MCT are cleaved and provide medium chain fatty acids, mostly octanoate and decanoate, which provide quick energy themselves and can be turned into ketone bodies by the liver. We directly compared the metabolism of medium chain fatty acid vs. ketone bodies in mouse brain slices. We found that the two substrates did not compete for oxidative metabolism. Medium chain fatty acids were metabolized directly by astrocytes, while ketone bodies were mostly metabolized by neurons. Thus, using MCT by themselves or in conjunction with ketogenic diets will provide auxiliary fuel to both major cell types in the central nervous system, which is expected to benefit neurological disorders where brain metabolism of glucose is impaired in neurons and astrocytes. This is anticipated to benefit people with epilepsy, and specifically also people with glucose transporter 1 deficiency syndrome, where glucose transport into astrocytes and into the brain via compromised glucose transporters (Glut1) expressed on astrocytes and on endothelial cells at the blood brain barrier is expected to be impaired.

The third publication I would like to highlight is from Dr. Abraham Al-Ahmad and his team in the Jerry Hodge School of Pharmacy at Texas Tech University Medical Center. The title of his publication is: “An in vitro model of glucose transporter 1 deficiency syndrome at the blood–brain barrier using induced pluripotent stem cells”. Glut1 Deficiency Syndrome is characterized by mutations in the SCL2A1 gene, which result in impaired glucose uptake at the Blood brain barrier (BBB). One of the limitations that exists to have a better understanding of the impact of such mutations on cells of the BBB and their function, is the absence of in vitro models of the BBB that reproduce Glut1DS. Dr. Al-Ahmad and his team published the results of their study which aimed to characterize an in vitro model of Glut1DS using human pluripotent stem cells (iPSCs). iPSCs are cells derived from skin or blood cells that have been reprogrammed back into an embryonic-like pluripotent state that enables the development of an unlimited source of any type of human cell needed for therapeutic purpose. Their publication reports the generation of two Glut1DS-iPSC clones that were differentiated into functional iBMECs (Induced brain microvascular endothelial cells), which showed a decreased expression of Glut1, decreased glucose uptake, as well as impaired angiogenesis (ability to develop new blood vessels). They conclude that these clones could be potential tools to study the pathophysiology of Glut1DS in vitro.

Finally, the last publication I would like to highlight is from Dr. Juan Manuel Pascual and his team at the Rare Brain Disorders Program in the Department of Neurology at UT Southwestern. The title of his publication is: “Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 Deficiency”.  This manuscript is the result of years of thorough research and observations of Glut1 Deficiency patients by Dr. Pascual. In this publication, it’s described how it is known that patients with Glut1 Deficiency experience epilepsy associated with decreased brain glucose, however, the mechanism by which blood glucose concentration and brain excitability (neuronal activity) are associated in this condition is still unknown. Dr. Pascual and his team performed different imaging tests in a group of Glut1 Deficiency patients, as well in mice deficient in Glut1, to analyze seizure activity and to determine the most affected areas of the brain during seizures. The results from these tests revealed that in the thalamocortical region of the brain in Glut1 Deficiency, there is an increased excitability and that failure to inhibit this electrical activity leads to seizures. In addition, their studies in mice showed that there is a decreased amount of glycogen in the brain but there is a normal level of glucose derived TCA cycle intermediates.

The results obtained in these studies indicate that the increased excitability in Glut1 Deficiency is a consequence of inhibitory neuronal dysfunction, more than due to the reduction of glucose transport into the brain.

These findings will help to open more paths to have a better understanding of the condition and how to develop better and more targeted treatments that will benefit our patient community. You can read an open access copy of the publication at this link.

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