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Glut1 Deficiency Summit Posters

Learn more about the posters presented at our Glut1 Deficiency Summit Scientific Sessions. We're grateful to all who took the time to share their work, experiences, and insights with us to lead to better understanding, better treatments, and one day a cure for this disease.

poster #1

TITLE: Pre-clinical in vitro and in vivo validation of GLUT1 Deficiency Syndrome therapeutic leads identified by high throughput and targeted drug screens
LEAD AUTHOR: Aiman Baig
AFFILIATION: CHEO Research Institute (Children's Hospital of Eastern Ontario)
ABSTRACT:
Glucose transporter 1 deficiency syndrome (GLUT1 DS) is an untreatable progressive autosomal dominant disorder caused by mutations in the gene encoding glucose transporter GLUT1, SLC2A1 (De Vivo MD et al., 1991). Although a rare condition, it is estimated to impact hundreds of families in Canada and America alone. Approximately 90% of GLUT1 cases are caused by disabling de novo missense mutations in a single SLC2A1 allele (Wang et al., 2005). Given that endothelial GLUT1 is the predominant means of glucose transport across the blood-brain barrier (BBB), the resulting approximately 50% reduction in this critical glucose transporter results in decreased brain glucose levels (Seidner et al., 1998). 

Haploinsufficient disorders involving mutations of a single allele, such as GLUT1 DS, are in essence dosage disorders, caused by pathologically reduced protein levels. In such cases, interventions increasing protein levels, including activation of the wild-type allele, may confer clinical benefit. In this regard, the SLC2A1 gene is known to be inducible, indeed various drugs have been shown to increase GLUT1 expression. Given that the concentrations needed to increase GLUT1 when tested in vitro in several cell lines often exceed that which is pharmacologically attainable, we propose the following research program to identify new therapeutic leads. 

A screen assessing the impact of 800 FDA-approved drugs, as well as several GLUT1 inducing compounds, gleaned from the literature, on GLUT1 levels in wild-type endothelial cells (SLC2A1+/+) was undertaken. The top-inducing drugs and small molecules found in the screen shall be further validated in both in vitro and in vivo disease models. Fibroblasts from two GLUT1 DS patients’ skin biopsies are being reprogrammed to induced pluripotent stem cells (iPSCs) and then further differentiated into induced brain endothelial cells (iBECs). The impact of the putative GLUT1 inducing compounds on glucose transport will be measured. We shall next test the impact of GLUT1 inducing drugs on heterozygous SLC2A1+/- mice, using both physiological and behavioural testing. 

 

poster #2

TITLE:  Astrocytic GLUT1 inhibition: implications for adenosine-mediated neuromodulation
LEAD AUTHOR:  Mattia Bonzanni, PhD
AFFILIATION:  Tufts University
ABSTRACT:
While the energetic implications of glucose metabolism are frequently explored, the relationship between astrocytic glucose uptake and neuromodulator levels remains to be elucidated. Among the neuromodulator, ATP serves as a neurotransmitter and a precursor to adenosine, a significant neuromodulator that inhibits neuronal activity. Astrocytes play a pivotal role in this process by providing ATP for extracellular conversion to adenosine and by facilitating adenosine reuptake, thereby modulating adenosine levels. This regulation becomes crucial during periods of heightened energy demand, such as epileptic seizures, where adenosine acts as a protective signal against abnormal neuronal activity. We thus investigated the hypothesis that astrocytic glucose uptake through GLUT1 influences neuronal activity by modulating adenosine levels. Field potential experiments were conducted on ex vivo hippocampal brain slices from 8-week-old male and female mice to measure net synaptic transmission in the Schaffer collaterals. Astrocytic GLUT1 has been pharmacologically blocked (acute vs chronic) with 50 nM of BAY876. Endogenous occupancy of the adenosine 1 receptor (A1R), which mediates adenosine's inhibitory action, was assessed by first measuring synaptic transmission under basal conditions (B). Subsequently, a saturating concentration of an A1R inhibitor (I) was added, followed by a saturating concentration of an A1R agonist (A). The occupancy was then calculated using the formula: 100*(I-B)/(I-A). Glucose levels were maintained at a constant level throughout the dissecting, recovery, and recording phases to simulate either fed conditions (10 mM glucose) or normal blood glucose levels (2.5 mM) in the brain. Preliminary findings confirmed a direct dependency on glucose for net synaptic transmission, as demonstrated by a comparison between 10 mM and 2.5 mM levels. Acute pharmacological inhibition of astrocytic GLUT1, at either glucose level, resulted in heightened synaptic transmission. However, chronic exposure to the GLUT1 inhibitor showed a declining trend in synaptic transmission, suggesting long-term remodeling effects of chronic astrocytic GLUT1 blockade. Although basal levels and inhibitory function of adenosine through the adenosine 1 receptor (A1R) were not influenced by glucose levels or chronic inhibition of GLUT1, the responsiveness to adenosine was decreased in the presence of the GLUT1 blocker at 2.5 mM glucose, despite a comparable pre-synaptic probability of neurotransmitter release as evaluated using a paired-pulse facilitation stimulation protocol. This implies that larger fluctuations in adenosine levels, compared to the wild type, are required to achieve equivalent depression of synaptic transmission in the presence of GLUT1 blockage. In summary, should these initial findings be confirmed, they suggest that pharmacologically ablating astrocytic GLUT1 could diminish the responsiveness of the synaptic function to adenosine variations. Consequently, this reduction may compromise the inhibitory effectiveness of adenosine fluctuations during abnormal neuronal activities or stressful conditions such as hypoxia. Future experiments will be repeated with a G1DS murine model, incorporating the neurodevelopmental consequences of G1DS on neuronal activity and adenosine levels.

 

poster #3

TITLE:  Intake of polyunsaturated fatty acids and its effect on the lipid profile among the Chilean GLUT1-DS cohort on a ketogenic diet
LEAD AUTHOR:  Professor Veronica Cornejo, MS, RD
AFFILIATION: Genetic and metabolic disease laboratory, INTA, University of Chile
ABSTRACT:
Introduction
: Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a neurological disorder caused by mutations in the SLC2A1 gene. The main treatment is ketogenic diet therapy (KDT), but long-term can cause adverse effects, such as osteopenia and dyslipidemia. Concerning dyslipidemia, several benefits have been associated with the consumption of PUFA in the diet, mainly with the omega-3 family: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This is because the intake of omega-3 has a significant effect on reducing triglyceride and cholesterol levels, thus providing important benefits for cardiovascular health.

Objective: Determine the intake of essential fatty acids (PUFA), specifically DHA and EPA, and evaluate the lipid profile in the Chilean cohort of patients with GLUT1-DS.

Methodology: 13 GLUT1-DS subjects were matched for age, sex, and nutritional status with controls. Anthropometry, dietary intake, including types of fat, and blood tests were evaluated (lipid profile, liver profile, and vitamin D levels). For the analysis of dietary intake, 24-hour reminders were applied for 3 days. Intake of energy (kcal/day), protein (% of total energy; %E), carbohydrates (%E), total fat (%E), and cholesterol (mg/day) was recorded. Intake of saturated fat (SF, %E), monounsaturated fatty acid (MUFA; %E), polyunsaturated fatty acids (PUFA; %E), omega 3 fatty acids (%E), α-linolenic acid (ALA; %E) , EPA (%E), and DHA (%E).

Results: A high-fat diet, especially saturated fat, was identified in the GLUT1-DS group (38 % of total calories), and 17% of the total calories were medium chain triglycerides (MCT). The GLUT1-DS group had a higher intake of MUFA 40.4 g/day (20%E) and PUFA 31.3 g/day (17%E) compared to the control group which had 14.1 g/day (8%E) and 8.2 g /day (5%E), respectively. Regarding omega-3 intake, including ALA, EPA, and DHA, 2 of the 13 subjects with GLUT1-DS failed to meet the recommendations. A positive correlation was observed between saturated fat consumption and alanine transaminase (ALT) concentration in blood (⍴= 0.47; p= 0.017). An inverse correlation between MUFA fat intake, triglycerides (⍴= -0.527; p= 0.005), and VLDL (⍴= -0.53; p= 0.005).

Conclusion: The GLUT1-DS Group consumes a greater amount of saturated fats, MUFAs, and PUFAs than the control group. Our results show that the highest consumption of saturated fats in GLUT1-DS does not cause significant differences in lipids profile or liver function values concerning the control group. Thus, MUFAs, PUFAs, and mainly EPA+DHA, should be included in KDT to prevent changes in the lipid and liver profile and to avoid adverse effects that could later cause pathologies associated with malnutrition.

 

poster #4

TITLE:  Investigating G1D pathophysiology in the large animal brain pig model
LEAD AUTHOR:  Aksharkumar Dobariya
AFFILIATION:  
Weill Cornell Medicine
ABSTRACT:
Research in mice and humans shows that hyperexcitability in Glut1 Deficiency Syndrome (G1D) is primarily due to a failure in thalamocortical synaptic inhibition. For deeper mechanistic insights, human research is limited by inference from indirect metabolic flux measurements from BOLD signals and 18-FDG PET, which do not directly measure Krebs cycle function. The mouse model too is limited in its phylogenic distance from the human brain and its small size limiting serial metabolic sampling.  Hence to identify the disease locus and to circumvent these limitations, we propose a pig large animal brain model. Proposed 13C tracer glucose and electrophysiological assays in pigs will allow for comprehensive behavioral, neurophysiological, and metabolic studies, which can better identify the disease pathophysiology and assess treatment efficacy.

 

poster #5

TITLE:  Glut1 Deficiency Collective Voices Project
LEAD AUTHOR:
Sandra Ojeda, PhD
AFFILIATION:
Glut1 Deficiency Foundation
ABSTRACT:
Introduction: Glucose Transporter Type 1 Deficiency Syndrome (Glut1 Deficiency, G1D, Glut1DS) is a rare, genetic disorder that impairs brain metabolism. It is caused by haploinsufficiency of the SLC2A1 gene coding for the glucose transporter type 1 (GLUT1) protein, which causes impaired glucose transport across the blood brain barrier and within the brain between astrocytes and neurons. The failure to appropriately transport glucose to the brain causes a wide spectrum of neurological symptoms including the classical phenotype of seizures, a complex movement disorder, speech and language disorders, and cognitive disabilities. There is currently no cure for Glut1 Deficiency; however, the recommended standard of care treatment is a medically supervised ketogenic dietary therapy (KDT), which helps improve most symptoms for most patients.

Objectives: The Glut1 Collective Voices Project was designed to have a better understanding of the patient and family experience across a broad range of areas, including diagnosis, symptoms, the experiences with KDT and the patients and families’ priorities among others. The goals of the survey were to better define the range of symptoms, identify gaps in treatment and patient care, identify gaps in knowledge and understanding of this disease, better understand disease burdens, and identify the most important components for our natural history study and our strategic research plan, our Research Compass.

Methods: Survey content was developed through virtual focus group discussions and questionnaires in the patient community. The anonymous survey was conducted on the Qualtrics platform under Castle IRB. There were 246 questions and statistical analysis was provided by Insights Advisors Group.

Results: We received 260 responses to the survey from 31 different countries. 95% of respondents were parents or caregivers and most of the patient population was within the 7–12 year-old range. The results indicate that on average it takes close to 3 years from the first symptom to get a diagnosis, and in most cases the diagnosis is made by a neurologist through genetic testing. Regarding symptoms, most patients experience the classical symptoms described in the literature; however, many other less common symptoms were also reported. In addition, the results show that most of the patients experience changes in symptoms during puberty and adulthood. Despite the KDT being reported as at least partially helpful for most of the patients and most of the symptoms, the patients and families’ top research priority is the development of new and better treatments. Furthermore, the priority outcomes that patients and families look for in new treatments are to be able to eat a normal diet, improve their cognition, and have better speech and communication skills. Finally, the results from the project helped inform the design of our natural history study as well as our Research Compass.

Conclusions: Overall, the results from the Collective Voices Project show that there is a diverse community of patients with Glut1 Deficiency presenting a wide range of symptoms which can vary over time. The results highlight that patients and families prioritize the need for developing better treatments that improve their quality of life, emphasizing the importance they place in the social aspects, such as being able to eat a normal diet and improving their cognitive and communication skills.

 

poster #6

TITLE: Our Taekwondo Experience
LEAD AUTHOR:  Sandra Ojeda, PhD
AFFILIATION:  
Glut1 Deficiency Foundation and Glut1 Mom
ABSTRACT:
"Taekwondo is one of the most systematic and scientific Korean traditional martial arts, that teaches more than physical fighting skills” (TKD USA).

Sofia is 15 years old and was diagnosed with Glut1 Deficiency when she was 3. She started treatment with the ketogenic diet once she was diagnosed, and is currently taking the Modified Atkins Diet. Sofia has been in many different types of therapy to support her growth and development. As part of this support, she is currently attending Taekwondo classes, which have helped to improve her balance, coordination, gross motor skills, strength and self-confidence.

 

poster #7

TITLE:  Supporting My Development
LEAD AUTHOR:  Cindy Oliver
AFFILIATIONS:  Glut1 Deficiency Australia
ABSTRACT:
Logan Oliver's development is supported with the many examples of therapies and techniques used to improve his cognitive, speech, language, gross and fine motor skills.

 

poster #8

TITLE: I Want You to Know
LEAD AUTHOR: Patient Advisory Board
AFFILIATION: Glut1 Deficiency Foundation
ABSTRACT:
People who live with Glut1 Deficiency are the true experts on how this disease affects their lives in so many different ways. In the past, advocacy efforts have focused more on the parent and caregiver perspectives, which are important and valuable, but it is essential that patients are given a voice to share what their lives are like, the struggles they experience, and the hopes and dreams they have for a better future. As people with Glut1 Deficiency grow and become adults and with so little known about the lifelong impacts of the disease over time, it is especially important for us engage them so that we can learn more and help more.

As part of the Glut1 Deficiency Foundation's Patient Centered Outcomes Research Institute (PCORI) Eugene Washington Engagement Award, a formal Patient Advisory Board has been established to help provide a representative voice to those who know and understand Glut1 Deficiency the most because they live with it every day. Members of the Patient Advisory Board were asked to share their thoughts, struggles, and hopes through the "I Want You to Know" poster.

 

poster #9

TITLE: The Power and Promise of Precision Medicine
LEAD AUTHOR: Glenna Steele, MEd
AFFILIATION: Glut1 Deficiency Foundation & Glut1 Mom
ABSTRACT:
Even among individuals with the same rare genetic diagnosis, their experiences, their treatment responses, and even the underlying cause of their disease can be different. In the case of Glut1 Deficiency, variants in the SLC2A1 gene result in decreased glucose transport into the brain and impaired brain metabolism. However, the type and location of each variant may have very different impacts on the function of the GLUT1 transporter, the key protein involved. Better understanding the functional implications of each genetic variant can pave the way for more precise, personalized treatments aimed at correcting and restoring glucose transport by targeting the underlying mechanisms involved. The power and promise of this type of  precision medicine is evidenced in the journey of Glut1 Deficiency patient Macie Steele.

 

poster #10

TITLE: A bespoke blend of MCT in the management of Glut-1DS
LEAD AUTHOR: Victoria Whiteley, MSc, RD
AFFILIATION: Royal Manchester Children's Hospital
ABSTRACT:
Objective:
To assess the impact of a bespoke blend of MCT (K.Vita) in the dietary management of Glut-1DS, in children and young people.

Introduction: K.Vita is a unique patented strawberry-flavoured medical food containing 80:20 of C10:C8 triglycerides. It is prescribable in the UK for the dietary management of drug-resistant epilepsy (DRE) from 3 years of age. Typical intake of K.Vita for a child is one pouch (120ml) per day with a maximum of two pouches (240ml) daily, or to provide a maximum of 35% of daily energy requirements. K.Vita should be taken at regular intervals, three or four times daily with food.

Method: A retrospective case note review was completed at Royal Manchester Children's Hospital, including patients with a confirmed diagnosis of GLUT1DS who were prescribed K.Vita as a medical food.

Results: Thirteen patients were included in the review (8 males), with the median age of 11 years at introduction of K.Vita (range 3-17 years). Length of use ranged from 6 months – 2 years.  Of those that commenced on K.Vita seven were also on the ketogenic diet and in therapeutic ketosis. K.Vita was used to replace the equivalent LCT or MCT fat source in the diet so that the dietary ratio was not altered. For the remaining six, they were advised to follow a healthy eating diet with regular meals and snacks including complex carbohydrate.  Patients were provided with a 4–6-week introduction plan aiming to achieve the target daily dose (120ml-240ml) in 3-4 daily doses. It took a median of 6 weeks to reach target dose of K.Vita (range 3 –24 weeks).

Compliance: Those who were compliant with the treatment schedule (n=10) noted improvements in symptoms within 12 weeks of reaching their target dose. Three patients discontinued K.Vita due to poor compliance and limited impact.  K.Vita was well tolerated with reports of only mild or transient gastro-intestinal discomfort.

Outcomes: After 12 weeks at their individual target dose, 85% (11/13) reported improvements in symptoms associated with GLUT-1DS. Three reported insufficient or inconsistent improvements and struggled to achieve the target dose or to comply with the dosing schedule long term. Of the seven following the ketogenic diet, three reported improved ketone levels with K.Vita.  All 13 patients reported paroxysmal movement disorders at baseline, with 77% (10/13) reporting improvements of at least 50%. Six patients reported seizures at baseline, with 67% (4/6) reporting 50% improvement 12 weeks after achieving target dose. All 13 patients had some degree of dysarthria at baseline and seven reported speech improvements. Severe or migrainous headaches +/- hemiplegia were reported at baseline in four patients and all reported improvements in the severity and frequency of episodes. Improved energy levels were reported in 69% (9/13) patients and 54% (7/13) reported improvements in fine and gross motor skills.

Conclusion: K.Vita is a promising and well tolerated addition to the options available for the dietary management of Glut-1DS and its associated symptoms. Interestingly it has shown benefits in the management of non-seizure manifestations including dysarthria and paroxysmal movement disorders.