Rare disease research is hard - there are limits and obstacles at nearly every turn. It is critically important that precious time, energy, and resources be spent in the most effective and efficient ways so that we can make progress, together, towards better understanding and better treatments to ensure that brighter future for our patients and families that we envision.
We've brought together stakeholders in our community to help develop a research compass, hoping to help guide the way to the most important problems to solve, biggest questions to answer, widest gaps to fill, and heaviest burdens to ease.
We believe progress will come quickest and easiest not in a straight path or step by step, but by creating relationships and collaborations across the many scientific corners that touch our disease. We hope this compass helps focus efforts and inspire action on behalf of those who need the answers to these questions - our patients. Thank you for your interest in helping us.
We've brought together stakeholders in our community to help develop a research compass, hoping to help guide the way to the most important problems to solve, biggest questions to answer, widest gaps to fill, and heaviest burdens to ease.
We believe progress will come quickest and easiest not in a straight path or step by step, but by creating relationships and collaborations across the many scientific corners that touch our disease. We hope this compass helps focus efforts and inspire action on behalf of those who need the answers to these questions - our patients. Thank you for your interest in helping us.
Research Compass
Below you'll find a list of resource tools needed and key questions to answer through research. Our plan as we further develop this resource is to continually add publications, projects, people, and places so that comprehensive information is easily accessible and progress can be followed.
Contribute resources or ideas for inclusion here.
Contribute resources or ideas for inclusion here.
Open Source Research Tools:
Develop the most relevant and reliable tools to use for research and make them easily accessible to any researcher.
Cell Lines and Bio Samples:
Animal Models:
Other Tools:
Clinical Tools:
Develop the most relevant and reliable tools to use for research and make them easily accessible to any researcher.
Cell Lines and Bio Samples:
- cell lines – iPSC to create other relevant cell types
- endothelial cell models - Blood Brain Barrier (BBB)
- organoids – Blood Brain Barrier (BBB), brain
- patient biospecimens – blood, tissue, fibroblasts, CSF, autopsy series
- omics and scRNA-seq data from patient samples
- better classification and characterization of variants
Animal Models:
- Are more mouse models needed?
- Is a pig model needed?
- Is there a role for a zebrafish model?
- omics and scRNA-seq data from animal models
- transcriptomics
- metabolomics
- proteomics
- epigenetic profiling (acetylation, methylation, etc.)
- standardized assays for quantifying functional Glut1
- standardized reagents: antibodies, viral shRNA vectors, others?
Other Tools:
- improved intracerebral glucose and ketone measurements
- better tools to study BBB transport
Clinical Tools:
- consistent and reliable biomarkers
- meaningful outcome measures
- natural history patient data – patient and clinician reported outcomes, electronic health records
- newborn screening tool
Related Publications and Resources:
CNS organoids: An innovative tool for neurological disease modeling and drug neurotoxicity screening
Modeling GLUT1 deficiency syndrome in a Petri Dish using induced pluripotent stem cells: A preliminary report
Coriell Biorepository
COMBINEDBrain Biorepository
Modeling GLUT1 deficiency syndrome in a Petri Dish using induced pluripotent stem cells: A preliminary report
Coriell Biorepository
COMBINEDBrain Biorepository
Cells:
More clearly define the cell types involved in the disease, their locations in the body, and which ones can and should be targeted for treatment.
More clearly define the cell types involved in the disease, their locations in the body, and which ones can and should be targeted for treatment.
- What cells are clearly and definitively impacted in Glut1 Deficiency? (endothelial, astrocytes, neurons?) others?
- Where are the impacted cells located?
other body areas and systems? muscles? retina? BBB or brain only? what regions of the brain? - What is the right cell model to use for drug screening activities?
- How many cell lines do we need considering the heterogeneity?
Related Publications:
Endothelium-derived lactate is required for pericyte function and blood-brain barrier maintenance
Bidirectional astrocytic GLUT1 activation by elevated extracellular K+
Near-critical GLUT1 and Neurodegeneration
Role of the GLUT1 Glucose Transporter in Postnatal CNS Angiogenesis and Blood-Brain Barrier Integrity
Bidirectional astrocytic GLUT1 activation by elevated extracellular K+
Near-critical GLUT1 and Neurodegeneration
Role of the GLUT1 Glucose Transporter in Postnatal CNS Angiogenesis and Blood-Brain Barrier Integrity
Glut1 – the transporter protein:
Better understand the function of Glut1, what influences that function, and how malfunctions can be corrected.
Blood Brain Barrier
Better understand the function of Glut1, what influences that function, and how malfunctions can be corrected.
- What are the other functions of Glut1 besides glucose transport? What are we missing?
- What impacts trafficking, expression, function, and configuration?
- Does Glut1 function and/or expression change over the lifespan?
- How is Glut1 activity impacted by binding partners?
- Why the familial differences with same variant - what else regulates Glut1?
- How is Glut1 regulated at the transcriptional level and post-transcriptional level?
- How can Glut1 expression or transport be upregulated in the target cells?
- Are there off-target implications of manipulating Glut1 expression?
- Can faulty Glut1 be bypassed? How?
- Can/do other Gluts compensate for impaired Glut1?
- What is the minimum amount of Glut1 needed to prevent disease?
Blood Brain Barrier
- What other factors at the BBB impact Glut1 activities?
- What all is involved in Glut1 regulation at the BBB? Is it different than in other tissues/cells?
- How do we maximize transport of glucose through the BBB?
- Do diet/metabolic therapies alter the BBB?
- Do diet/metabolic therapies change glucose transport at the BBB?
- Can we discover pharmacological approaches that alter transport at the BBB?
- Does exogenous Glut1 behave the same as endogenous at the BBB?
Related Publications:
GLUT1 biological function and inhibition: research advances
Glucose transporters in brain in health and disease
Endothelium-derived lactate is required for pericyte function and blood-brain barrier maintenance
Glucose transporters at the Blood-Brain Barrier: Function, regulation and gateways for drug delivery
Near-critical GLUT1 and Neurodegeneration
Role of the GLUT1 Glucose Transporter in Postnatal CNS Angiogenesis and Blood-Brain Barrier Integrity
Modeling GLUT1 deficiency syndrome in a Petri Dish using induced pluripotent stem cells: A preliminary report
New insights into GluT1 mechanics during glucose transfer
Multiple Interactions of Gluoxe with the Extra-Membranous Loops of GLUT1 Aid Transport
Glut1 deficiency syndrome: New and emerging insights into a prototypical brain and energy failure disorder
Mechanistic insights into GLUT1 activation and clustering revealed by super-resolution imaging
Glucose transporters in brain in health and disease
Endothelium-derived lactate is required for pericyte function and blood-brain barrier maintenance
Glucose transporters at the Blood-Brain Barrier: Function, regulation and gateways for drug delivery
Near-critical GLUT1 and Neurodegeneration
Role of the GLUT1 Glucose Transporter in Postnatal CNS Angiogenesis and Blood-Brain Barrier Integrity
Modeling GLUT1 deficiency syndrome in a Petri Dish using induced pluripotent stem cells: A preliminary report
New insights into GluT1 mechanics during glucose transfer
Multiple Interactions of Gluoxe with the Extra-Membranous Loops of GLUT1 Aid Transport
Glut1 deficiency syndrome: New and emerging insights into a prototypical brain and energy failure disorder
Mechanistic insights into GLUT1 activation and clustering revealed by super-resolution imaging
Metabolism:
Better understand the metabolic functions that are impaired by Glut1 Deficiency and identify ways to compensate.
Better understand the metabolic functions that are impaired by Glut1 Deficiency and identify ways to compensate.
- What are the downstream implications of impaired brain glucose transport? Is it more than an energy issue?
-other substrates?
-other Gluts?
-other molecules ? (BDNF?)
-cycles and pathways (glycolysis, glycosylation, glucogenesis, ATP, lactate shuttle, others)?
- Can these downstream implications be treatment targets?
- What are the glycogen and glycosylation levels in mouse models?
- What is the role of glycogen in Glut1 Deficiency? Can glycogen metabolism be manipulated for potential utilization?
- What is the role for adenosine in Glut1 Deficiency?
- What about substrate competition vs. utilization?
- How do we better understand the astrocyte/neuronal lactate shuttle?
- What are the astrocytes taking up vs. the neurons? What does each need more of?
- What about substrate driven toxicity?
Related Publications:
Endothelium-derived lactate is required for pericyte function and blood-brain barrier maintenance
Glut1 deficiency syndrome: New and emerging insights into a prototypical brain and energy failure disorder
Glucose transporter 1 critically controls microglial activation through facilitating glycolysis
Glia-neuron energy metabolism in health and diseases: New insights into the role of the nervous system metabolic transporters
Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet
PKCs Sweeten Cell Metabolism by Phosphorylation of Glut1
Glut1 deficiency syndrome: New and emerging insights into a prototypical brain and energy failure disorder
Glucose transporter 1 critically controls microglial activation through facilitating glycolysis
Glia-neuron energy metabolism in health and diseases: New insights into the role of the nervous system metabolic transporters
Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet
PKCs Sweeten Cell Metabolism by Phosphorylation of Glut1
Genetics:
Identify all the genes that may play a role in Glut1 Deficiency, how defects in the genes contribute to disease, and how their function can be repaired.
Identify all the genes that may play a role in Glut1 Deficiency, how defects in the genes contribute to disease, and how their function can be repaired.
- What are the variants clearly associated with disease?
- What are the functional consequences of those variants?
- What are the genotype/phenotype relationships- what determines or influences a patient’s progression/journey?
- What other factors influence gene expression, especially in cases of multiple family members with varying phenotypes?
- Are other genes or other regions of SLC2A1 implicated in Glut1 Deficiency?
Related Publications:
Glut1 deficiency syndrome: New and emerging insights into a prototypical brain and energy failure disorder
Variety of Symptoms of GLUT1 Deficiency Syndrome in Three-Generation Family
Mechanistic Insights into Protein Stability and Self-aggregation in Genetic Variants Causing GLUT1-Deficiency Syndrome
A frame-shift deletion in the PURA gene associates with a new clinical finding: Hypoglycorrhachia. Is GLUT1 a new PURA target?Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs
Mutational and functional analysis of Glucose transporter I deficiency syndrome
Pathogenic mutations causing glucose transport defects in GLUT1 transporter: The role of intermolecular forces in protein structure-function.
Absence of SLC2A1 Mutations Does Not Exclude Glut1 Deficiency Syndrome
Evaluation of non-coding variation in GLUT1 deficiency
Screening of SLC2A1 in a large cohort of patients suspected for Glut1 deficiency syndrome: identification of novel variants and associated phenotypes
Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group
Variety of Symptoms of GLUT1 Deficiency Syndrome in Three-Generation Family
Mechanistic Insights into Protein Stability and Self-aggregation in Genetic Variants Causing GLUT1-Deficiency Syndrome
A frame-shift deletion in the PURA gene associates with a new clinical finding: Hypoglycorrhachia. Is GLUT1 a new PURA target?Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs
Mutational and functional analysis of Glucose transporter I deficiency syndrome
Pathogenic mutations causing glucose transport defects in GLUT1 transporter: The role of intermolecular forces in protein structure-function.
Absence of SLC2A1 Mutations Does Not Exclude Glut1 Deficiency Syndrome
Evaluation of non-coding variation in GLUT1 deficiency
Screening of SLC2A1 in a large cohort of patients suspected for Glut1 deficiency syndrome: identification of novel variants and associated phenotypes
Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group
Gene Therapy:
- Does the ketogenic diet expand the therapeutic window of gene replacement?
- Is AAV9 capable of reaching the target cells in the target location?
- Is AAV the optimal capsid for human brain endothelial cells? How durable will it be?
- What other cells types will need to be targeted? Astrocytes?
- What is the optimal route of administration going to be?
- Is there a role for ex vivo gene therapy through autologous bone marrow transplant?
- What about the toxicity and/or cancer risks of producing too much Glut1? Especially with respect to AAV-based gene therapy
Related Publications:
Gene therapy for Glut1-deficient mouse using an adeno-associated virus vector with the human intrinsic GLUT1 promoter
Gene therapy for a mouse model of glucose transporter-1 deficiency syndrome
Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein
Intra-cisterna magna delivery of an AAV vector with the GLUT1 promoter in a pig recapitulates the physiological expression of SLC2A1
Gene therapy for a mouse model of glucose transporter-1 deficiency syndrome
Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein
Intra-cisterna magna delivery of an AAV vector with the GLUT1 promoter in a pig recapitulates the physiological expression of SLC2A1
Pathogenesis:
Better define the clinical course of Glut1 Deficiency, what causes the symptoms, and why they change over time.
Better define the clinical course of Glut1 Deficiency, what causes the symptoms, and why they change over time.
- What happens to the human brain with prolonged glucose or Glut1 deficiency? (growth, structure, inflammation)
- What other organs or body systems may be impacted by Glut1 deficiency?
- What are the mechanisms behind the evolution of the disease and changes from infancy to adulthood?
- What happens to elderly/aged patients?
- What can we learn from studying other Glut1-involved diseases? How can we synergize efforts?
Related Publications:
Glut1 deficiency syndrome: New and emerging insights into a prototypical brain and energy failure disorder
GLUT1 deficiency: Retinal detrimental effects of gliovascular modulation
Keeping Glucose Transporter Type 1 Deficiency Syndrome in Mind: A Late Diagnosis and Unusual Neuroimage Findings
Glucose Transporter Type I Deficiency (G1D) at 25 (1990-2015): Presumptions, Facts, and the Lives of Persons With This Rare Disease
Long-Term Clinical Course of Glut1 Deficiency Syndrome
GLUT1 deficiency syndrome into adulthood: a follow-up study
Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group
Glucose Transporter Type 1 Deficiency Syndrome: Gene Reviews
GLUT1 deficiency: Retinal detrimental effects of gliovascular modulation
Keeping Glucose Transporter Type 1 Deficiency Syndrome in Mind: A Late Diagnosis and Unusual Neuroimage Findings
Glucose Transporter Type I Deficiency (G1D) at 25 (1990-2015): Presumptions, Facts, and the Lives of Persons With This Rare Disease
Long-Term Clinical Course of Glut1 Deficiency Syndrome
GLUT1 deficiency syndrome into adulthood: a follow-up study
Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group
Glucose Transporter Type 1 Deficiency Syndrome: Gene Reviews
Therapy Development:
Better understand the benefits and limitations of current therapies and develop new and better ones.
Better understand the benefits and limitations of current therapies and develop new and better ones.
- Why/how does ketosis fail to fully resolve symptoms in Glut1 Deficiency?
- What options are there if ketogenic diets fail?
- Can we make ketogenic diets more effective and easier to implement?
- Does genotype/phenotype impact diet efficacy?
- What is the role for MCT’s (oils, triheptanoin, K.Vita)?
- What is the role for ketone esters?
- What level of ketones should we aim for? Does this change over time? Are ketones even important?
- What happens with the need for ketogenic diets into adulthood? Are they less or equally necessary?
- Is there a role for ketogenic diet in patients with Glut1 Deficiency identified before symptoms start (e.g. genetically or due to an affected parent)?
- What is the role for diazoxide? Why?
- What is the role for acetazolamide? Why?
- How can we rescue the movement episodes?
- Which anticonvulsants could help with seizure control? Which ones should be avoided?
- Which movement disorder drugs could help? Which ones should be avoided?
- Are there treatments to target speech and communication symptoms?
- Are there treatments to target cognitive symptoms?
- Is personalized medicine necessary based on level of transport, genotype, and/or phenotype?
- Can Glut1 activity or expression be enhanced by repurposed drugs?
- Can Glut1 Deficiency be cured completely?
- Will there be lingering or return of symptoms with gene therapy?
- Are there clearly defined treatment windows?
Related Publications:
GLUT1DS and the ketogenic diet
Ketogenic Diet in Patients with GLUT1 Deficiency Syndrome
Quality of Life in Chronic Ketogenic Diet Treatment: The GLUT1DS Population Perspective
Failure of ketogenic diet therapy in GLUT1 deficiency syndrome
Use of modified Atkins diet in glucose transporter type 1 deficiency syndrome
Use of dietary therapies amongst patients with GLUT1 deficiency syndrome
Acetazolamide-responsive Episodic Ataxia Without Baseline Deficits or Seizures Secondary to GLUT1 Deficiency: A Case Report and Review of the Literature
Outcome of ketogenic diets in GLUT1 deficiency syndrome in Japan: A nationwide survey
New Paradigm for the Treatment of Glucose Transporter 1 Deficiency Syndrome: Low Glycemic Index Diet and Modified High Amylopectin Cornstarch
Therapeutic Strategies for Glucose Transporter 1 Deficiency Syndrome
Glut1 deficiency syndrome: New and emerging insights into a prototypical brain and energy failure disorder
Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group
Ketogenic Diet in Patients with GLUT1 Deficiency Syndrome
Quality of Life in Chronic Ketogenic Diet Treatment: The GLUT1DS Population Perspective
Failure of ketogenic diet therapy in GLUT1 deficiency syndrome
Use of modified Atkins diet in glucose transporter type 1 deficiency syndrome
Use of dietary therapies amongst patients with GLUT1 deficiency syndrome
Acetazolamide-responsive Episodic Ataxia Without Baseline Deficits or Seizures Secondary to GLUT1 Deficiency: A Case Report and Review of the Literature
Outcome of ketogenic diets in GLUT1 deficiency syndrome in Japan: A nationwide survey
New Paradigm for the Treatment of Glucose Transporter 1 Deficiency Syndrome: Low Glycemic Index Diet and Modified High Amylopectin Cornstarch
Therapeutic Strategies for Glucose Transporter 1 Deficiency Syndrome
Glut1 deficiency syndrome: New and emerging insights into a prototypical brain and energy failure disorder
Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group
Clinical Tools:
Develop tools to improve the diagnostic process, support better clinical care, and advance meaningful treatment development.
Develop tools to improve the diagnostic process, support better clinical care, and advance meaningful treatment development.
- What is the full phenotypic spectrum of Glut1 deficiency?
- How do we improve and best measure cognition and communication outcomes for patients, the top priorities identified by patients for quality of life improvements?
- What are the appropriate endpoints for clinical trials?
- What are the best biomarkers to use?
- Is there a way to use advanced imaging analysis/machine learning for outcome measures?
- Is there a role for continuous glucose monitoring in clinical care?
- Should we incorporate the glucose ketone index into clinical care?
- Should we develop master protocols – what is the optimal therapy for each patient group?
- Newborn screening tool – can we intervene early?
Related Publications:
Blood test accurately detects GLUT1 Deficiency Syndrome
Development of a rapid functional assay that predicts GLUT1 disease severity.
10 patients, 10 years - Long term follow-up of cardiovascular risk factors in Glut1 deficiency treated with ketogenic diet therapies: A prospective, multicenter case series
Overall cognitive profiles in patients with GLUT1 Deficiency Syndrome
Does ketogenic diet improve cognitive function in patients with GLUT1-DS? A 6- to 17-month follow-up study
Cerebrospinal Fluid Analysis in the Workup of GLUT1 Deficiency Syndrome: A Systematic Review
Clinical Aspects of Glucose Transporter Type 1 Deficiency: Information From a global Registry
Payroxysmal Eye-Head Movements in Glut1 Deficiency Syndrome
Stroke mimics add to the phenotypic spectrum of Glut1 deficiency syndrome
Sporadic and familial glut1ds Italian patients: A wide clinical variability
A novel SLC2A1 mutation linking hemiplegic migraine with alternating hemiplegia of childhood
Long-Term Clinical Course of Glut1 Deficiency Syndrome
GLUT1 deficiency syndrome into adulthood: a follow-up study
Glucose Transporter Type 1 Deficiency Syndrome: Gene Reviews
Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group
Development of a rapid functional assay that predicts GLUT1 disease severity.
10 patients, 10 years - Long term follow-up of cardiovascular risk factors in Glut1 deficiency treated with ketogenic diet therapies: A prospective, multicenter case series
Overall cognitive profiles in patients with GLUT1 Deficiency Syndrome
Does ketogenic diet improve cognitive function in patients with GLUT1-DS? A 6- to 17-month follow-up study
Cerebrospinal Fluid Analysis in the Workup of GLUT1 Deficiency Syndrome: A Systematic Review
Clinical Aspects of Glucose Transporter Type 1 Deficiency: Information From a global Registry
Payroxysmal Eye-Head Movements in Glut1 Deficiency Syndrome
Stroke mimics add to the phenotypic spectrum of Glut1 deficiency syndrome
Sporadic and familial glut1ds Italian patients: A wide clinical variability
A novel SLC2A1 mutation linking hemiplegic migraine with alternating hemiplegia of childhood
Long-Term Clinical Course of Glut1 Deficiency Syndrome
GLUT1 deficiency syndrome into adulthood: a follow-up study
Glucose Transporter Type 1 Deficiency Syndrome: Gene Reviews
Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group
