Science with Sandra – new paper summary from Prof. Dr. Jörg Klepper

Hello and welcome to science with Sandra!

This is an exciting time in our community, many different researchers and clinician/researchers have been busy working on different projects and writing very interesting publications.

At this time, I would like to highlight a recent publication by Dr. Joerg Klepper. Dr. Klepper is the Medical Director of Aschaffenburg Children’s Hospital in Aschaffenburg, Germany and a member of our medical and scientific Advisory Board. His clinical interests include disorders of brain energy metabolism such as GLUT1 Deficiency and pyruvate dehydrogenase. His research interests include the mechanisms and adverse effects of the ketogenic diet on these disorders and establishing international protocols for the use of the ketogenic diet for epilepsy and metabolic disorders.

The name of his latest publication is “Glut1 Deficiency Syndrome: Novel Pathomechanisms, Current Concepts, and Future Perspectives“.  This paper gives an updated overview of what researchers and clinicians now understand about GLUT1 Deficiency, how it works, how it manifests in patients, and what treatments might help.

Dr. Klepper begins explaining the disease and how the absence of glucose in the brain, as the main energy source, compromises the development of the brain and its function. Typically, the disease is caused by mutations on the SLC2A1gene which encodes for the GLUT1 protein.

The standard treatment for GLUT1 Deficiency is the ketogenic dietary therapy (KDT), which provide ketones as an alternative fuel for the brain. However, many questions remain: Why do symptoms vary so widely? Why doesn’t KDT work for everyone? And what else is going wrong in the brain besides energy failure?

This 2025 review by Dr. Joerg Klepper brings together the most current knowledge, including newly discovered disease mechanisms, challenges in clinical care, and promising avenues for research and treatment.

What are the key points of this publication?

Dr. Klepper talks about the phenotype or symptoms experienced by GLUT1 Deficiency patients. Seizures, developmental delay, and movement disorders are still common symptoms but patients also experience:

• Speech disorders, especially dysarthria which is difficulty speaking clearly
• Cognitive issues that range from mild to severe
• Paroxysmal eye–head movements in infants, now recognized as an early hallmark of the disease

Dr. Klepper mentions how symptoms vary significantly with age with seizures being more common in infancy and childhood, while paroxysmal movement disorders and speech disturbances such as dysarthria increasing in puberty and adding more burdens to the quality of life of adolescents and adults.

Genetics

• About 90% of cases are caused by mutations in the SLC2A1 gene, often new (de novo) mutations.
• Inheritance is mostly autosomal-dominant but there have also been cases of autosomal-recessive inheritance described in consanguineous families.
• Some patients have no detectable mutations in this gene, suggesting:
  -Other genes may contribute to symptoms in GLUT1 Deficiency.
  -Extending genetic screening to noncoding regions will help identify more patients with low CSF glucose and other GLUT1 Deficiency symptoms when exome sequencing is negative.
  -GLUT1 malfunction may be caused by issues in how the protein is processed or trafficked inside cells.

Protein Structure

The GLUT1 protein has 12 transmembranes with highly conserved small regions of the protein structure that are common for other GLUT proteins, and it also has some unique conserved small regions. Pathogenic variants in those conserved regions can impair glucose transport.

Dr. Klepper describes many different variants and some “hot spots” or areas that are especially prone to genetic alteration, that have been identified on the SLC2A1 gene and how they can alter the structure and function of the protein. 

An interesting point that Dr. Klepper discussed briefly was the inhibition of the GLUT1 transporter. He mentions some GLUT1 protein inhibitors including tea, caffeine and red wine. In addition he mentions how ethanol and antiepileptic drugs such as diazepam and chloralhydrate, have been shown to inhibit GLUT1-mediated glucose transport in vitro. 

Current Challenges in Clinical Practices

Dr. Klepper focuses his attention to multiple challenges facing the community in clinical practice. Some of the challenges are listed below:

• The incidence of the disease, which according to different studies that have been done around the world, ranges between 1:24,000 and 1:90,000.
  
• The patient and family community has been key into identifying different symptoms including paroxysmal eye-head movements in infancy as one of the early signals of GLUT1 Deficiency. In addition, has been instrumental in helping clinicians and researchers know how different symptoms affect the quality of life of our loved ones affected by this condition. The GLUT1 Deficiency Foundation has been key leading these efforts through the collection of data through the Glut1 Deficiency Collective Voices Project, the Natural History Study, and other surveys that have helped guide research and have shared the patient and family experience with all stakeholders in the community. The Italian GLUT1DS Association registry has also been the source of several publications.
  
• The phenotype or symptoms experienced by our loved ones is broad with many different symptoms and a broad spectrum of severity. In addition, there are still many unknowns including how symptoms change during adulthood and the benefits of the KDT in patients diagnosed late in adulthood or in the elderly.

Treatment

• KDT remains the standard care of treatment and it is particularly effective at controlling seizures in children.
  
• It’s less effective for movement disorders and speech issues.
  
• Some patients do not respond to the diet, and researchers don’t yet know why.
  
• The diet can be hard to maintain long-term and has potential side effects.
  
• There’s uncertainty about KDT use in pregnancy and aging adults.
  

Current Challenges in Research

When GLUT1 Deficiency was first described, it was believed that the main pathogenic mechanism of the disease was the impaired glucose transport across the Blood Brain Barrier. Currently, the metabolic interactions between different cell types in the brain including astrocytes and neurons and the impact on other GLUT and MCT transporters have come into focus. There have been a few studies focusing on analyzing metabolites and identifying potential biomarkers, but further studies are needed.

GLUT1 has been found to transport not only glucose but other molecules such as dehydroascorbic acid, the oxidized form of vitamin C and more recently, L-fucose. Dr Klepper mentions how in the brain, fucose is important in fucosylation, a process reported to affect learning and memory, neuronal outgrowth and migration, synapse formation, and others. 

Additionally, Dr. Klepper pointed out that there is another current research focus and this is the effects of GLUT1 Deficiency in vascular effects. Studies have shown that low CSF glucose may impair brain angiogenesis or blood vessel development.

Finally, Dr. Klepper ends his publication by stating all the successes in the GLUT1 Deficiency community including progress in the disease understanding, the consensus guidelines, the growing research network, patient registries, education, support to patients and families and the recognition and acceptance of the KDT at the international level, among others.

On the other hand, he also states the things that still need to be done including the identification of reliable biomarkers and predictors for outcome and response to the KDT, the development of newborn screening tests and potential therapeutic strategies including gene therapy.

We thank Dr. Klepper for publishing this wonderful review and for always supporting and caring for our community!

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