[Neurosciences/BBB] 8th GLUT1 Deficiency Conference – Summary


Today wrapped the second and last day of the 8th GLUT1 Deficiency conference that was held in Nashville, TN this year. It was my second time I am attending this conference and honored to be a guest speaker this year.


The whole conference took place at the Inn at Opryland, part of the Gaylord Resort at Opryland. It is a fairly impressive complex with shuttle to the Opry Mills outlet shopping center and, the Gaylord Resort & Convention Center (in which the AACP is also holding a meeting starting today but I am just attending one day meeting there).

According to the organizers, we had about 220 attendees, with 68 families present. What I liked this year was the blending between parents, healthcare providers and scientists. In the previous conference, the first day was family and healthcare providers and the second day was the professional day. This allowed a unique interactions, questions & answers and discussion.



It was also a very good time for updating my knowledge on the disease. Not much on the basic science, but more on the current treatment and dietary intervention with various experts of the field including Pr. Jorg Klepper (University of Essen, Germany); Pr. Juan Pascual (UT Southwestern, Dallas, TX); Pr. Eric Kossoff (John Hopkins University, Baltimore, MD) and other scientific experts.

My learning from the conference is that the disease in an evolutive disorder. We learn more about the disease as we learn from the patients growing in. As the patient grows, he or she displays different symptoms: “funny eyes movements” during infancy, presence of absence seizures during toddler times and learning attention and deficit during early school age, presence of movement disorders in both during childhood and adulthood and migraines, hemiplegia and “writers hand fatigue” syndrome. This seems to be linked by an impaired glucose uptake in the cerebral cortex and the thalamus. ┬áIt also seems that there is at some point in the disease the presence of a sexual dimorphism, as female patients seems to experience in their teenage years a “paroxysmal dystonia” that seems triggered by moderate and vigorous exercise. So, the GLUT1DS is not a static disorder. It is a disorder evolving over time with its clinical manifestations evolving as well.
The second thing I learned is the variety of “ketogenic diets”. There is not one single “keto diet” but several variants with different dosages and variety, including a Modified Atkins Diet.


It seems there is not a “one size fits all” but rather different types of diets that also seems to vary with age.


The younger age appears to need the following of a strict keto diet and as the patients age, some softening and flexibility can be introduced. It seems the critical time for the keto diet is infancy and childhood. The earlier the child is introduced, the better. There are also several companies providing cookbooks, supplements like keto powders or kets-friendly products aimed for patients.

In terms of diagnosis, some interesting news came from a French biotech startup that can measure GLUT1 levels in RBC within 24 hours using a proprietary cell assay (that looks like an antibody assay) using a flow cytometry-based approach.
Another interesting result is the outcome of the ketogenic diet for GLUT1DS patients. For the vast majority of GLUT1DS patients (95% of patients), the keno diet significantly decrease the number of seizures by at least 50%. In contrast, other types of epilepsies combined only show a 50% of patients showing a responsive outcome to keto diet. Still, 5% of GLUT1DS do not respond to keto diet and there is a fraction of patients that show a normal glucose CSF levels and/or GLUT1 expression. We certainly have a lot of patients that undergo undiagnosed or misdiagnosed for years as “drug-refractory epilepsies”. But it seems that some patients maybe falsely diagnosed as GLUT1DS. Hopefully, with the decrease in price for DNA testing (it seems 23andMe can detect some GLUT1 SNPs) may help to broaden the diagnosis and identification of patients.
Some interesting topics presented at the conference was some possible drug adverse effects reported in G1D heterozygous mice in particular to diazepam and phenobarbital but also other drugs. Some parents noted the anecdotical adverse reactions following certain treatment. However, the absence of studies directly investigating such drug adverse effects in G1D patients most of the time go under the radar, with the health practitioner attributing it to the disease condition rather than some particular drug adverse effects. Having from screening tools can greatly help.
Another interesting presentation is the study of G1D heterozygous mice. These mice seems to display a lower brain vascular density compared to wild-type. This is not surprising considering the recent work of Pr. Peter Carmeliet (Universidaed Leuwen, Belgium) on endothelial cell metabolism. According to Pr. Carmeliet, brain endothelial cells highly depend on glycolysis to function despite being in presence of plenty amount of oxygen levels.
There have been also discussion of trying to setup a comprehensive guide for parents for a consensus on GLUT1DS diagnosis and management that can help them as a source for documentation during their visit with their doctors. There is also a discussion of improving the community outreach to professionals and politicians to improve the funding and the recognition of GLUT1DS as a condition, discussing about supporting open-access options for certain papers allowing parents a free-access to these new studies and also finding ways to support GLUT1DS awareness and management among minority populations and in other geographic areas (especially South America).
The person missing at this meeting by his presence was certainly Pr. Daryl DeVivo (Columbia University, New York, NY). Little patients left him some very kind words and their name on a paper board. I found it was a very cute gesture and remembered us that his absence was felt.

The interesting silver lining comes from Europe, as they have set now a sister association that held their first European GLUT1 meeting last fall and plan to hold it in London in 2018 and in Paris in 2020.
For me, I am looking forward to attend the 2019 meeting in Washington DC and hopefully bring on some more breaking news from my lab there.





[Blood-brain barrier] GLUT1 Deficiency Foundation Conference


Today was my first day with the GLUT1 deficiency syndrome community, as i attended the professional program. That was a very interesting scientific meeting as GLUT1 is a relative new disease for me and remained fairly cryptic as it is considered as a rare neurological disorder. It also fascinates me as a relative has been diagnosed by it and another may indeed display a form of it.
GLUT1 deficiency syndrome (GLUT1DS) is a particular disease for me, as it is a genetic disease directly affecting the blood-brain barrier (BBB) resulting in an incapacity of glucose to be transported across it, resulting in a deficient energy supply to the central nervous system. It is associated with epileptic-like seizures usually starting early on in children (few months to a couple of years after birth). However, interestingly enough, it is also marked by delayed cognitive development and ataxic features. Such features would easily get unnoticed by a neuropediatrician and may classify it into a type of epilepsy or into a neurodevelopmental disorder.
There are no particular etiology known, there are some genetic background when tracing family history. There are different types of mutations that results in different phenotypes and severity in the clinical settings, making difficult to get a prognostic for the children affected. An interesting thing I have learn is the variety of different types of mutations that have been identified but more importantly the possible prevalence of this disorder. It went from 2 recorded cases in 1991 to over 500 cases in 2015 and there are some estimates that if we look at the whole epileptic patients population (estimated as 50M worldwide) we can estimate number as high as 250’000.
The only treatment known is the ketogenic diet (with a 65% fat and less than 10% sugar) to force the body to rely on ketone bodies as a source of fuel. Thats no fun and often becomes a problem when patients become teenagers. There are been some interesting outcomes using heptanoin and heptanoin derivatives (such as triheptanoin), acting as an anaploretic diet. The interesting thing that remains is to explain the origin of the improvement of certain drug-resistant patients following such diet despite showing no mutations.
Interestingly enough, it seems the disease progresses over time transitioning from a seizure-like type of epilepsy into an exercise-induced dyskinesia marked by a muscle limb painful spasms followed by a transient muscle fatigue.
It was a small conference but it was great as parents of G1DS patients were meeting with professional and the small G1DS community that maybe around 20 PIs investigating the disease at this time. It was a great starter and really let me think how I can use the iPSC platform to bring an additional model that can add the patient-specific aspect to the disease and hopefully better understand the mechanisms underlying such condition. This is the kind of meeting in which you can get to know some of the patients, have these patients directly in touch with the basic sciences and have them see sciences advancing but also opening new questions.
Surely, G1D conference 2017 is my next agenda and looking forward to bring this time something to the community.