[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.  It 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.





[BBB] A thank you note for G1D foundation

Few days ago, I experienced as a scientist one of the greatest gratitude moment you can experience: being awarded a research grant for funding my research.
This was not an ordinary grant for me, as it came directly from the GLUT1 Deficiency (G1D) Foundation. This is a grant getting funded by money fundraised by patients suffering from G1D and their families, the sum of tireless effort and time of baking sales, fundraising walks and other activities to raise funds to promote basic and clinical research in order to find a cure of G1D patients.

  1. What is GLUT1 and what it is function in the brain?


Glucose is the main source of energy in the brain.  We estimate that almost 25% of daily glucose is exclusively reserved for the brain tissue. Given that the brain average weight is only 2% of the total body weight, we can easily understand how the brain is overwhelmingly dependent on glucose.
Glucose is a small molecule, but yet glucose is a highly polar molecule. It dissolves very well in water but it dissolves very badly in fat. Because cell membranes are made of fat (phospholipid bilayers), glucose cannot freely diffuse across the BBB and needs a carrier that will shuttle glucose from the blood to the brain.
GLUT1 is a member of the glucose transporter superfamily. We estimate over 14 different GLUTs expressed in mammalian cells lithesome specificity in where such transporters are expressed. At the BBB, GLUT1 is considered as the predominant isoform expressed, although some studies suggested the presence of GLUT3 and GLUT4 at mRNA levels but no one demonstrated their presence at protein levels and their presence as functional transporters. GLUTs function as facilitated carriers, they do not need energy to function and only rely on gradients (more concentrated to less concentrated to function).

2. GLUT1 deficiency syndrome (G1D)

Glucose transporter 1 deficiency syndrome (G1D or GLUT1DS) is a genetic disease firstly coined by Pr. Daryl De Vivo (University of Columbia Medical College) in 1991 in the seminal paper published in the New England Journal of Medicine.
G1D may have been already a existing disease but by its nature may have been largely undergo misdiagnosed as an type of epilepsy.
The major clinical feature of the disease is the onset of epileptic seizures during early infancy, usually by the age lesser than 1 year old. The diagnosis is usually reinforced by a spinal tap that usually note a low glucose level in the cerebrospinal fluid compared to normal range. The final diagnosis is usually obtain by measuring glucose uptake in patients red blood cells, however this procedure remains cumbersome and not systematically performed.
Patients respond in general poorly to their epileptic seizures and until now the major intervention with these children is the  use of ketogenic diet (KD), a variation of the Atkin’s diet (no-carbs diet).
Under fasting condition, the body can break down fatty acids from the fat storage compartment into ketone bodies (acetoacetate, beta-hydroxybutyrate). These ketone bodies can used as alternative fuel for the brain and allow to function quasi normally.
The disease is triggered by mutations in GLUT1 transporter, yet the relationship between sites of mutations and severity of the clinical symptoms are not yet established.
The average number of G1D cases worldwide is relatively small (~250 patients) but it may be a more prevalent condition, as it is often misdiagnosed as an idiopathic type of epilepsy.
The KD is not the panacea and has its challenges and limitations, in particular in terms of dyslipidemia and also in following the dietary requirements and personalization.
Recently, the development of anaploretic diet using triheptanoin (short odd-chain fatty acid) supplementation may help improve the quality of life for G1D patients.

3. Why do we need fundraising and why researchers need grants?

Scientific research is a long and expensive intellectual endeavor with no guarantee of success to translate findings into patients.
In academic research, most of the money comes from public agencies such as the National Institute of Health (NIH). This money is originated by every citizens through taxes, thus we can say that research funds are made of “taxpayers money”
Because money is not an infinite ressource and you cannot ask taxpayers to pay ludicrous amount of taxes,  funding agencies have to set funding priorities for diseases that have the highest priorities. Most of the time, this priority is determined by the prevalence of the condition. This is where we are facing challenges when you have a “rare disease”. Because “rare diseases” are by essence rare (less than 1 patient out of 100’000), funding agencies are reluctant to invest into this disease and pharmaceutical industries are reluctant to invest into a drug discovery program that will be costly and with little return to cover the cost.
This is why foundations are essential for us scientists. They provide us with funds that allow us to generate experimental data that are robust enough to be considered by special funding agencies (that support research on rare diseases) to take us seriously and provide us with a higher fund to further investigate such disease.
Funding agencies and foundations rarely if not never fund any projects without having it evaluated by a scientific broad that assess the validity of the science behind and the robustness of the investment to be made.
This is why I am very thankful to the G1D foundation to give me their trust in my research proposal and fund my work. If you want to help the G1D, you can donate them money through their donation page.
If you have another disease you want to contribute, please look up for a foundation held by patients or families, in particular support foundations that have a low fundraising maintenance cost (15% or less) and that have defined programs and goals including research grants and patient care.
Again, I would like to thank G1D and really looking forward to attend their 2017 meeting, with data as fruits of the scientific harvest made possible by this seed grant.



[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.

[Sciences] Today’s awareness day is Rare Diseases Day

Today is February 28th, it is Rare Disease Awareness day. Rare disease (or orphan disease) are diseases that have a small incidence among the population. We talking about patients fewer than 200’000 (Source: raredisease.org). That’s paradoxically a lot of patients suffering from diseases most of the time misunderstood or as I like to call a scientific “black box” although 80% of them are genetic and 50% affect children.

They are challenging for two reasons: parents and patients have to visit many doctors to find a cause of their disease condition and once identified they often end up with the same answer: no known cures. No cures because the number of individuals affected are small and making a drug costs a lot of money.

Don’t blame Big Pharma, Big Pharma is a business and like another business he has to make benefits out of its products to live. Unlike other markets in which return on investment are fairly good (e.g. hi-tech companies), pharmaceutical companies gamble high on R&D with a high risk on dead-end with a big negative value (important money loss). To give you an idea, only 1 out of 10’000 compounds that have shown promising hit in a screening platform will end up FDA-approved, in other means starting to bring cash in.

I am a scientist and you may know from my blogs that my research focus on the blood-brain barrier. Its play an important role as a gatekeeper, a cellular custom border patrol allowing the entrance of documented aliens necessary for the proper brain functions and to block the entrance of undocumented or suspicious aliens that may have harmful activities inside the brain.

We know that the blood-brain barrier breaches during several neurological diseases, but yet we poorly know how genetic disorders may affect the blood-brain barrier integrity. There are indeed some rare diseases that have a dysfunctional BBB but because it affects neurons, it mostly go unnoticed and are classified as neurological disorders. To raise awareness about rare diseases, I wanted to present two of them that have been linked to some of my research:

– Allan-Herndon-Dudley Syndrome (AHDS):

The Clive Svendsen’s lab (Cedars-Sinai) focuses on understanding neurological diseases using induced pluripotent stem cells (iPSCs) from patients. I have worked with Pr. Svendsen, Dr. Gad Vatine and Pr. Eric Shusta (University of Wisconsin-Madison, not pictured) to try to better understand the contribution of the blood-brain barrier in the disease.

AHDS is what I call a fairly rare disease (<100 cases) but we may just have tipped an iceberg. It is what we call an X-linked mental retardation. It mostly affect boys and rarely girls. Why? If you remember your high-school biology class, mens have a XY pair and women have a XX pair. The X always come from the Mom, the Dad in the other hand gives either a X (thus XX) or a Y (thus XY). The mom carries the mutation, thus the son display the disease.
The disease is very dramatic has its sign appears during the first year of life. Infants start to show problems in their psychomotor growth and cognitive development. According to Dr. Vatine, these kids brain somehow stop growing around 8-12 months, whereas their body keep developing normally. They barely babble words, have severe impairment (require constant care) and have no cures.
These patients suffer from a mutation in MCT8 (monocarboxylate transporter 8), a nutrient transporter involved in the uptake of bioactive thyroid hormone (T3). Patients show a high plasma level of T3, yet some studies suggest a low T3 level in the cerebrospinal fluid. Although mouse models of the disease (MCT8-knockout mice) have been developed, they failed to fully represent the signs of the disease. A problem observed with rodents is the interspecies differences, rodents are not humans and sometimes they do not reflect human diseases. It has been that indeed OATP1C1 (a nutrient transporter expressed only in rodent BBB) can transport T4 (the precursor of T3) into the BBB. Humans do not have any identified T4 transporter.

If you want to know more about the AHDS syndrome, feel free to consult the SMILE/Sherman foundation: http://mct8.info

– GLUT1 deficiency syndrome (GLUT1-DS)

The brain surely not run on Dunkin Donuts, but run on something highly enriched in their donuts: sugar. Glucose in particular. The brain is a high glucose consumer. Compared to its size (1% of the total body mass), the brain take over 20% of glucose of your total intake. However, if you fast or starve on an Atkins diet, the brain can bypass the glucose as source of energy and can use fatty acids degradation byproducts, in particular ketone bodies as a alternative source of energy. Yet there is this disease called GLUT1-DS or De Vivo Syndrome.

In this disease, the patients have in the mutation in GLUT1 transporter, a nutrient transporter that uptake glucose from the blood to the brain. These kids are doing fine during their first year and then start to develop epilepsy type of seizures in the same age, that is very unusual for children (usually toddlers and kids have absence seizures or “petit mal”). These kids fail to respond to their anti-epileptic drugs and their only positive outcome is the diagnosis and the change in supplementation into a ketogenic (Atkins) diet.
I am wondering if such condition may be more spread than expected, as nearly 30% of patients have refractory response to common anti-epileptic drugs
Hopefully, there is some good news ahead from these patients, as some clinical trials with trihepatonin have shown some positive outcome as a dietary supplement in lieu of the ketogenic (Atkins) diet.
If you want to know more about the GLUT1 deficiency syndrome, feel free to consult the GLUT1 foundation: http://www.g1dfoundation.org