Today is February 28th. It is also named “Rare Diseases Day” that normally takes place on February 29th but since that day is also rare, we celebrate it on February 28th.
Why celebrate “Rare Diseases Day”? Because as their name suggest, there are diseases that affect only few individual and therefore are classified rare.
Because they are rare, they are under less attention from major healthcare actors at different levels.
From the basic scientist standpoint, these are diseases that are so rare that the interest to fund these diseases are almost zero because budgets are tight and priority is given to research for diseases with a much more prevalence.
From the pharmaceutical company standpoint, these are investment that are risky by their failure and also by the prospect of seeing investment on return. It costs a lot to validate the therapeutic efficacy and ensure the production of these therapeutics into a cGMP grade (pure and safe enough for being used in humans). Therefore, pharmaceutical companies stay away from these diseases and put their bet on safer projects.
From the clinical standpoint, clinicians may encounter only one or two cases during their whole professional career. For families, it is devastating to not put a name on the condition affecting their child for years, only to hear at the end that there is no curative treatment for.
One of these rare diseases is the GLUT1 deficiency syndrome (GLUT1 DS).
Glucose is the number 1 source of energy for eukaryotic cells, from yeasts to human cells. It enters the cells via a transporter (a protein present in the cell membrane). Glucose uptake is indeed ensured by different transporters all belonging to the solute carriers (SLCs) super-family. We have some of these carriers that are sodium-independent (GLUTs) and some sodium-dependent (SGLTs).
The brain is particularly avid of glucose: 25% of our daily glucose uptake is directed strictly to the brain. Considering the small size of the brain (3lbs organ out of a 140lbs individual), you can understand how important glucose is for nerve cells.
The uptake of glucose to the brain is ensured by the presence of several transporters at the blood-brain barrier (BBB), with GLUT1 being the most abundant glucose transporters. There are also reports of other glucose transporters (GLUT3, GLUT4, SGLT1 and SGLT6) but their contribution is less well understood (Meireles et al. 2013). In the brain, astrocytes and neurons also express some glucose transporters (GLUT1 and GLUT3 in astrocytes; GLUT3 in neurons) but it is considered that upon crossing of the BBB that astrocytes reduce such glucose into lactate (a fermentation byproduct of glucose degradation). Such lactate is believed to serve as a rapid source of fuel for neurons.
GLUT1 deficiency syndrome (GLUT1DS) was firstly reported by Pr. Darryl DeVivo (Columbia University, New York, USA) in 1991 (De Vivo et al. 1991) and was characterized by the presence of a low level of glucose in the cerebrospinal fluid (the fluid in which the brain baths in) despite a normal blood glucose level. It was later identified that GLUT1 (encoded by the gene SLC2A1) was responsible of such clinical presentation (Seidner et al. 1998). This condition is affecting children in their infancy resulting in the presence of epileptic seizures that are classified as refractory or “drug-resistant”. Indeed, a recent study suggests that GLUT1 DS is the second most abundant genetic form of childhood epilepsies (Afawi et al. 2016).
Until now, there are no treatment for this condition. The only common symptomatic treatment and intervention is forcing these children bodies to switch their brain metabolism from a carb-inclusive normal diet into a ketogenic diet (similar to the Atkins diet). By removing carbs, you are forcing the brain to fast and solicit lipids from fat storage as a source of energy. These fatty acids can be broken down into ketone bodies (acetoacetate, acetone and beta hydroxybutyrate). These ketone bodies can be transported into the brain via the monocarboxylate transporter 1 (MCT1, another member of the SLC super-family) and serve as alternative fuel. Yet, such treatment is only a temporary fix as it requires an extreme observance of this diet as well non-negligible side effects on the body.
My current research focuses on trying to develop a patient-specific model of the BBB using patient-derived induced pluripotent stem cells (iPSCs) in order to understand how glucose is uptaken at the BBB and how such mutations impact such uptake. I am still new in the field and it takes time and money to validate such models, as we have to move to incremental steps to validate such models. However, little things can make changes and it takes a village to raise someone.
Today, I would like to give my thanks for the GLUT1 Deficiency Foundation (http://www.g1dfoundation.org) to support part of my research through their research grant program aimed as a first step to better understand the diseases. Some of my current research would not have been possible without the effort of families that have been actively fundraising and raising awareness about this disease.
The fund I have been awarded through the foundation is simply an amazing effort and reward, as I am grateful for this fund raised through cookie sales, lemonade stands or simply generous donations from anonymous donors.
If everything goes well, the GLUT1 Deficiency Foundation is due for a bi-annual meeting (this July) involving scientists, clinicians, patients and families discussing about the recent research and outcomes obtained both at the bench and the bedside. I am very excited to have my research project moving on and being able to present a poster to this meeting and share how this research grant has been able to help to shed new lights on glucose transport at the BBB and hopefully moving to a diseased model, one little step at the time.
This is why I am thankful to the GLUT1 Deficiency Foundation and please help me support their campaign by helping them to raise funds through their “Love Some1 with Glut1”: http://www.g1dfoundation.org/ways-to-give/donate/.
Afawi, Z., Oliver, K. L., Kivity, S. et al. (2016) Multiplex families with epilepsy: Success of clinical and molecular genetic characterization. Neurology, 86, 713-722.
De Vivo, D. C., Trifiletti, R. R., Jacobson, R. I., Ronen, G. M., Behmand, R. A. and Harik, S. I. (1991) Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med, 325, 703-709.
Meireles, M., Martel, F., Araujo, J. et al. (2013) Characterization and modulation of glucose uptake in a human blood-brain barrier model. J Membr Biol, 246, 669-677.
Seidner, G., Alvarez, M. G., Yeh, J. I. et al. (1998) GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat Genet, 18, 188-191.