Dr. Klepper shared with us that the Glut1 Deficiency Consensus Guidelines were written by him with the help of several Glut1 Deficiency specialists (several neurologists and 2 nutritionists from different countries). The purpose was to put together in one document the current status of Glut1DS, symptoms, how it is diagnosed, treatment and research. Once they defined what is known about the condition today, they discussed areas of disagreement, what was most controversial, and what requires further investigation.
The Consensus Guidelines will be published as a peer-reviewed paper in Epilepsia Open and will be available as open access.
Question and Answers from the Session:
What surprised you most about writing this consensus?
One of the things that surprised me the most was being able to get 23 specialists to agree and write this manuscript. The second thing that surprised me was what we don't know about the condition yet. I'm sure this consensus is the first of many that will come in the future when more is known about the condition. In this manuscript we can become aware of what is known about the condition and what we need to know.
Glenna Steele commented that the Glut1 Deficiency Foundation received a grant from the Chan Zuckerberg Initiative for holding the first scientific conference to bring together researchers to determine what is known about the condition and what we need to do to have better treatments and understand more of the condition. This manuscript will play an important role.
What medicines are recommended for epilepsy in this condition?
There is very little in the literature and few reports regarding which are the ideal medicines to control seizures in patients with Glut1 Deficiency. We do not have a consensus on this aspect. There are no medicines that should never be used. We have in vitro, laboratory data showing that caffeine and theine inhibit the functioning of Glut1. It is recommended that Glut1 Deficiency patients do not take a lot of caffeine or theine.
How much is known about the mutations that cause this condition and what are its effects?
This information requires us to write another manuscript, there are still many things that we do not know. What we know, is we have some mutations that generate a milder condition and others that generate a more severe condition. We also know that there are different sites in the gene that are considered “hot spots,” that is, many patients have mutations in that region of the gene. There are other mutations that are unique and may only be present in one patient. This information is collected in the registry that Dr. Pascual has in Texas. Parents of patients can enter this type of information into the registry.
Are there long-term effects of the ketogenic diet?
This diet is used to treat epilepsy and Glut1 Deficiency, the treatment for the two conditions does not differ. What changes is that for Glut1 Deficiency it is a treatment for life and for this reason we must be more attentive to the long-term effects. We don't have much long-term information. Long-term concerns are effects on growth (which may or may not occur), kidney stones (which can be prevented with high consumption of liquids and other medicines), osteoporosis, and cardiovascular diseases. The information we have does not indicate that this is an effect, but we need more data to be certain of the long-term effects.
Should supplements that are given to patients on the classic keto diet be continued when patients switch to the modified Atkins diet?
Yes, supplements should be continued on the modified Atkins diet.
Are there some foods that patients should definitely not consume?
There is no food that should not be consumed. But it is best to work with dietitains, The Charlie Foundation, Matthew's Friends and learn about the specific food about which you want to have information and they can give you the information.
At what age should Glut1 Deficiency patients be on a certain diet, for example, the classical ketogenic diet versus the modified Atkins diet?
This is a point of controversy. Patients are generally recommended to be on the classic ketogenic diet in childhood when the brain needs more energy. Many times this depends on the level of ketosis. In general, when patients grow older, when they reach puberty, they can switch to the modified Atkins diet. What is ideal, is to keep patients on the version of the diet that gives them greater ketosis.
Should patients who do not have seizures follow a treatment with the ketogenic diet?
If this is the case, the diet should still be used because the diet provides what the brain needs to grow and develop.
Do the Glut1 Deficiency symptoms change over time?
In childhood the predominant symptoms are seizures; in puberty and adulthood the predominant symptoms are paroxysmal movements and PED (exercise-induced paroxysmal movements). The ketogenic diet doesn't seem to help as much to control these movements.
What is the consensus about the treatments there may be in the future?
We need more investigation. One is medicine for the treatment of paroxysmal movements, another is gene therapy. Regarding gene therapy, good results have been obtained in the mouse model, however, there is still a long way to go before we can test these treatments in patients with Glut1 Deficiency. Lastly, there is the possibility of establishing screening in newborns. This would help provide treatment for Glut1 Deficiency as soon as possible, greatly helping the management of symptoms.
On the other hand, studies are also being carried out to evaluate different drugs that have been approved for the treatment of other diseases, and thus determine if they can help in the treatment of Glut1 Deficiency.
Is there a strategy to try to reduce paroxysmal movements?
What we have learned about this from parents is that in addition to the need to rest after these episodes occur, drugs like acetozolamide and L-Dopa have worked in some patients for the treatment of these movements.
Glenna commented that one of the things that some parents discussed last year at the conference and in the adult patient survey is that moderate exercise, with some frequency, improves those types of movements.
What can we do as parents to make our children's transition from pediatric neurologists to adult neurologists a smooth one?
You can inform your adult neurologists about the condition, and interest them to learn about this condition. This way they can evaluate and treat our patients when they become adults. Glenna has informed us that the Glut1 Deficiency Foundation has attended conferences of neurologists and epileptologists, among others, in order to raise awareness and educate medical professionals about Glut1 Deficiency and thus try to approach these neurologists to make an impact on them so that they are interested in treating our patients.
Therapies like language, occupational, are easily offered to patients in childhood, but once they reach adulthood, these therapies are not offered to patients. Does the consensus article say anything about this topic?
We didn’t discuss this subject in the paper because it is not a problem we see all over the world; this is more a problem seen in individual countries and we didn't add it to the consensus. Dr. Klepper agreed that these types of therapies are beneficial for Glut1 Deficiency patients from infancy to adulthood.
Does the consumption of 1-2 grams of sugar have long term effects in Glut1 Deficiency patients?
It doesn’t have long term effects, however, it can affect short term by decreasing ketone levels.
What is the consensus regarding C7 oil (triheptanoin)?
We had high expectations about C7 oil, but the clinical trials performed with triheptanoin (C7 oil) by Ultragenyx regarding seizure control and movement disorder control were not efficient; this company stopped the trials. However, there are other clinical studies, like the ones being done by Dr. Pascual in Texas, that are working with triheptanoin. These studies are still going on with hopeful results. Possibly, the set up of these clinical studies is different than the ones for Ultragenyx. So there is still hope regarding the treatment with triheptanoin.
Is there any chance to have tele-health visits available with Glut1 Deficiency specialists and patients?
The first problem about these visits is a legal problem. Doctors don’t like to give advice to patients who they don’t know because of legal problems. Second, if a specialist talks to a patient and the parents without having included the patient’s neurologist, this can generate uncomfortable situations for all the people involved. Dr. Klepper suggests to first reach out to the patient’s neurologist and ask them to contact the Glut1 Deficiency specialist to get some recommendations about treatment.
Do you think most of the Glut1 Deficiency patients experience anxiety? Did you talk about this in the consensus paper?
I think anxiety is a characteristic of Glut1 Deficiency patients. The question is, is the anxiety an effect of Glut1 Deficiency, or is it a secondary effect due to the patient feeling different than others or due to being treated with the ketogenic diet and eating differently than other people. There’s not much information about the psychological and psychiatric problems experienced by Glut1 Deficiency patients, these are things we need to research more.
Glenna informed us that in the next parent zoom meeting in August, the sister of one of our Glut1 Deficiency patients and a homepathic doctor, will be joining us to talk about strategies to handle anxiety.
Which is the ideal level of ketosis?
The consensus is that for Glut1 Deficiency, patients need to reach the maximum level of ketosis they can achieve and tolerate. There is not an absolute value, but we have seen that many Glut1 Deficiency patients have a ketosis threshold, and when those patients go below the minimum level (which is usually 2 mmol/L), they start experiencing problems. If the adult patients cannot maintain at least their minimum level, they don’t feel well. If the ketosis is too high, the patient can start to feel bad due to the acidity of the ketones. They can start vomiting, lose appetite, and that is not good for the patient’s health.
Are there anomalies in the brain of Glut1 Deficiency patients? If that’s the case, can the anomalies change over time?
Magnetic resonance data from Dr. Pascual’s registry has shown anomalies in some areas of the brain of Glut1 Deficiency patients; however, we don’t have enough data to determine whether or not this is present in all Glut1 Deficiency patients. More research needs to be done on this issue.
Are there any situations that can cause Glut1 Deficiency patients to show certain symptoms; for example, change on altitude, when patients are traveling by plane?
I have not seen any studies done regarding brain metabolism during flights. It is known that Glut1 Deficiency patients respond to stressful situations and they can present symptoms. My personal experience is that when some patients fly to visit the hospital where I work, EEGs performed after the trip can be disastrous, however, when we perform an EEG on the next day after their flight their EEG is completely normal. Glut1 Deficiency patients can react to stressful situations like change in their meals schedule or traveling. I think the stress generated by a flight is higher than a change on altitude.
Are there any new diagnostic or treatment tools for Glut1 deficiency?
Yes, there are. There is a group of small molecules that enable the Glucose transporter to work better, and there are other compounds that can help produce more glucose transporters. There is a diagnostic test for red blood cells available in France. We have a team that is evaluating Glut1 Deficiency patients to see if the defect they present is due to a reduction in the number of Glut1 transporters or if the number of Glut1 transporters present is normal, but they are just not working well.
The Consensus Guidelines will be published as a peer-reviewed paper in Epilepsia Open and will be available as open access.
Question and Answers from the Session:
What surprised you most about writing this consensus?
One of the things that surprised me the most was being able to get 23 specialists to agree and write this manuscript. The second thing that surprised me was what we don't know about the condition yet. I'm sure this consensus is the first of many that will come in the future when more is known about the condition. In this manuscript we can become aware of what is known about the condition and what we need to know.
Glenna Steele commented that the Glut1 Deficiency Foundation received a grant from the Chan Zuckerberg Initiative for holding the first scientific conference to bring together researchers to determine what is known about the condition and what we need to do to have better treatments and understand more of the condition. This manuscript will play an important role.
What medicines are recommended for epilepsy in this condition?
There is very little in the literature and few reports regarding which are the ideal medicines to control seizures in patients with Glut1 Deficiency. We do not have a consensus on this aspect. There are no medicines that should never be used. We have in vitro, laboratory data showing that caffeine and theine inhibit the functioning of Glut1. It is recommended that Glut1 Deficiency patients do not take a lot of caffeine or theine.
How much is known about the mutations that cause this condition and what are its effects?
This information requires us to write another manuscript, there are still many things that we do not know. What we know, is we have some mutations that generate a milder condition and others that generate a more severe condition. We also know that there are different sites in the gene that are considered “hot spots,” that is, many patients have mutations in that region of the gene. There are other mutations that are unique and may only be present in one patient. This information is collected in the registry that Dr. Pascual has in Texas. Parents of patients can enter this type of information into the registry.
Are there long-term effects of the ketogenic diet?
This diet is used to treat epilepsy and Glut1 Deficiency, the treatment for the two conditions does not differ. What changes is that for Glut1 Deficiency it is a treatment for life and for this reason we must be more attentive to the long-term effects. We don't have much long-term information. Long-term concerns are effects on growth (which may or may not occur), kidney stones (which can be prevented with high consumption of liquids and other medicines), osteoporosis, and cardiovascular diseases. The information we have does not indicate that this is an effect, but we need more data to be certain of the long-term effects.
Should supplements that are given to patients on the classic keto diet be continued when patients switch to the modified Atkins diet?
Yes, supplements should be continued on the modified Atkins diet.
Are there some foods that patients should definitely not consume?
There is no food that should not be consumed. But it is best to work with dietitains, The Charlie Foundation, Matthew's Friends and learn about the specific food about which you want to have information and they can give you the information.
At what age should Glut1 Deficiency patients be on a certain diet, for example, the classical ketogenic diet versus the modified Atkins diet?
This is a point of controversy. Patients are generally recommended to be on the classic ketogenic diet in childhood when the brain needs more energy. Many times this depends on the level of ketosis. In general, when patients grow older, when they reach puberty, they can switch to the modified Atkins diet. What is ideal, is to keep patients on the version of the diet that gives them greater ketosis.
Should patients who do not have seizures follow a treatment with the ketogenic diet?
If this is the case, the diet should still be used because the diet provides what the brain needs to grow and develop.
Do the Glut1 Deficiency symptoms change over time?
In childhood the predominant symptoms are seizures; in puberty and adulthood the predominant symptoms are paroxysmal movements and PED (exercise-induced paroxysmal movements). The ketogenic diet doesn't seem to help as much to control these movements.
What is the consensus about the treatments there may be in the future?
We need more investigation. One is medicine for the treatment of paroxysmal movements, another is gene therapy. Regarding gene therapy, good results have been obtained in the mouse model, however, there is still a long way to go before we can test these treatments in patients with Glut1 Deficiency. Lastly, there is the possibility of establishing screening in newborns. This would help provide treatment for Glut1 Deficiency as soon as possible, greatly helping the management of symptoms.
On the other hand, studies are also being carried out to evaluate different drugs that have been approved for the treatment of other diseases, and thus determine if they can help in the treatment of Glut1 Deficiency.
Is there a strategy to try to reduce paroxysmal movements?
What we have learned about this from parents is that in addition to the need to rest after these episodes occur, drugs like acetozolamide and L-Dopa have worked in some patients for the treatment of these movements.
Glenna commented that one of the things that some parents discussed last year at the conference and in the adult patient survey is that moderate exercise, with some frequency, improves those types of movements.
What can we do as parents to make our children's transition from pediatric neurologists to adult neurologists a smooth one?
You can inform your adult neurologists about the condition, and interest them to learn about this condition. This way they can evaluate and treat our patients when they become adults. Glenna has informed us that the Glut1 Deficiency Foundation has attended conferences of neurologists and epileptologists, among others, in order to raise awareness and educate medical professionals about Glut1 Deficiency and thus try to approach these neurologists to make an impact on them so that they are interested in treating our patients.
Therapies like language, occupational, are easily offered to patients in childhood, but once they reach adulthood, these therapies are not offered to patients. Does the consensus article say anything about this topic?
We didn’t discuss this subject in the paper because it is not a problem we see all over the world; this is more a problem seen in individual countries and we didn't add it to the consensus. Dr. Klepper agreed that these types of therapies are beneficial for Glut1 Deficiency patients from infancy to adulthood.
Does the consumption of 1-2 grams of sugar have long term effects in Glut1 Deficiency patients?
It doesn’t have long term effects, however, it can affect short term by decreasing ketone levels.
What is the consensus regarding C7 oil (triheptanoin)?
We had high expectations about C7 oil, but the clinical trials performed with triheptanoin (C7 oil) by Ultragenyx regarding seizure control and movement disorder control were not efficient; this company stopped the trials. However, there are other clinical studies, like the ones being done by Dr. Pascual in Texas, that are working with triheptanoin. These studies are still going on with hopeful results. Possibly, the set up of these clinical studies is different than the ones for Ultragenyx. So there is still hope regarding the treatment with triheptanoin.
Is there any chance to have tele-health visits available with Glut1 Deficiency specialists and patients?
The first problem about these visits is a legal problem. Doctors don’t like to give advice to patients who they don’t know because of legal problems. Second, if a specialist talks to a patient and the parents without having included the patient’s neurologist, this can generate uncomfortable situations for all the people involved. Dr. Klepper suggests to first reach out to the patient’s neurologist and ask them to contact the Glut1 Deficiency specialist to get some recommendations about treatment.
Do you think most of the Glut1 Deficiency patients experience anxiety? Did you talk about this in the consensus paper?
I think anxiety is a characteristic of Glut1 Deficiency patients. The question is, is the anxiety an effect of Glut1 Deficiency, or is it a secondary effect due to the patient feeling different than others or due to being treated with the ketogenic diet and eating differently than other people. There’s not much information about the psychological and psychiatric problems experienced by Glut1 Deficiency patients, these are things we need to research more.
Glenna informed us that in the next parent zoom meeting in August, the sister of one of our Glut1 Deficiency patients and a homepathic doctor, will be joining us to talk about strategies to handle anxiety.
Which is the ideal level of ketosis?
The consensus is that for Glut1 Deficiency, patients need to reach the maximum level of ketosis they can achieve and tolerate. There is not an absolute value, but we have seen that many Glut1 Deficiency patients have a ketosis threshold, and when those patients go below the minimum level (which is usually 2 mmol/L), they start experiencing problems. If the adult patients cannot maintain at least their minimum level, they don’t feel well. If the ketosis is too high, the patient can start to feel bad due to the acidity of the ketones. They can start vomiting, lose appetite, and that is not good for the patient’s health.
Are there anomalies in the brain of Glut1 Deficiency patients? If that’s the case, can the anomalies change over time?
Magnetic resonance data from Dr. Pascual’s registry has shown anomalies in some areas of the brain of Glut1 Deficiency patients; however, we don’t have enough data to determine whether or not this is present in all Glut1 Deficiency patients. More research needs to be done on this issue.
Are there any situations that can cause Glut1 Deficiency patients to show certain symptoms; for example, change on altitude, when patients are traveling by plane?
I have not seen any studies done regarding brain metabolism during flights. It is known that Glut1 Deficiency patients respond to stressful situations and they can present symptoms. My personal experience is that when some patients fly to visit the hospital where I work, EEGs performed after the trip can be disastrous, however, when we perform an EEG on the next day after their flight their EEG is completely normal. Glut1 Deficiency patients can react to stressful situations like change in their meals schedule or traveling. I think the stress generated by a flight is higher than a change on altitude.
Are there any new diagnostic or treatment tools for Glut1 deficiency?
Yes, there are. There is a group of small molecules that enable the Glucose transporter to work better, and there are other compounds that can help produce more glucose transporters. There is a diagnostic test for red blood cells available in France. We have a team that is evaluating Glut1 Deficiency patients to see if the defect they present is due to a reduction in the number of Glut1 transporters or if the number of Glut1 transporters present is normal, but they are just not working well.
