Q&A With Dr. John Mitchell

How many GSD patients do you treat and which types?

I currently (see) over 10 patients with GSD. This is a combination of both adult and pediatric patients. For the pediatric patients, I share treatment with my endocrinology colleagues. For the adult patients, I follow these individuals in my adult genetic clinic. We have 5 patients with GSD III, 3 patients with GSD Ia, one patient with Ib, one patient with GSD IX and one with GSD 0.

What are some challenges you face as a doctor in the treatment and management of Glycogen Storage Disease?

With respect to challenges, GSD patients are fairly complex and we have limited resources for management. Admission to hospital for titration or optimization of diet would be ideal but this is not possible in our current health care system. Another big challenge is transition to adult care. We have a good team for management of pediatric patients but finding specialists that are familiar with GSD in the adult world is tough. We have been building this service up since I started seeing adults a few years ago.

Which is optimal, cornstarch or continuous feeds at night?

I currently use cornstarch at night. This is what I was trained to do and I believe that my patients respond well to this. However, there are centers in Canada and other places around the world that use continuous feeds and have good results.

What is meant by the term 'symptomatic carrier'? Do you see this in your practice?

This is a tough question. Genes come in pairs and we receive one member of each gene pair from our mother and the other member from our father. Genes code for proteins in our bodies like the enzyme that is deficient in GSDs. Normally to be affected, you need to receive one non-working gene from each parent. In this case, there will be no gene that is working properly to make enzyme and there will be an inability to break down glycogen to make glucose. The parents are obligate carriers meaning that they have one gene that does not work but the other member of the gene pair is working and this is enough to prevent the glucose problems. Symptomatic carriers refer to an individual that has one genetic change in one of the autosomal genes responsible for glycogen storage BUT also has symptoms related to their inability to break down glucose. I have had this question raised in my practice but I have difficulty accepting this as a mechanism of disease. I wonder if we are missing other DNA changes that are modifying the effects of the enzyme or sugar metabolism.

If my child is going in for surgery, what considerations should be made?

The first thing to do is to make sure that your GSD doctor is aware. This is extremely important as we want to make sure that the operation goes without any hiccups. The treating team will talk with the surgeon and ensure that the risks are minimized. Often a special consult with the anesthetist is necessary to ensure that fasting is managed without undo risk. In this consult, the possible risks will be addressed and solutions will be thought about BEFORE the surgery. There needs to be a clear plan that is written down and provided to the anesthetist and surgeon. Communication is of the utmost importance and if the plan is not clear, the surgery should be delayed.

When a GSD patient is brought to the ER because of the stomach flu, they are usually connected to D10. Often, especially for children, the iv site does not last for more than 24 hours. Under what circumstances would a pic line be considered?

This is dependent on how long the IV solution is going to run. A PIC line is a possible solution for longer hospitalizations but this often requires specialists in radiology to do the procedure. Gastroenteritis often last a short time and more often than not, occur during the night or weekend. The treating team will often not consider this for a short admission. If there are perceived difficulties with IV access or if the admission is projected to be longer, discussion with your treating GSD physician and the treating team should occur early on.

Do GSD type IX patients need cornstarch overnight? What considerations need to be made? Is the cornstarch then life long?

This is another tough question as the genetics of Type IX is complex. The enzyme for GSD IX is made up of 8 subunits that is coded for by 4 genes. Each of the genes can be affected and this can affect how much of the enzyme is made in the body. Depending on the residual level of the enzyme, an individual may be more or less symptomatic. If they have virtually no enzyme, they may be more symptomatic while if they have a higher percentage, they may be less symptomatic. Some patients with GSD IX may only have symptoms when stressed (i.e a gastroenteritis) while others may have daily symptoms. There is no easy answer to the question other than to treat each individual based on their presentation and be as aggressive as needed. One way to decide on therapies is to look at the glucose, liver function, lactate and ketone levels during a fasting challenge. If there are symptomatic hypoglycemia or ketones being produced, cornstarch during the evening is indicated. This may change as the child grows so they may be able to tolerate longer fast later in life. Again vigilance should be increased during times of stress to the body (i.e illness).

Some patients experience delayed growth/height. Will delayed growth/height catch up at some point?

Historically growth has been shown to be poorer in patients with GSD than their unaffected siblings or as compared to the unaffected population. In the past, this has led to significantly decreased end adult height. However, this difference has been decreasing with improved metabolic control and end adult height is approaching the non affected population. in general, patients who are treated aggressively and who have good metabolic control grow well. However, we can not compare all GSD patients together for instance, individuals with GSD Ib may produce antibodies that affect growth. Furthermore, they may have other complications such as inflammatory bowel disease or anemia that may interfere with growth in a way that we would not see in GSD 1a patients. The most important goal is to optimize metabolic control and to give the best opportunity for growth. If there is a deviation from what is expected, ensure that other causes for a delayed growth are also ruled out.

Should GSD patients get the flu shot?

I believe that all my patients should have the flu shot. This is important for patients with metabolic problems that have a limited reserve. The flu can stress patients and cause metabolic derangement.

Do high ketones in the morning mean there was a low overnight? What is the optimal way of keeping them under control?

Monitoring ketones is an important part of management in GSD. This can be done by using dip sticks (urine to measure acetoacetate) or by using a ketone meter (blood to measure betahydroxybutyrate). I prefer blood measurements as it gives a more timely reading. Ketones in the morning may reflect a low glucose during the night but this also may be an early sign of inadequate fuel. The bottom line is that if the ketones are elevated, this is showing that there was an undue stress to the system. This fuel may be inadequate carbohydrate as in GSD I but we may also help to lower the ketone production by providing adequate protein (i.e. GSD III). This should be reviewed with your GSD team.

Will gene therapy for GSD 1a be offered in Canada?  If so, will you be leading it at Montreal Children's Hospital?  Do you have a timeline?  Can you describe what will be involved for each of the patients accepted into the trial?

The gene therapy trial with Ultragenyx is planned on having a site at our institution in Montreal.  We are in the last stages of preparing our site to accept patients for January 2019.  The details for the trial are listed on https://clinicaltrials.gov/ct2/show/NCT03517085?cond=gsd1a&rank=1

I have summarized what I believe is important when reading this document:

* This is a Phase II trial and it only for adults 18 or over.

* Phase II trials are dose finding and safety trials where we are looking for the right dose of the viral vector and trying to ensure that there are no major safety issues. 
* Individuals considering this trial can look at the inclusion and exclusion criteria on the website. 
* As this is a first in human trial, the protocol is fairly heavy with a lot of testing. The main outcome is safety but the secondary outcome is length of fast before going hypoglycemic.  This requires admission to hospital for close monitoring on at least 5 occasions.


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Canadian Association for Glycogen Storage Disease