Written Q & A from Verhage Lab Research Webinar

11 September 2020

On 11 September 2020, Matthijs Verhage and his team provided an update on their lab’s research. The video is here. They also stayed after to provide written answers to additional audience questions.

Audience Question:
Does STXBP1 dysfunction cause pathology in other body systems? I've read it's involved in exocytosis of insulin from the pancreas, for example

Written Answer from Matthijs Verhage:
You are correct that STXBP1 regulates insulin secretion and many other secretion processes, like adrenalin secretion from the adrenal. We know this from null mutant studies, where BOTH copies of the STXBP1 gene are inactivated. As far as I know, there are no indications that mutations in ONE copy of the gene also lead to pathology. For nerve cells we do know this is the case (giving rise to STXBP1-syndrome)

Audience Question:
Will you be able to include patients in the U.S. in your studies?

Written Answer from Matthijs Verhage:
We would love to. We are talking with Ingo Helbig to make that possible. Please remember such a global scale study requires a lot of funding. Step one is obtain this funding

Audience Question:
Hello, do you have any involvement with clinics in the UK? We would love to be involved. Asking around, there doesn’t seem to be anything happening in the UK

Written Answer from Matthijs Verhage:
We will reach out to people in the UK soon. The person best known in the field of synapse dysfunctions is Kate Baker: kate.baker@mrc-cbu.cam.ac.uk

Audience Question:
Do you need a special EEG protocol for the Inhibition-Excitation analysis or can routine clinical EEG protocol be used?

Written Answer from Simon Houtman:
Excitation-Inhibition balance can be computed for all routine clinical EEG recordings. Important is that the recordings need to be pre-processed and cleaned to remove artifacts (for example eye blinks or muscle movements) before the measure can accurately be applied. Another note is that we compute the measure for seizure-free periods of the EEG.

Audience Question:
Do you think MSG (monosodium glutamate) excites the brain?  My daughter has seizures if she ever has it, wether manufactured or naturally occurring.  It seems to be too much of a coincidence?

Written Answer from Matthijs Verhage:
This is beyond our expertise. We know that gluatamate in the brain excites neurons, but we do not know how glutamate in diet affects glutamate levels in the brain and excitation of neurons. Please ask your clinician

Audience Question:
There are two main isoforms of STXBP1 in the CNS. Do you know which isoform drives the STXBP1 pathology?

Written Answer from Matthijs Verhage:
Very good question! All experiments we have done so far suggest that the two isoforms compensate for each other and both support the same synaptic functions. Virtually all mutations occur in parts of the gene that are present in both isoforms. Hence, so far we have no indications that one is more important than the other. However, there may be differences between mice (that we studied so far) and human nerve cells. Moreover, there may be more than 2 isoforms. We are working on this!

Audience Question:
Must all STXBP1 patients / STXBP1 mutations be examined using cells?

Written Answer from Matthijs Verhage:
No. working with human neurons is still very labor-intensive. We now have enough lines to reach robust conclusions. In the future, I anticipate that we will ask samples from all patients to improve personalized treatment strategies

Audience Question:
Is there any way to include the US patients in your research?  We have skin biopsy and participate in research at CHOP.  We also gave blood work to Simons.  It seems like we should be combining efforts.  Also, thank you all for your hard work

Written Answer from Matthijs Verhage:
Thanks. Yes we are very interested in collaborating with partners in the US. We have good interactions with CHOP (Ingo Helbig). Once we have the study going in EU we will reach out and try to connect.

Audience Question:
Have you studied any patients with an STXBP1 partial duplication?

Written Answer from Matthijs Verhage:
No, we have no experience with that. My prediction would be that partial duplication will not produce (more) functional protein. If you want we can give a more detailed assessment if you send us the exact genetic info

Audience Question:
What is the most effective way for a patient to get involved in your projects? Directly with you or through a partner clinic in another country?

Written Answer from Matthijs Verhage:
I would say: keep in touch with us via the Foundation for now and through a partner clinic once we have a global scale study going

Audience Question:
Are you having success with any drugs in your studies?

Written Answer from Matthijs Verhage:
We have success in suppressing abnormal EEG in animal models with existing drugs like Levetiracetam. Two pharma companies are developing new compounds with our help and new leads hopefully come out of the screen we are doing in flies. But nothing concrete yet

Audience Question:
Is it more helpful for research purposes to have a patient's EEGs since the beginning of diagnosis or the most updated is the most relevant?

Written Answer from Simon Houtman:
Good question, and difficult to answer! We don’t know yet how EEG biomarkers change over time in STXBP1 syndrome. So having EEG recordings for multiple timepoints would be very valuable. But EEG biomarkers can be computed for recordings at all timepoints.

Audience Question:
What specific patterns do you see on EEG?

Written Answer from Simon Houtman:
I am not a clinical neurologist or neurophysiologist, so I can’t comment so well on that. The literature reports EEG abnormalities / spike-wave patterns in many patients and I think around 75-80% of all patients have presented with epilepsy.

Audience Question:
For future EEG'S... Is there anything specific we may ask the technician to focus on, either directly or through the patient’s neurologist?

Written Answer from Simon Houtman:
For the EEG recordings in the clinic the technician does not have to focus on anything specific. So no routines or protocols need to be changed. Important is that the EEG recordings have to be seizure-free for future computation of biomarkers and recordings need to be carried out during the ‘resting-state’, so while the patient is not performing a specific task.

Audience Question:
Hi, thank you for the very interesting presentation and for all of your work! Is the fly assay a high-throughput one? How many compounds can be tested?

Written Answer from Matthjis Verhage:
The library of compounds we were able to buy using the [Million Dollar Bike Ride grant] funding is 2400 compounds. That’s a good start?