85 – Further lessons from prospectively deep phenotyping individuals with SYNGAP1-DEE

Jimmy Holder, MD, PhD, Baylor College of Medicine


0:05Dr holder’s an associate professor of Pediatrics and neurology at bayor College of Medicine in Houston he earned

0:10his MD PhD at the University of Texas Southwestern his PhD focused on genetics

0:16and development and he did his residency in Pediatrics and neurology at Baylor College of Medicine and post-doctoral

0:22fellowship in neurogenetics at the University of California San Francisco Dr holder is currently a neurologist at

0:28The Bluebird neurology clinic CLC at at Texas Children’s and Main investigator at the holder Lab at the Jan Duncan

0:35pediatric neurological Research Institute at in Houston the holders

0:40lab’s primary research is in genetic and neurobiological basis of neurodevelopmental and neuros

0:46psychiatric disorders their goal is to discover individualized therapies for neurodevelopmental disorders syap is one

0:53of those main areas of study and using cell-based screens to mass models of

0:58disease to to neurons derived from induced plop poent stem cells their

1:04ipscs of syap 1 patients they try to find genetic modifiers of the protein stability to identify therapeutic entry

1:11points for singap one his lab has also a focus on finding biomarkers and deep

1:17phenotyping investigating particular areas like sensory sleep and

1:22walking patterns of syap one their ultimate goal is to translate the findings from the lab back to the clinic

1:29to improve the quality of life of children with singap 1 Dr holder has

1:36participated apologies Dr Helder has participated in several Paramount Publications in syap and is considered

1:43one of the clinicians and researchers with deep knowledge of the disease he’s extremely compassionate enthusiastic and

1:50kind when seeing his singap patients in his neurology clinic we are truly grateful for the work that he has done

1:55on his interest in singap one a recorded web version of the webinar will be available on the srf

2:01website under webinars by the end of this presentation you will have the opportunity to get the answer to your

2:07questions we’d love to hear from you so please write your questions in the Q&A below and for those of you just joining

2:13us welcome and again our speaker today is Dr Jimmy holder and his presentation is further lessons from perspectively

2:20Deep phenotyping individuals with singap 1 de it’s now my pleasure to turn things

2:26over to Dr holder well thank you so much for that introduction good morning everyone um

2:32the introduction was more than I deserved but I I appreciate it thank you so much um so uh today I’m going to

2:39really focus mostly on phenotypes or symptoms associated with uh patient

2:45mutation patients with mutations in syap one um which is a an area um that I’ve

2:51been interested in um I guess now for over five years um so today I’m really

2:56going to focus on uh two um newer studies um one that was just published

3:02uh in December of last year and the second um that we’re still analyzing the

3:08data we’ve collected all the data we’re still working on analyzing it and hope to um submit that for publication this

3:14year um but I’m going to give you kind of a sneak peek at some of that data um and then at the end I’m going to kind of

3:21wrap up by um just really quickly going through uh some of the previously

3:26published data uh some things that I’ve presented here before but there might be some new um new families that are are

3:33joining us today that haven’t seen some of that uh information um and then of course I’ll be happy to to take your

3:39questions so uh a couple of disclosures I I will talk about some off Lael use

3:44medications very briefly and I’m a site pii for a number of clinical trials so it’s now been over a decade um

3:53since uh mutations in the syap one gene were first identified in three little girls with intellectual disability

4:00um this work was published from jot misho in Canada um and what he found

4:05were three denovo loss of function mutations in the syap one gene

4:11associated with again intellectual disability um since that really Landmark paper uh published in

4:182009 um there have been there were rapidly a number of additional papers broadening the phenotype associated with

4:25simap one mutations um to include epilepsy AU ISM

4:30um and of course uh intellectual disability as being uh Hallmark phenotypes associated with mutations in

4:37this Gene and then in 2020 uh what I really consider a landmark paper published in

4:43cell came out um in which a a group of

4:49uh Labs um collaborated together to try to understand the genetic landscape

4:54associated with autism uh to do this they sequenced over 10,000 um

4:59individuals who had clinical diagnosis of autism and evaluated for denovo loss

5:05of function mutations in genes um that could be causitive um and what they identified were uh really the largest

5:12number of uh genes that had ever been associated with autism but what’s most important for this group is that syap

5:19one uh came out on top as one of the most prevalent prevalently mutated genes

5:24um monogenic forms of autism now mutations in syap one are still relatively rare in this group they found

5:32something around 16 or 18 to nooc of function mutations but among all of these really rare causes monogenic

5:38causes of autism singap is one of the the most prevalent so I’m just briefly going to

5:45uh talk about what singap one does U so singap one the gene en code syap one the

5:51protein um and the very first function that was associated with uh the syap1

5:56protein was at the synapse at this point point of communication between neurons

6:02um this work was pioneered by Rick huganir uh and Mary Kennedy and uh what

6:08they found over a number of Publications and a number of years them as well as others um is that syap works at the

6:17synapse and specifically within the post synaptic density within the part of the

6:22synapse that receives communication from other neurons to regulate other proteins

6:28in particular it acts as an inhibitor for a number of small uh G proteins

6:33among these um one of the most important is the rest protein syap inhibiting Ras

6:40then leads to less activation of R of irk by Ras and that in turn leads to

6:47less insertion of ampire receptors these are glutamate receptors at the synap so what does all of that mean what that

6:54means is that if there are fewer receptors at the synapse then when there

6:59there is excitation of a neuron onto another neuron there is less it requires

7:04more activity for that post synaptic neuron to become active to fire um in

7:11contrast when there is a reduced amount of Sy Gap this leads to overactive rat

7:17as well as other small G proteins overactive irk and then increased ampire

7:24receptor insertion within the postoptic membrane and that makes it just easier for these postoptic neurons to Fire and

7:32so the result overall we think is some of the behavior issues that we see both

7:38in children with mutations in s Gap as well as in mice that have been created and other animal models as well as this

7:44increase excitability probably is the basis for uh the hyper excitability of

7:50neurons and potentially of seizures uh now more recent work and I won’t dive into this um because this is

7:57you’ve had other uh investigators that talk Al about this um but more recent work has shown that Sy Gap actually has

8:03other functions um including in neurogenesis as well as in um early

8:09neuronal differentiation um pioneered by Gavin rumball and others um so I just wanted

8:15to uh give you kind of an overview of the function of Sy Gap at a molecular level I really won’t discuss this uh in

8:22any more detail like I said the focus of this talk is is more on the clinical symptoms and phenotypes associated with

8:28uh mutations Gap so what I’ll talk about today um is

8:33our prospective work to understand the symptoms and phenotypes associated with syat one mutations uh which has been

8:40going on now for about five years and has relied heavily on you the families

8:46uh to participate to help us gain this better understanding so I I really appreciate all of your time and effort

8:52in that I I know how difficult it is to find the time um even for some of our short studies that are just 15 or 20

8:58minutes long so again I really appreciate that uh and then at the end very briefly I’ll talk touch a little

9:04bit on the heterogeneity of clinical phenotypes associated with synap

9:10mutations so a number of years ago we published this figure uh demonstrating the genetic landscape of syap one

9:16mutations um this is certainly outdated at this point I’m not sure a single figure could include all of the

9:22different mutations now that have been identified um but I think this is still useful in that um it demonstrates that

9:30mutations really can occur anywhere in the syap one gene almost um so we most

9:35commonly find uh loss of function mutations or missense mutations um that

9:41cause neurodevelopmental disorder and sort of the middle exons basically

9:46between like exons two or three most commonly three out to 18 uh the singap

9:52gene has 19 total exons and we uh very infrequently or hardly ever find

9:57mutations that cause sort of the plasic uh phenotype associated with syap one mutations in exons one or two or exons

10:0519 um and this is probably for a number of reasons there’s a lot of what’s called alternative splicing or

10:10alternative uh start sites what this all means is that although syap one is a

10:16single Gene it can produce several different types of proteins and so

10:21mutations in the gene that affect all of the different types of proteins are probably more

10:26dilas than mutations that only affect one or two different forms of the syap

10:33one protein but leave the other forms of the syap one protein intact um so that’s

10:38probably at least part of the reason why we we most commonly find these mutations sort of in these middle part in this

10:44middle part of the the syap one gene so as I said um I’m going to focus

10:50really on two studies um that we have completed one that’s already been published um that focuses on

10:58socialization behaviors social behaviors in children and uh in children with syap

11:04one mutations um and then the second is some some further work that we’ve done with regards to sleep in children with

11:11syap one mutations so U really the most comprehensive paper um describing uh the

11:18symptoms and phenotypes associated with SYM mutations uh came out now on number of years ago in neurology from ingred

11:25sheffer’s group in Australia and she um her colleagues um used sort of a

11:31standardized questionnaire um to talk to individuals um really around the world

11:39um who are caring for children and adults with syap one mutations to really dive into what are the phenotypes what

11:45are the symptoms that that you guys see um and so she published really a a very

11:51nice paper describing a number of the phenotypes that are seen and the prevalence of those um shown here is

11:58just one table with some of that data um demonstrating that nearly all um

12:03somewhere around 90 to 95% of individuals with mutations in the syap1 gene have intellectual disability

12:10um of course nearly all um kids with mutations in this Gene are probably around 90% have epilepsy but what I

12:18really want to focus on is this bottom row here where she reported that about half of the kids that they uh for the

12:25families that they interviewed had a clinical diagnosis autism or Autism Spectrum

12:32Disorder so um you know we were interested in this diagnosis of autism

12:37and more broadly in uh social behavior abnormalities in children with um with

12:44syap one mutations um because this work while really wonderful and really laid

12:49out you know what what the phenotypes are that we commonly see with singap one did rely on uh you know Guardian recall

12:58or or a clinical diagnosis of all of these uh all of these phenotypes and so

13:04we wanted to look a little bit more quantitatively and a and more prospectively and in more detail at uh

13:12socialization defects in kids with syat BL mutations and so to do this we used a

13:17tool called the social responsi scale uh Second Edition or srs2 um this is a

13:23standardized tool that’s been used repeatedly in a number of populations including

13:29um individuals with idiopathic autism as well as some other neurodevelopmental neurogenetic disorders um such as

13:36fragile X syndrome as well as philc dermin syndrome which I’ll I’ll come back to in a minute um it’s a relatively

13:42simple uh tool in that it’s just a parent questionnaire um and so we recruited

13:49individuals both from my clinic here in Houston as well as really from around the country again thank uh a big thank

13:57you to all of the uh the caregivers that took time out to uh to talk to our research coordinators and answer our

14:04questions and so I I mentioned that this tool has been used in a number of neurodevelopmental disorders and one of

14:11those where it’s already been used before is in something called phmc dermit syndrome and as you’ll see in the

14:16next few slides um we in my group we very frequently um have compared um kids

14:24or individuals with mutations in the syap one gene with individuals with philom mcder syndrome which is due to

14:30mutation in this Gene called shank 3 so why do we do this um well part of the

14:35reason we do this is the syap one and shank 3 um function uh in a Sim similar

14:42area of the neuron of the principal brain cells um and that is in the

14:48postoptic density um so I’ve already talked um quite a bit about syap one and

14:53its function um in the postoptic density um shank 3 has somewhat of a similar function in that um it works both as a

15:01scaffolding protein in the postoptic density as well as potentially a signaling molecule and in fact shank 3

15:08and syap one is shown over on the right here um are hubs in protein interaction

15:14networks and actually either uh directly or indirectly physically interact with each other uh moreover um sort of

15:22looking at a in a broad sense kids with Phil mcder syndrome and mutations in Sy Gap one have some phenotypes and that

15:29they’re broadly have U almost all have intellectual disability uh about half

15:34have autism um and many have epilepsy so we thought it would be good to compare

15:41um these two um what we call developmental synaptopathies uh two genes that encode proteins that are

15:48really critical for how neurons communicate with each other so um for this SRS uh 2 study um

15:56just show you the demographics here we were um fortunate enough to recruit overall um over a hundred uh families to

16:03participate um in our study um you can see here on the left we had about an even number of males and females um if

16:11you look over on the right um the age of the three groups that we looked at kids with syap one mutations kids with philc

16:18dermin syndrome as well as healthy controls who were siblings um of um kids

16:23either with sin Gap one mutations or failing mcdermit syndrome um the Ages were were similar among the three groups

16:31um the biological sex was similar among the three groups there was no

16:36statistical difference although I will say we had we ended up with a few more uh kids with uh uh a few more uh girls

16:43with syap one mutations than boys um but overall we had a pretty um even number

16:50of um of kids uh of both males and females and a a similar Agee

16:57distribution so what did the data show um so if you focus first over here on

17:03the far left looking at the total score um of kids either with sin Gap one

17:09mutations fail mcder syndrome compared to healthy controls we see that uh kids

17:14in both with both of these neurodevelopmental disorders had um significant social impairments compared

17:20to healthy controls and I’ll show um a little bit more detail about the breakdown of um kids with syap one fail

17:28mcder syndrome in terms of um who scored in the normal range and the severity of score um that they had but but looking

17:36kind of broadly um not surprisingly these kids had significant social impairments um this instrument um can

17:44also um give us some information about different domains of uh social

17:49interactions um and that’s shown in the uh the figures to the right here we can look at Social awareness social

17:55cognition um social communication Etc and what we found from all of these is

18:01that there are significant impairments in all of these domains of socialization in kids with s Gap one mutations

18:07compared to healthy controls and moreover statistically there was really no difference between the kids with Sy

18:14Gap one mutations and the kids with philam mcdermit syndrome so again looking in a bit more

18:20detail here on the lower right side um when we break down the scores based on

18:26What’s um kind of standardly used um in the field for um for scores u in the

18:34srs2 uh for normal range versus those affected what we found for S Gap one is

18:40that only about 10% or so a little bit more than 10% of of these kids um scored

18:45within the normal limits um and I’m going to talk a bit more detail about

18:51that in a slide or two um whereas um about over 80% of the kids um we found

18:57had um definite deficits in socialization and you can see that the majority of those kids had severe

19:03deficits um slightly different in the fic dermin syndrome group that we looked at as well as what’s been published

19:09before um where we saw no kids in our group with uh scores within the normal

19:14limits on this srs2 um scale um and then again the vast majority of these kids um

19:21with fail mcder syndrome had severe deficits at socialization again all of this is very much in contrast to um the

19:28health controls so looking back at uh ingred sheffer’s paper in neurology again I I

19:35mentioned that about half or so of the kids with uh syap1 mutations in her uh

19:41group that she recruited had a clinical diagnosis of Autism Spectrum Disorder so why is there this discrepancy we see

19:48near over 80% of the kids in our group um with social deficits that have singap

19:54one mutations whereas um ing’s Group found about 50% are diagnosed with autism well I think there are

20:01potentially a number of reasons one as I told you earlier um her work is retrospective so it relied on a

20:07physician at some point recognizing that a child potentially had autism and either making a clinical diagnosis just

20:14based on interview and um an exam or or based on some of the standardized instruments that are used clinically um

20:22so if a a child just happened to not have seen a um a clinician that made

20:27that diagnosis that could underestimate the um the prevalence of autism the the

20:32other reason is that autism really requires a number of discret elements in order for that diagnosis to be made

20:39whereas what we’re looking at is really socialization kind of broadly um not really looking at things like um

20:47expressive or receptive language in great detail with this instrument so it’s possible that um some kids with

20:54definite social deficits that we identified through the srs2 uh instrument um just don’t meet all of

21:01the criteria for autism in any case this gives us a better idea that kids with

21:06snap1 mutations that the vast majority do in fact have U social

21:13deficits um we also um looked at the data in a little bit of

21:18a different way um and that is using something called the uh the short form

21:23of the srs2 so this basically um involves excluding some of

21:29the questions in the full form um which was administered to everyone and the reason we um we exclude these questions

21:36is that through previous studies it’s been found that um individuals with intellectual disability that some of the

21:42questions are really hard for parents to answer they’re they’re really just not applicable um and some of you that have

21:48that participated in our study may have found that um and so a previous study published a number of years ago um

21:56evaluated well if we exclude those those questions that are most commonly can’t be answered by um by families um caring

22:04for individuals with um um intellectual disability um can we get a better idea

22:10of of what’s going on and part of the reason of this is if a certain number of questions are excluded we have to end up

22:17throwing out the data Al together because there just isn’t enough data to to really do the analysis um and what we

22:23found when we did this is that in fact we had a number of of uh individuals

22:28with syap one mutations I think it was around eight or nine um that we had to exclude from the um U from the analysis

22:36from the using the full form that we could then most of them include them again when we use the short form um and

22:43so overall um for this what we found was very similar which is the kids with sgap

22:48one mutations as well as kids with phom dermis syndrome um have significant

22:54social deficits using the short form um as well as the long form I think more uh

23:00kind of to the point and thinking about this tool is potentially um uh something

23:06that could be used as as an endpoint for future clinical trials probably the short form would be a better tool

23:12overall um for our kids with synap one mutations so next uh you know we were

23:18interested um and and I’ll be honest this actually came up because when we submitted this paper a reviewer asked us

23:24this question um is there any um change or is there any difference in

23:31those individuals with who are a bit older in their srs2 scores compared to

23:37to younger individuals and and my first inclination was well probably not there’s probably not going to be much of

23:43a difference um and uh when we looked at this in a bit more detail in the

23:49literature um this one paper uh came uh came out that we we took a look at which

23:55showed actually in uh idiopathic iic autism so in all comers all children uh

24:01individuals you can find with autism that you uh administer this SRS to uh instrument to you actually have a

24:08reduction in their score so their autism symptoms uh potentially seem to get better um as they get older and there

24:15can be a number of reasons for this um you know one obvious one is that many of these individuals may have had therapies

24:22throughout the years and uh developed uh mechanisms to cope with some of the symptoms that they have

24:28associated with autism um so their scores potentially improve over time um

24:34so we we looked at um scores in our sgap

24:39one kids as well as phom mcder syndrome kids and healthy controls and correlated

24:44those with uh with age at time at the time that we administered um this instrument and actually we found

24:50something really surprising um which is that um in general um the the total

24:56score on the srs2 seems to get quite a bit worse um as kids and older kids with s

25:03Gap one uh and adults compared to the younger kids with syap one mutations and

25:09this is in you know really stark contrast to the kids with ph mcder syndrome where we saw absolutely no

25:16difference at different age groups no correlation between uh total score and age and this is both as you can see on

25:24the full SRS uh two form as well as on the short form and then of course healthy controls also there’s no

25:30correlation between age and um and and total score on the srs2 so um this was really surprising to

25:38us and um you know I at this point I I have some hypothesis about why that

25:45might be but I’m not really going to share those because I have no data yet um to really address this um but uh

25:52something that I think we and others really need to look at um I’ll just point out that if you recall from a few

25:58slides ago I said that four kids um scored within the normal range on the uh

26:03with sing one mutation scored in the normal range on the srs2 instrument and those kids are all very young so if you

26:09look at this upper left graph you can see those kids are um there on the far left at the younger

26:17ages all right so I’m going to change gears now and talk uh move from talking about socialization in kids with syap

26:24mutations to talking about sleep um so again in this really Landmark paper from in she uh ingred

26:31sheffer’s group um she looked um again at a number of phenotypes associated

26:36with some1 mutations and one of the ones that of course she looked at were were sleep problems um and what she found in

26:42this paper um was that about 60% or so of individuals that they um or families

26:49that they had interviewed uh reported some sort of sleep problem and this could be you know a lot of different things this could be difficulty

26:55initiating sleep difficulty in maintaining sleep um anxiety associated

27:01with sleep Etc um so all different you know types of uh issues with sleep um

27:06she found about 60% um had issues so how can we in a more sort of

27:14prospective quantitative way um address these sleep issues in kids with syap one

27:20mutations so I’m just going to outline here a few approaches that that one could potentially

27:25take um and this includes really what I would say are three General approaches

27:31uh One is using sleep questionnaires um so the prime example of that is the childhood sleep habits questionnaire um

27:38and I’ll talk about some data that we and uh some of my collaborators Connie Smith Hicks in Andrew Stanfield um that

27:47we published together um using this instrument this questionnaire instrument to investigate sleep in kids with syap

27:53one mutations uh some of the reasons to use this some of the probes for this is that

27:58it’s really pretty easy to administer um those of you that participated with one of our groups you’ll recall it just

28:04takes about 15 or 20 minutes um to answer this questionnaire which can be done either in person um can be done

28:11just by the parent you can you know we opted to have a research coordinator call all of our um all of our

28:19participant families um or in person uh to administer it and it’s inexpensive so

28:25it’s relatively easy to administer to a large number of individuals uh some of

28:31the cons it does rely on caregiver recall um so you know there can be

28:36potentially at least some bias there associated with that uh Second approach is

28:42actigraphy um example of this is something called active watch um this and I’ll show you a little bit more

28:48detail about this in a minute again a number of you have probably participated with us on on this project so again

28:54really appreciate that and I will be showing you some data from that we’ve collected uh from this um moderately

29:01easy to administer um you can get objective data from this um some of the

29:08cons it does require uh the participant to tolerate the device which is

29:13basically looks like a smartwatch um and turned out to be a significant problem um in our kids with

29:19s Gap one is all just really briefly mention um you know these kids have um

29:25significant sensory processing ISS issues and significant issues with sensory tolerance and so that ended up

29:32leading to a number of kids having to be excluded because they basically just could not wear the watch um and then

29:39it’s quite a bit longer um to collect data for this instead of 15 to 20 minutes this usually requires one to two

29:44weeks of continuous data collection although for those kids that tolerate it you just put the watch on and then let

29:50them go about their their normal daily activities and then the Final Approach

29:55um which is probably the most qu quanitative most objective of all and you get the most data from is polysomnography or or sleep studies um

30:03if uh any of your kids have had these um you know this involves going into usually going into a sleep lab uh sort

30:11of this foreign environment that’s not you know the typical home environment having a lot of uh leads plays having a

30:18respiratory activity recorded all through the night um one of one of the

30:23advantages of this though is that you do get a lot of information about sleep and a lot of the information about the brain

30:30activity the different stages of sleep um that an individual has I’ll show a

30:36little bit of data that we’ve collected in that regard uh the cons of this definitely requires a lot of Tolerance

30:42having these leads Place being in this foreign environment um and this is of course is a very expensive approach

30:48especially you know from a kind of a clinical research uh perspective all right so uh a question

30:57theirs um we we published again a study um I guess now A couple of years ago um

31:03using the cshq um as I mentioned it involv for us it involved a research coordinator

31:09either talking in person or by phone um giving the questionnaire and involved uh

31:15something around 35 questions or so um so what did we find so we found that um

31:21kids with s Gap 1 mutations um have uh significant sleep issues so on on this

31:28scale looking at the total score any score above 41 is considered to to indicate significant sleep abnormalties

31:35and nearly all the kids with syap one mutations um had um significant sleep

31:41abnormalities we again compared uh to kids with failing dermid syndrome as well as healthy control siblings um and

31:48not surprisingly or syap one kids um were had were much more likely to have

31:54abnormalities in sleep than healthy controls uh interestingly for this study

31:59we found that kids with synap 1 mutations tend to have more severe uh

32:06scores on the cshq than kids with fomic dermit syndrome and I’ll get into a bit more detail about that um in a minute

32:14again with this questionnaire we can break down um the Sleep abnormalities into different domains such as bedtime

32:21resistance uh sleep anxiety sleep onset delay and night Awakenings again found

32:26that for all of these domains kids with s Gap one mutations have significant issues U but again interestingly for

32:33many of these um we saw a difference um between kids with syat one

32:38mutations and kids with philc dermin syndrome in general for most of the domains kids with syap 1 mutations seem

32:44to have more severe uh sleep issues than those with philonic dermid syndrome U

32:49and again there’s kind of rounding that out uh looking at parasomnia daytime sleeping sleepiness sleep disordered

32:56breathing which you can sort of think of as sleep apnea and sleep duration again

33:01significant abnormalities in our kids with with syap one mutations so why do kids with syat one

33:08mutations have more issues with sleep than kids with a similar disorder Phil

33:13mcder syndrome who very I see these kids clinically and and parents very frequently come to me with with sleep

33:20issues so we looked at this in a bit more detail and again looking at whether age was a factor um and it turns out it

33:27looks like age is a factor more so for phc dermid syndrome than for syap one um

33:33in that um kids with looking at total score of kids under 11 years of age um

33:40we saw significant abnormality still in the kids with s Gap one mutations but did not see a significant difference

33:47between uh healthy controls in kids with phc dermin syndrome in this young uh age

33:53group um and this is in contrast to the older kids 11 years and older where we

33:58see significant abnormalities both in syap 1 kids with syap 1 mutations and

34:04kids with fomic derin syndrome um and we saw some other differences um overall in

34:11some of the different sleep uh domains uh such as sleep onset delay where at

34:16least statistically we saw no significant difference in the S Gap one kids or the fail mcder syndromes with

34:22the healthy controls but then when we looked at the kids 11 years and older so this is again around puberty or so um

34:29both the kids with syap one mutations and with Phil mcder syndrome had significant issues with sleep on

34:35set all right so I’m going to turn now to um the second study that we embarked

34:40on which is to use actigraphy to get a little bit more objective and again quantitative data regarding sleep um so

34:48again uh looking at this middle panel here this involved uh uh kids wearing a smartwatch that records really movement

34:55um so these smartwatch es have a um have an accelerometer so that we can uh

35:02record movement um so when kids are awake and active obviously we see a lot of movement um when kids are are asleep

35:09we see much less movement and that’s how the uh algorithm that looks at this data breaks down whether someone’s awake or

35:15asleep and so the type of data that we get is shown here on the right um where you see all these squiggly lines yellow

35:22lines blue uh blue lines black lines this is the time of day where there’s a

35:27lot of activity and the lights on um and the kids’s awake um as compare that to

35:33sort of the teal um blocked area uh which is where you know the computer

35:38algorithm is saying that the kid is asleep and that’s because there’s a little activity usually the lights are

35:44out during this period um so you can see it can differentiate those two um

35:49wakefulness and sleep and so really early on it looked like there was uh going to be something

35:56really really interesting interesting and different between uh between sinap one kids and sibling healthy controls

36:01based on actigraphy and that’s really sort of Illustrated here um where if you look at the time this child is asleep

36:09during a onewe period on the left singap one patient you can see that the amount

36:15of time that there is sleep really varies dramatically from day to day there’s a lot of variability and this is

36:21in contrast to the healthy sibling where you can see while there is some variability it doesn’t seem be nearly as

36:28much um and so for for this pair of patients if you look at the quantitative

36:33data and I’ll have you focus kind of on that middle column there with Total Sleep time you can see that if you look

36:39at the average the average actually is not much different between the syap one patient and the uh healthy control

36:47sibling but then the minimum amount of time a sleep in the syap one patient

36:52compared to the healthy siblings significantly different as is the maximum amount of sleep so at least for

36:57this pair there was a big difference between uh minimum amount of time and maximum amount of time of sleep during

37:04that the during the twoe reporting period whereas the average ended up being exactly the same so this looked

37:11really promising at first um and but then we’ve collected data um from a

37:16fairly good number of kids with synap 1 mutations and healthy controls we took a lot of pains to make sure I’m not going

37:23to show this um but to really age map and match based on biological sex so

37:29that those weren’t uh variables that were very different and could skew the data um and so when we uh you know were

37:36able to collect uh um enough individuals we analyzed the data and what we found

37:42was actually um kind of disappointing and that is the looking at all of the different variables um total time in bed

37:48total time of sleep the latency uh from time to go to bed till sleep initiated

37:55uh sleep efficient wakefulness after sleep um and number of wakenings none of these were

38:01significantly different between our syap one kids and healthy controls um and this was really

38:07surprising because for all of these kids we also had data from the Sleep uh sleep

38:13um habit questionnaire and what we found is looking at the um correlating data from

38:21the cshq we see we saw in this in these same kids very significant differences

38:27in in things like sleep duration in bedtime resistance Etc um so I I did mention that you know

38:34one of the the factors here might be that some of these variables there might not be a difference in the mean amount

38:41of time um for example that there is sleep but the variability could be greater um and that does turn out to be

38:48the case we do see a greater amount of variability in our kids with Sim Gap one mutations compared to healthy controls

38:55and uh you know you know in many of the the variables that we looked at uh but then you know overall we really did not

39:02see a statistically significant difference between the kids with syat one mutations and healthy controls so um

39:09again why is this um you know like I said some of it could be that the while there’s more variability that you know

39:16in the end the Sleep need is the same um I I tend to think that’s probably not

39:21entirely true because you know definitely what uh you know you the parents tell me about um your kids’s

39:27sleep would would suggest otherwise and then you know the data we collected from the cshq would also argue otherwise so you

39:35know we’re still trying to to to work through why this might be I think part of it may just be the technology um just

39:41is not great for our kids with uh neurodevelopmental disorders um this

39:46system has been used in other neurodevelopmental disorders and a lot of that data has never been published

39:52because uh people find the same thing which that which is that you know there’s not a lot of robust data with

39:58the act graphy or robust differences um in with the ACT graphy compared to

40:04various neurodevelopmental disorders and um and healthy controls um so we’re

40:10still sifting through the data a bit but um overall this is kind of the the first line of of findings that we had from

40:16this so as I mentioned before um the third uh approach to looking at sleeping

40:21kids with uh neurodevelopmental disorders is sleep studies or poly sonography um again this involves um you

40:29know going to a sleep lab usually occasionally can be done at home um and having kids you know have electrodes

40:36placed um a few electrodes placed um on the head as well as some respiratory

40:42monitors again can potentially be very difficult for our kids with s Gap 1 mutations to tolerate this but we can

40:48get very good data uh not just you know some of the parameters I talked about before sleeping waking uh but also look

40:55at more detail at um the different stages of sleep um in kids with

41:01neurodevelopmental disorders compared to healthy individuals and for this we really just have some very preliminary

41:07data but um you know already emerging some interesting findings um I’m not

41:12going to go through all of this but um these are all kids with s Gap one mutations who had uh sleep studies uh

41:18for clinical reasons so you know it’s one caveat to this is all these kids um are known to have sleep issues and so

41:26that’s the reason they were referred for sleep study but nevertheless when when looking at this data a couple things

41:31popped out one is that it seems that sleep efficiency uh can be significantly reduced in these kids so what is sleep

41:38efficiency that’s basically uh once kids go to bed you know how much of the time that they’re spending in bed are they

41:44spending asleep and for neurotypical kids we expect this to be around you know 85 90% And we saw for for a number

41:52of kids where we had sleep study reports significantly reduced sleep efficiency really in the 60 uh percent range which

42:00is very very low uh compared to you know what we expect and then the other thing

42:05that that I found to be very interesting is the percentage of time that spend in REM sleep so REM sleep is a part of

42:11sleep that’s really important uh especially for learning in memory um it’s been found that um having a healthy

42:18amount of Rim sleep is important for um any individual to um um to to develop

42:24new memories and normal for uh for kids or adults is somewhere around 20 to 25%

42:30of the time that they’re asleep they spend in this Rim State um what we saw in the small number of kids um with s

42:37one mutations that a lot of them have a significant reduction in time they spend

42:42in Rim sleep in in fact some of them had very very little Rim sleep down to like two to 4 per. um and you know the reason

42:49for this is not clear although I I will say there in in other disorders there is some correlation between um uh between

42:58epilepsy and reduction in U in REM sleep which may play a role here um but uh you

43:05know what we can definitely say is that um you know with a significant reduction this could lead to impairments in

43:12ability of these kids contribute to ability of these kids to um have difficulty developing new memories and

43:20learning all right so that’s um really all of the new data that I’m going to show today um I have just about maybe 10

43:27minutes left so I’m going to just rapidly go through uh some of the studies that we published before again

43:33this is mostly just as a reminder um but also um for for any new families that

43:40have not heard me talk before uh so one of the earliest studies we did published in 2019 was looking at development in

43:46kids with syat one mutations um and what we found from this early study is that

43:52kids with SYM mutations really have issues with um uh with uh developmental progression

44:00really in all domains of development so shown here are some key Milestones that that kids um go through during

44:06development including first word spoken time uh sitting uned time walking uned

44:13uh scribbling um and using utensils and for all of these um um Milestones which

44:19represent gross motor fine motor language development we saw significant delays um looking at this a bit more

44:26quantitatively um our kids with syat one mutations have uh delays that persist um

44:32through development in gross motor um acquisition of skills um they do uh

44:38continue to learn continue to develop um which is why I always encourage all of my families as much as possible as much

44:44as they can tolerate as much as insurance will allow um to continue in physical therapy occupational therapy

44:51speech therapy all of these therapies you know through much of the certainly early development but really potentially

44:58through much of the lifetime can help with acquiring new skills um and although our our kids with s at one

45:03mutations again acquire these skills much more slowly than neurotypical kids they do continue to acquire these skills

45:10um and this is true again for gross motor development fine motor development as well as language development um looking specifically at

45:17language development we do see um probably for this developmental domain more than uh more than any other um

45:23quite a bit of scatter at least um in in the um in early developmental stages um

45:30where you can see on average like at 50 months of age um the um these kids have

45:36um skills at around 20 months of age but then you see a lot of scatter where where some kids are are nearly um at at

45:43a neurotypical um level and you know one question that we’ve wondered about is

45:49why is this you know and there could be a number of reasons but one could be that there’s something about the uh type

45:55of mutation or where a mutation is in the Sy Gap 1 Gene um and its correlation

46:00with developmental progression um and we potentially see um uh something

46:06interesting with in the in the kids um that we identified um have a bit higher

46:14developmental acquisition in language and that is um you know some of them have either missense mutations which may

46:20not fully um render the the mutated Al completely

46:26um um um deficient or we have very

46:31mutations very early in the syap oneing such as this kid with the mutation at position 52 uh which probably only

46:39affects a subset of isoforms of the protein um so kids with uh so at least

46:44some rare kids with mutations like this might have um slightly different developmental progressions than those

46:50kids with the more classic complete loss of function uh mutations kind of in the middle the

46:57gene uh we also looked at seizures in some detail and I I think most in this

47:02group kind of appreciate that uh it seems like the most common seizure type or these atypical absance or uh

47:09frequently referred to as absance with eyelid miconia uh but we all we see a wide variety of different types of

47:15seizures including more classic um uh tonic clonic generalized ton clonic

47:21seizures or you might refer to them referred to as Grand Mall seizures we also see some seizures atonic seizures

47:28appear to be relatively frequent U myoclonic seizures um relatively

47:33frequent um uh this is a little bit of older data um I do have one child now

47:38with a syap one mutation who did have infantile spasms which are kind of really early um relatively

47:45severe seizures but that seems to U not be terribly common at least in kids with

47:51snapon mutations um we also looked at medications used in these kids and at

47:57least retrospectively whether they’re efficacious and found a few medicines that seem to be a little bit more

48:03efficacious than others including valproic acid lamotrin as well as gloam

48:08and these are some medicines I use fairly commonly in these kids um and then some medicines that really seem to

48:14not work very well at all either they don’t improve seizures or they’re not really well tolerated and this includes

48:20what are called sodium Channel Inhibitors such as oxaras aene um um as

48:26well aside and rfamide um parmel is interesting um there are some sort of

48:33case studies published suggesting that maybe lowd dose pronel helps with not seizures but some other aspects of s Gap

48:40one phenotypes um at least for seizures uh We’ve not had a lot of success with

48:46with parmo and then we move on to uh EEG abnormalities so probably most if not

48:53all of your kids at some point have had an EEG G um you know this involves placing electrodes on the scalp um and

49:00then um reporting electrical activity um and shown here on the right is sort of

49:05the type of graph that neurophysiologists get and what they interpret um and looking again this was

49:12a few years ago now but has really held up over time kids with synap one mutations they tend to have what are

49:19called inal abdali most commonly in the oipal lobe uh these inal abdal ities are

49:27neurophysiologic abnormalities that are not associated with seizures meaning the child is not having a clinical seizure

49:33at that time um but we can still see um electrical abnormalities by EEG um and

49:39again the most common type that we see is in the back of the head which is the occipital region of the brain um don’t

49:45know why um kids with s Gap one have this pattern um this is not something we see in all neurodevelopmental disorders

49:52or even most neurodevelopmental disorders but does seem to be fairly specific for uh singap 1 kids um just

49:59showing you a couple of eegs here this is an EEG from a kid that was having an

50:05ATP gapson seizure with eyelid myoclonia and you can see kind of on the left side

50:10of the graph see a lot of really tight squiggly lines then suddenly U you know

50:16these really high amplitude really broad um waveforms that indicate an

50:22abnormality associated with seizure um and then again I’m not going to

50:28belabor this point but we we very frequently see uh abnormalities in the uh posterior part of the brain the

50:33occipital part of the brain even in children with s Gap one that are not having a clinical seizure um we see

50:41these abnormalities and then uh Behavior abnormalities we see very frequently in these kids I’m not going to go into a

50:47lot of detail about this but um the types of activity uh abnormalities that we see include hyperactivity uh

50:53self-injurious Behavior aggressive behaviors seem to be very very common in these kids and I work with a lot of of

51:01the parents that bring their kids to me uh on this uh pain tolerance is high

51:06pain tolerance is very common then many of these kids are on medications and on the right here are some of the medicines

51:12that we commonly prescribe um I’ll I’ll just briefly mention that it seems like

51:17although these kids are hyperactive um those kids that I’ve seen where stimulant medications have been

51:22tried these are like Focalin rlin these sorts of medicines very rarely see much

51:28improvement and very often see a lot of uh worsening of behavior so I I tend to stay away from those and use other

51:35options um and then sensory processing um this is uh data from Gavin rumball

51:41group showing that mice that are deficient for S Gap one have a lot of sensory processing issues uh and so we

51:48looked at this in kids with s Gap one mutations um I’m not going to go into all of the details of this but just

51:54suffice to say say that we see a lot of um abnormalities in sensory processing in our kids with uh syat one mutations

52:02and very comparable to those kids with fomic dermid syndrome um and looking at kind of in

52:09detail at the types of sensory abnormalities that these kids have can sort of broadly think of uh sensory

52:14abnormalities as being either kids that have a lot of seeking behaviors that is they seek out a lot of sensory input or

52:21they tend to avoid sensory input um for uh family mcder syndrome we kind of see

52:27both um we have some kids that have both sensory seeking and sensory avoiding

52:32behaviors we have some kids that just have avoiding behaviors and some kids that just have seeking behaviors

52:38actually quite a few kids that with fail MC Derm syndrome that just have seeking behaviors this is in contrast to our

52:43syap one kids which are a bit who are a bit different um in that a lot of them have both seeking and avoiding behaviors

52:50but very few of them have just seeking behaviors and very small number and then

52:56only a few have only avoiding Behavior so they seem to have both types of sensory

53:02abnormalities sensory uh seeking and sensory uh avoiding and then very

53:07quickly I’m going to talk about a gate study that we’ve had ongoing for a while now um we’re using a number of really

53:15objective um um ways to analyze gate uh again I’ve talked about this before so

53:21I’m not going to go into a lot of detail because of time but basically we can use what’s a called a motion capture system

53:28to look at joints and Joint angles and stride stride length stride time Etc um

53:35this does require kids to tolerate putting on this uh suit where we can attach these reflective

53:42monitors uh or reflector uh yeah reflective reflectors um at various

53:47joints and various parts of the body usually we restrict it to the lower extremities um then we then have kids

53:53walk either um over a carpet which can also measure um some activity like stride again stride length and time as

54:01well as force of of strides or we have them walk on a treadmill um so that um we can use these

54:08um this motion capture system to measure look at gay P males U and this is the

54:14kind of data that we can collect um so although they’re are cameras they actually only record the reflective um

54:21balls that are again placed on joints or on uh on surfaces of extremities um you

54:28can see at the bottom there that’s sort of some of the raw data that we get um we’ve published one paper looking at one

54:33individual with syap one mutation compared to a neurotypical control and did see some significant abnormalities

54:40um that primarily involve differences in symmetry um so um especially at at the

54:47ankle um there should be a significant amount of symmetry between the left and right side and we saw that um in the

54:55neurotypical control whereas our individual with syap one mutation had a

55:00high degree of asymmetry um which ends up uh other than you know causing a lot of instability also leads to a greater

55:08amount of energy expenditure um because of having to to rebalance with so much

55:13with each step um and so we’re we’re now we’ve expanded we’ve recorded um data

55:19from eight individuals with s one mutations hoping to report from two more to kind of collect a one data

55:25preliminary data set to analyze and um and be able to say something bit more broadly about um gate issues in kids

55:33with synap mutations so to just summarize what I’ve talked about today I just briefly uh

55:40discuss the what singap one is and that mutations in syap one are are one one of

55:46the most common monogenic causes of autism uh but kids with syat one

55:51mutations don’t just have autism they have really a complex neurodevelopment disorder associated with sleep

55:57disturbances abdali and socialization really delay in all developmental domains um also very

56:04commonly with seizures characteristic EG abnormalities also have sensory processing abnormalities as well as gate

56:10abnormalities that we’re looking at now in more detail so a number of people uh

56:15to thank um a lot of people that I’ve worked with here at Texas Children’s in Baylor College of Medicine um we work

56:22with the University of of Houston and Charles Lane there for the gate study uh

56:27thanking my collaborators Connie Smith Hicks and Andy Stanfield who’ve been really key um for the the sleep study

56:33that we that I talked about and then of course all of you who’ve participated um in our in our work and and helped us get

56:40the the work done uh through various mechanisms like funding Etc I really appreciate all of you and and working

56:48with me you know our goal is to um with all of this work is to develop those endpoints that can be used for future

56:54clinical trials um and then talk about the work that we’re doing in the lab related to you know molecular

57:01understanding of uh how mutations in s Gap One affect brain activity or um

57:07potential mechanisms for treatment um which we’re working on and number of really nice uh papers have come out

57:13recently um with some potentially new approaches um so I think there are good things on the horizon um for S Gap one

57:20and hopefully some of the work that that we’ve done here uh can Aid us and um in

57:26developing those clinical trials in the future so thank you very

57:37much I guess I’ll take questions if there are any yeah thank you Dr holder we’re gonna hand it over to

57:44Katherine thank you so much Dr holder what a what a tour to force that was a

57:49lot of um different uh a lot of data within different um

57:56domains so thank you for that um I want to encourage people in the webinar to

58:02either put your yeah to put your questions in the Q&A and um pardon me uh I I’ll just read

58:11off the first one here or there’s only one right now in the Q&A I I have a lot of questions but since I can go on I’m

58:17going to ask what Erin’s question is first um when you’re looking at the Sleep uh could differences

58:26uh you know things being different than you expect could that be impacted by supplements like melatonin and stuff is

58:32are you because we our kids have such a hard time sleeping that we do everything we can to try to get them to sleep yeah

58:40excellent question and absolutely um we we did um you know record um whether

58:48sleep supplements or medications to help with sleep um are being taken um

58:55but what I would say is um you know even with that with the cshq you know a lot of those kids were taking those

59:01supplements and still had a lot of sleep issues um so we still see that whereas

59:06in actigraphy we did not see that and again you know same kids using the same two instruments saw different results so

59:14you know I think um it’s a good question and very on point that that can

59:19absolutely impact um you know any study looking at sleep but um you know

59:25specifically for you know those two approaches to to looking at sleep um I

59:30think there’s a little bit more going on and probably just you know the technology um that we used is not good

59:36enough to really capture those those symptoms yeah I while you’re talking about that I want to ask um with the

59:45actigraphy did were there any was there any ability to look at heart rate yeah um no um although I said they

59:53kind of look like smart watches actually they kind of look like dumb SmartWatches yeah but like my Fitbit

59:58tells me like I have a Fitbit right and so that that gives me some information I think it’s based mostly on heart rate

1:00:04yeah yeah these are are really old devices um I mean they were new when we bought them but they were developed a

1:00:11long time ago and so they really can only measure activity and light they do

1:00:16measure you know whe whether light’s on or off but they did not measure heart rate oh interesting they measure light

1:00:21okay um that’s not one I would have thought of um okay well I uh Megan in the chat says

1:00:30are there any strategies to help with the Sleep um sure so um strategies I guess

1:00:38that I use kind of clinically is what she’s asking um so as you said um I also

1:00:44try everything um uh certainly you know to begin with I

1:00:49I try melatonin um which rarely alone really help helps um kids with syap

1:00:57occasionally the younger kids will respond well enough to to melatonin um

1:01:02uh but then um you know after that um there are some other classes of medicines um so things like clonidine uh

1:01:10can sometimes help especially with sleep initiation um and then some of the kids that I see clinically uh use Trazodone

1:01:18um which is an SSRI that um you know developed initially um as for depression

1:01:25doesn’t actually work well at all for depression but has the side effect of making people really sleepy sometimes so

1:01:30I I try that as well um but as you said I mean some some of these kids you know

1:01:37will respond great to those medicines and some don’t respond well at all so

1:01:42but those are things I try of course I also encourage parents you know keep lights you know turn the lights out you

1:01:48know an hour before you want your kids to go to sleep don’t let them have devices and things like that um but

1:01:53these kids um really have pretty severe sleep issues sometimes yeah I just want to um put my

1:02:01own two sense in there um I don’t know how old Megan’s child is but when my

1:02:07child was very my child’s 22 now and he sleeps much better than before but when he was young like he could he wouldn’t

1:02:14nap like as a as a newborn he wouldn’t really nap he’ barely sleep um it was it was really strange and he didn’t even

1:02:20change his day night cycle like most newborns do um it was months before he

1:02:26before he um even really slept at night and uh I think that was a sensory thing

1:02:31like I think he was kind of shut down during the day but then he’d be awake at night because there was less going on I

1:02:37think he could handle it better but um I just wanted to say that uh early on he

1:02:43would um I I’ve I’ve read and heard that toddlers uh they get kind of get nervous

1:02:49when they start feeling sleepy and so they start kind of running around to wake themselves up and so

1:02:55what I wouldn’t say this worked for me but what I did was I would um just sit next to his bed and just keep telling

1:03:00him to lay down and so like every 10 to 90 seconds he he’d start lifting his

1:03:06head and I’d say lay down and he’d put his head down again we could do that for an hour or two I mean it’s it’s in it’s

1:03:12it’s a long kind of boring time but it’s interesting to try to not be interacting but also telling him to lay down and he

1:03:18would and then eventually he’d get tired and he’d start kind of like rubbing his hands and then he he’ go to sleep

1:03:25another thing was that he really had to have a light on and so I took all the lights out of his room and I put a 20 W

1:03:32bulb in the ceiling lamp and so and I kind of like reduced the amount of light

1:03:37so he had very little light in his room because he he would jump out from bed and turn that on like he had to have

1:03:43that on so I just want to say that anytime you have something like that is to kind of recreate the environment so

1:03:50that the thing they are trying to change is already changed for them so those are

1:03:58my that’s my advice okay so um let’s see with sleep I also wanted

1:04:06to ask um with I wonder if there’s a way to

1:04:11have like a a mattress pad with a sensor in it that sort of shows movement and it wouldn’t just show movement it would

1:04:17show like how much of the bed they were moving on right because I I wonder if

1:04:22like distance moved would be um and then like not in bed at all right like the

1:04:28sensors could tell you that so I wonder if that is something that would help and then um let me see what was

1:04:37my yeah so I’ll I’ll just answer that um there there are instruments uh that have

1:04:43now been developed that that do exactly what you’re saying that you place them under the sheet um so instead of you

1:04:49know having something on your wrist measuring activity it’s in just in bed you know how how much time is spent uh

1:04:56moving in bed versus not and you know calculate sleep from that so we we did

1:05:02not use those yeah yeah that might be good yeah I’m just thinking because I don’t think the actigraphy is ever

1:05:09gonna uh get good enough with our kids sensory unless you had like an entire sleeve like if you had the entire like I

1:05:17putting a watch on is never ever going to work for my child like he can’t put a he can’t put a bracelet on for being in

1:05:22the hospital right like they like pin it to his clothes on the back because it’s he won’t he just he can’t do it and so

1:05:29um it’s like having s having but I think that what that means is that feeling this part being different from this part

1:05:36is not okay right and so if it was a whole sleeve that had some sort of you

1:05:41know like if you’re using compression garments and have like sort of a whole feel so you’re not really feeling the difference I think that would that would

1:05:48be a way to work it out although that’s not the same as just going to Best Buy and buying a smartwatch or buying a fit

1:05:54or something right um okay let’s go to um

1:06:03Marta Dr Marta de Marta do you w to um get on

1:06:09the call or do you want to be well actually I don’t know how to unmute you so I’ll just say it she says

1:06:16thank you so much for the great presentation based on your clinical experience what therapy do you find more valuable for behaviors and autism in

1:06:23singap p paat yeah great question um so you know

1:06:29certainly um one of the first line therapies we recommend is Aba therapy

1:06:35for our kids with um um with autism in singap one I I will say um you know this

1:06:43is a challenge I’m sure many people here have had um I talked to during my

1:06:49presentation that only about half or so of kids with singap one mutations are actually Clinic diagnosed with autism um

1:06:56I think that’s probably a bit of an underestimate but they’re definitely kids with syap one that do do not

1:07:01manifest um all of the phenotypes necessary for an Autism diagnosis that doesn’t mean ABA therapy excuse me would

1:07:09would not be beneficial apologize um ABA therapy was actually

1:07:14developed for uh kids with intellectual disability at Kennedy creger was not developed initially for autism um and it

1:07:21was demonstrated to to work or to overall lead to improvements in kids

1:07:27with intellectual disability um however you know it’s it’s only generally

1:07:32approved um by insurance companies for kids with autism um anyway that’s just a

1:07:38bit of an aside but but that’s always my my first line recommendation um and then in terms of

1:07:45medications I I can give you a list of medicines that we use I I cannot tell

1:07:50you oh this is the medicine for syap and you know these kids always always respond to this medicine or that

1:07:56medicine um but there are you know certain ones that we try certainly you

1:08:01know I can talk about respiron in general is uh you know the only FDA or one of the only FDA approved medications

1:08:08for behavior in autism not in not for syap specifically but for autism and

1:08:14some of the kids that that I see use resperidone and have some improvement I’ve had some that it didn’t work or the

1:08:21side effects were intolerable um so um you know like the antis psychotic

1:08:27medications and then the U um uh the Alpha 2 and energic um um

1:08:36Agonist or another class so clonidine and um guanosine or some medicines that

1:08:42I that I try uh like I said with some improvement in some kids but um some

1:08:49kids don’t respond great great thank

1:08:54you um it when you were when you talk about

1:09:01therapies um you mentioned in your presentation

1:09:07that patients with singap are are continuing to learn and are you

1:09:13know getting skills over time and that continuing with the therapies is important this is something that I ran

1:09:20up against of course having you know my son’s 22 now he did all therapies early on and after a time they start saying

1:09:27okay well insurance will pay for eight but you have to show that he’s improved over eight sessions or we’re not going

1:09:32to keep paying because and it it’s really a burden you know these are set up for the the privilege of the kids

1:09:40that have the brain with the plasticity that can actually do this in a shorter amount of time right and so our kids

1:09:47have this larger obstacle they can learn but it’s it’s going to be more on their own time scale it’s going to be harder

1:09:53to see over eight sessions absolutely I’m wondering if there’s any way you can

1:09:58write a case study or a opinion piece or something something that is published so

1:10:05that we can hand this to our insurance company and start advocating with a

1:10:10publication oh that’s that’s a great Point um I hadn’t thought about that but

1:10:15um so it’s all it’s all we think about well certainly the the data in

1:10:20terms of development continuing over time you know I we published that in 2019 um from the the very first paper we

1:10:28published on syap uh but it’s a great point that um you know one that that may

1:10:34not be enough for insurance companies to say oh okay we understand we’ll we’ll approve it so um yeah it’s a good point

1:10:41and it’s definitely something I’ve run into as well um and I I’ve certainly you

1:10:47know one thing I’ve done is is written you know appeals um to try to you know

1:10:52get that reversed uh with very variable success depending absolutely absolutely

1:10:58but as as a um you know since since I don’t want everyone to go to you to write every appeal it would be awesome

1:11:05if you wrote one paper that had just said in very plain terms this is what’s happening this is their obstacle this is

1:11:11part of the disease if you’re going to get a free and you know you you could

1:11:17you could put in verbage that includes school you know free and appropriate

1:11:22education you could um include verbiage that would that

1:11:27would be um uh you know recognized by insurance

1:11:34I’m not saying insurance would then pay of course like I think the the whole job of the insurance company is to try to not pay for things and then you try and

1:11:41then you have to like get your ammunition in order and like try to shoot through the shields so that you

1:11:47can actually get payment so I I understand that but it it would be so so so helpful uh if you Andor anyone else

1:11:55like even it’d be more helpful for each clinician to do this separately so that

1:12:01we had multiple individual articles that could show rather than like a group doing it together right that that’s my

1:12:08own personal opinion I don’t know if that’s actually what would happen okay I’ll stop talking about that but that’s

1:12:14that’s got me very excited okay so Olga asks what age

1:12:21groups were involved in the gate study and is is surgery ever warranted um so for the gate study I

1:12:28mean in general we’re looking at individuals that’re under 18 um and

1:12:36um I think down to four years of age uh we didn’t want to go much below that

1:12:42just because it’s difficult for younger kids to sort of participate um and then

1:12:47their Gat still developing um so you know we’re really looking at after gate

1:12:52should be um you know more or less developed um you know what are the

1:12:58differences from from neurotypical um so basically like four to 18 oh is surgery I’m not sure what

1:13:04she means by surgery warranted I think sometimes people have oh I guess Ola can ask you herself go

1:13:11ahead Ola hi it’s all right thank you for um yeah I want well Drew’s already

1:13:16he’s had I’m speaking personally obviously uh Drew’s had surgery and we just consulted again with Physical

1:13:22Medicine and there’s there are other surgeries that would help repair everything I mean to where it should be

1:13:30as far as rotating the bones Etc so he would walk in a a more normal Manner and

1:13:38I just didn’t know if you come how many kids if they’ve done the gate study had have had any surgery or these are just

1:13:43typical just kids with maybe using Orthotics and using and having physical

1:13:49therapy I mean I thought Physical Therapy was one of the was one of my first targets when he was younger and

1:13:55once I he started walking everything seemed fine and then about eight or nine years old things just went Ary and right

1:14:03we did happen to have we were fortunate to have some surgery before his you know his growth plate was we were able to uh

1:14:11do a couple of procedures to help but he still got issues got it no okay I understand now um what what I can say is

1:14:18that in general um among the kids that I see with syap one mutation s um uh

1:14:27qualitatively um many if not most have gate abnormalities uh I’ve had very few um

1:14:36that have needed surgery like exceedingly few so I all I can say is it’s not common um that the gate

1:14:45abnormalities lead to surgery um so

1:14:51yeah okay Ola I have a follow-up question for you is that due is that due

1:14:57to hypermobility is that like tendons and ligaments needing to be shortened or is that something else is that

1:15:02Orthopedic is it more bones What’s happen it’s all Orthopedic yeah it’s Orthopedic I mean there there are if he

1:15:09could tolerate the next round of surgeries which would be rotations and

1:15:15things like that but he’s not developmentally at a place cognitively

1:15:22where we you know is he going to sit for 6 weeks in cast that that’s kind of what we but he said this is something that

1:15:28could be done when he’s 20 or 30 if if we wanted yeah so we’re just kind of monitoring the situation right now it’s

1:15:35still attempting to use Orthotics yeah I just would say for us that um seeing seeing my son at 22 he’s

1:15:42he’s he’d be way better able to handle that at 22 than at um then at 15 16 17

1:15:50yeah okay so that’s yeah um and then Dr holder I wanted to ask you also about

1:15:56gate my son uh walked at around I don’t know 18 months and he definitely had a

1:16:03little bit of a different gate he’s had that the whole time when as he he didn’t

1:16:09grow for quite a long time so he had four years like there was a when he was 14 his bone age was delayed by four

1:16:15years so he had a he had we see this with a number of scapens where they uh

1:16:21won’t eat or they’re eating but they’re do gting weight you know he kind of like drops off his growth curve for a while

1:16:27um he then was able to restart and uh and he grew pretty

1:16:34fast and then in his gate got much worse so I’ve always wondered

1:16:39is like I did a lot to help him figure out his body map right like I did I did all this baby massage I was always

1:16:45giving him like input in his body because he was he had such a high pain tolerance that I figured he was and and

1:16:52he like he wouldn’t know where his hands were he’d want to eat and he’d go like this and if I touched his hand he’d reach out and grab it right so he like

1:16:59he didn’t have a you could tell he wanted something but he didn’t have an awareness of where his body was and what

1:17:06he what was possible for him so I did a lot to give him sensory input to give

1:17:12him because like our in our brain our body map is like takes up the whole brain right so

1:17:17um so I was wondering if after his gross spurt his synap his like lack of

1:17:24synaptic plasticity didn’t really allow him to change his his body map and so

1:17:30he’s like moving with these long levers and his body map is still for a little guy I was wondering if that’s partly why

1:17:37he has such a much harder time moving around and doing things now yeah that

1:17:43it’s a great question um I mean I I don’t have the answer to that it’s certainly plausible um it’s hard to say

1:17:51but yeah he used to be ble to run and I wouldn’t say he ran um in a really

1:17:57typical way like he looked different than my other kids who could run and Sprint but he he I don’t think he ever

1:18:03really like now he kind of Lopes he’s got like these big heavy feet and he’s got you know he doesn’t he doesn’t

1:18:08really run which is you know good because I probably couldn’t keep up with him he’s taller than me now right right

1:18:16okay so let’s go to um huh Megan says she’s two and will’ll

1:18:23wake up multiple times a night that’s probably because I asked I don’t think that’s a question I think that’s me just

1:18:29asking her about her um so Mara said what about seizure control and its relationship with decreased behaviors

1:18:35and Improvement of sleep so that’s that’s an amazing question um and um one

1:18:42that we’ve not addressed specifically but should be and not just about seizure control but also about um you know

1:18:51degree of EG aboral ities and does that correlate in any way with behaviors with

1:18:57development um and we don’t know the answer to that certainly for S Gap one I

1:19:03I’ve you know I’ve been interested in this in for a while for phal mcder syndrome I’ve looked into the data that’s available for autism in general

1:19:11um and you know it’s for all of that it’s still inconclusive I would say

1:19:17um you would think that in general if someone is having um

1:19:23a lot of even inal activity increased activity that that could impact their

1:19:29development um and you would you know hypothesize that if you gave medication

1:19:35to try to reduce that interal activity maybe that would improve development uh

1:19:41the data just doesn’t exist for that as far as I know unless something has come out really recently um people have tried

1:19:46this in very small numbers for autism um there are only some uh seizure

1:19:52medications that are known to um reduce this what I keep calling interal

1:19:57activity so these are abnormal discharges but not associated with a clear clinical seizure um and in those

1:20:03very small studies there was no significant improvement with or without medication um again these are really

1:20:11small and um when you say when you say Improvement do you mean Improvement on

1:20:16cognition what what’s the what’s the Improvement they’re looking for yeah so I’m stretching a little bit it’s been a while since I read the I mean they used

1:20:23instruments I I I feel like one of them used What’s called the ABC the aberant behavior checklist so looking kind of

1:20:28broadly at behaviors um i’ have to review those but there were clear there

1:20:34were endpoints that are kind of standardized endpoints yeah yeah and I should say I said that there’s there’s

1:20:40no convincing evidence some of those studies do show Improvement and then

1:20:46some don’t um and they’re all generally open label so everyone knows that everyone’s

1:20:53getting the medicine um so that’s a confounder as well um so I you know what

1:20:58I’m saying overall is um although I I I think the hypothesis is very interesting

1:21:03it just hasn’t been tested um as far as I know for any neurod developmental disorder and

1:21:09certainly not for syap one uh but a very interesting

1:21:14question um can I add an anecdote Absolut my son my son has had

1:21:20the absent seizures his whole life had the eye rolls but we were he he was born in 2001 and I was told repeatedly when

1:21:27he had EGS that just had epileptiform discharge activity but not you know not actual seizures that he wasn’t having

1:21:33seizures so we weren’t on meds at all and he wasn’t diagnosed until 16 so he

1:21:38started having drop seizures at 18 so that’s when we started on uh Val various

1:21:44medicines and now he’s on valproic acid and ony but when I first started the

1:21:49valpro acid he went from being able like

1:21:54if I asked him a simple question like give me your cup that’s not a question that’s a

1:22:00that’s a command I’d say give me your cup I would need to give him I’d need to repeat it several times I’d need to give

1:22:07him prompts I’d need to show him you know point to where the cup is then when he had it in his hand I’d need to like

1:22:12put my hand near him so he could put it to my hand right like it was it was a big it was it was a scaffold he could do

1:22:18it but it was very scaffolded with lots of input for me um M after a while I I I

1:22:24remember saying to him give me your cup he like looked for it he got it he handed he looked at me he handed it to

1:22:29me I was like you’re kidding me so this was he did the same thing but it was without all these supports right now he

1:22:35didn’t start talking he didn’t start solving puzzles he didn’t start you know he didn’t he didn’t do more things but

1:22:41to me that was a very significant change but it also had its limit right he he

1:22:47like there was an improvement but it was very localized and and uh it was limited he didn’t just it didn’t just say okay

1:22:54now he’s GNA develop the way he supposed to develop so that’s my anecdote yeah and I’ve definitely seen that frequently

1:23:01um in clinic um I I I can’t necessarily say for syap one for some of the

1:23:07patients probably but but for neurodevelopmental disorders in general um I’ve seen that anecdotally that U

1:23:15especially if there’s a high seizure burden the you know getting some improvement can lead to better ability

1:23:22to learn yeah um so when when somebody was asking or when you were discussing the

1:23:29um the medicines for behaviors I noticed you didn’t say something like fluoxitine

1:23:35so something that’s like an anti-anxiety that’s been that just I know that’s

1:23:40helpful for some kids it’s been incredibly helpful for my kid and through school whenever whenever

1:23:46there’re be like a week with really increased behaviors we would up the fluoxitine and it would they’d come back

1:23:51down so that that we sort of stepped that up and that’s been um helpful for us I want that I just wanted to say that

1:23:57leading into Marta’s next question what’s your theory as to why singap has such Market Marked aggression not

1:24:04explained by ID or Autism itself and appears much worse than other similar diseases yeah so great question um and

1:24:12uh that’s just an oversight on my part I I have a few kids that take SSR with s

1:24:17one so sorry that was just an oversight for me um Marta asked all all the great

1:24:23questions that I don’t have answers to I think she knows I don’t have answers um but it is it’s a very

1:24:30important question um yeah I mean there are other disorders and I’ll you know

1:24:36somewhat use fail mcder syndrum as an example since that’s you know the other population I see a lot um it does seem

1:24:44that in general kids with Sy Gap have more aggressive behaviors it’s more Broad in the syap CL kids now some of

1:24:51the fail mcder syndrome kids have definitely have aggressive behaviors and you know some of the S Gap one kids

1:24:57don’t have very many aggressive behaviors uh but I would say in general and anecdotally of course again no no

1:25:04data to show you um the singap one kids seem to have more aggression um and why

1:25:11is that I mean you know I can handwave and come up with all sorts of hypotheses

1:25:16uh I don’t have you know any data uh you know singap one in

1:25:22General deficiency of that causes greater you know hyper excitability of

1:25:28neurons whereas mcder syndrome um that tends to decrease excitability of

1:25:33neurons maybe that somehow plays a role um but I I you know maybe the expression

1:25:39pattern of s Gap one compared to the expression pattern of uh shank 3 in the

1:25:45brain could could have some impact on that but that’s all just you know hand waving and um it’s a very important

1:25:53question that we don’t know the answer to we I

1:25:59don’t thank you Dr holder okay so our next question is from Nancy Kesler she’s

1:26:06a very beloved member of the S Gap Community and she’s asking she’s the sister of

1:26:13um uh Karen the oldest syap patient that we know and have there been studies

1:26:21looking at gate decline with age and she says thank you for this excellent presentation and and study well first

1:26:27thank you so much for for listening to me um no uh so that’s that’s a really interesting question um as well um there

1:26:36have not been any studies looking at uh longitudinally at gate actually there

1:26:43there’s not been much um in terms of longitudinal studies for snapon at all H

1:26:49which is really an important Next Step um everything I showed you today was cross-sectional uh meaning just you know

1:26:55one patient one point in time um several of those but looking at gate

1:27:00longitudinally also looking at development and sensory processing and sleep I think this would be these would

1:27:06all be great to look longitudinally and I I will say just as a little bit of a plug um we are looking

1:27:13longitudinally at sleep um using the cshq um those of you that have participated many of you probably got a

1:27:21second round of calls to um collect data for a second year a while ago and we

1:27:27should be collecting a third year soon so hopefully that will provide some some

1:27:32information at least about sleep but I I agree all of the phenotypes should be looked

1:27:39longitudinally um are you still using are your gate is your gate mat still in use is I mean do is it still set up and

1:27:46can you still C can you get the patients that were in the first thing and you know you I can imagine even like every

1:27:52two years or three you know yeah not not needing a lot not needing a lot of granular data points

1:27:59but maybe even a longer study yeah so again

1:28:04another excellent point um and I’ve talked to Dr Lane who is our um so he I

1:28:10didn’t go into detail about him he runs um Center for human performance at University of Houston so all he studied

1:28:17all of his life is gate in various populations so he started I think with astronaut

1:28:23uh looking before and after space flight um and he’s also looked at like Parkinson’s disas some adult um

1:28:30disorders and really in kind of the last five years or so um it started working with us at Texas Children’s looking at

1:28:37various neurodevelopmental disorders um first publishing in in R syndrome um and

1:28:43then he’s worked with me for for singap one and some other neurodevelopmental disorders um and that so yes the the the

1:28:51gate lab is still still up and operational and it would be really interesting to look longitudinally um

1:28:56with the same kids um okay and then Marta has a I

1:29:03think more of a comment she says prophylactic anti-seizure Med uh there’s a study on uh T Tubular

1:29:12Sclerosis I’m sorry I’m not sure how to I I know that um disase but I’m not sure how to say it with um clobazam showing

1:29:20cognitive Improvement so I guess there is a little yeah yeah and that’s a great thank thank you again Marta I I I do now recall that

1:29:28study that’s a fairly recent study um looking at clobazam so um yeah that’s

1:29:33thank you so much um so and then finally with your gate suit I was wondering if I was just

1:29:40thinking all that gate stuff could be somehow transitioned to the bed right so

1:29:46you could have instead of a gate mat you could have a gate mattress pad and then

1:29:52you know like a not not gate but a pressure mattress pad and then a suit

1:29:57that has like little little points on it so maybe you know a like sleeper jammies

1:30:03that have some something and then low light in the room or infrared I don’t know I don’t know what it would be but I

1:30:09know there’s a lot of technology these days that yeah and there there is a lot of new technology coming out um one

1:30:15thing I’m really excited about is um there is new technology that’s being developed to to actually Rec U psgs

1:30:23polysomnography sleep studies um at the home um using less um irates or yeah

1:30:31yeah it’s like uh you know something that can be just placed on the forehead again this you know could be an issue in

1:30:38terms of tolerance for our kids with s Gap one and all of their sensory issues but doesn’t have all of the leads going

1:30:43everywhere um you know it’s uses Bluetooth I guess or or something to transmit the data so you know a lot of

1:30:50lot of new technology I think that can maybe address some of these these questions yeah I wonder if there’d be

1:30:57any info in um blood pressure and heart rate like I I I feel that our kids have

1:31:04like when I think about my my young children sleeping I feel like their blood pressure and heart rate was

1:31:09different while they were sleeping right even if one moved and even if they both

1:31:14moved and I’m also thinking that the REM sleep that like for the Fitbit kind of

1:31:20algorithms for REM sleep those might not be

1:31:26um uh since they’re since they’re made for people with that that do go into REM

1:31:32sleep that when you’re that you might look asleep you might look like you’re in REM sleep in the actigraphy but

1:31:39actually be awake right like you might not like the the algorithm might not be

1:31:44catching what’s happening for you sure I’m just wondering if the actigraphy is kind of just off somehow but you’re but

1:31:49you’re saying it’s only movement and yeah yeah so the actigraphy actually can’t distinguish any of the uh uh

1:31:56phases of sleep um it can only the one we used anyway only yeah so

1:32:02that’s it’s really it’s interest it’s puzzling right it’s puzzling what that difference was about yeah okay

1:32:09well do you have any last words for us as parents uh no you know I again I just

1:32:15want to thank everyone whove participated in all of our studies um you know it’s it you guys have been

1:32:22wonderful and I really appreciate it and um you know I I would say for

1:32:27neurodevelopmental disorders in general but for syap in particular I’m more optimistic today than I than I was you

1:32:33know five years ago when I started that we’re on the the right path to clinical trials and um and hopefully treatments

1:32:42in the future yeah thank you so much um it’s been such a pleasure to see your

1:32:48slides hear your words and you gave some amazing gave a really amazing introduction to uh sing one I just I

1:32:56really appreciated that and um and thank you for all your research and um I hope

1:33:02lots of patients continue to come see you all right well thank you and

1:33:07everybody have a good day okay