45.d – 3rd Annual Synapse Roundtable, Sleep & other potential biomarkers -SHANK3 & SYNGAP1

Event Time

December 3, 2021 at 4:00 pm


0:10good morning everybody thank you for

0:12coming to the third annual synapse

0:13roundtable my name is michael gralia i

0:15am the managing director of the singap

0:17research fund

0:18and it is such a thrill to welcome our

0:21incredible speaker here today

0:23um our next speaker is dr connie smith

0:26picks from johns hopkins the kennedy

0:28krieger institute

0:29um i can’t say enough nice things about

0:31her but in the interest of time i will

0:32just let her wow you herself dr smith


0:37take it away and thank you for being

0:38here and i will brag that she is on our

0:40sab you get the privilege of her

0:44where are you connieWelcome

0:46okay hi everyone can you see my slides


0:51okay wonderful

0:53all right so

0:54uh thanks mike

0:56and the organizers for inviting me so

0:58i’m going to talk about

0:59sleep and synaptopathies um

1:03and uhAgenda

1:05i’m going to briefly just talk about uh

1:08an overview of syneptopathies and then

1:10why we chose to study study sleep


1:14some focus on uh some of our work

1:17looking at sleep in philadelphia and


1:24then i’ll i’ll end with a little summary

1:27and some next steps and perhaps some

1:29thoughts about limitations of the work

1:31that we have done so far


1:34um you know when we think of

1:36synaptopathies we’re thinking about

1:38disorders of the nervous system in

1:41general but it can

1:43certainly be a consequence of uh

1:46dysfunction at the synapse both

1:47peripherally or centrally

1:50but for the purposes of this talk i’m

1:52really going to be thinking about what

1:53occurs uh centrally

1:56meaning in the central nervous system


1:59there’s there’s been a significant

2:02increase in the number of genes that

2:03have been linked to ndd and

2:06currently they’re thought to be over

2:082000 genes that have been associated

2:10with neurodevelopmental disabilities

2:13um many of them function

2:16at the level of the synapse

2:18both pre-synaptic and


2:22but the the schematic uh here features

2:26uh three genes that are being discussed

2:28today so sdx bp1

2:31uh shank and uh syngap1

2:35and what you’ll notice is that sdxbp1

2:38primarily functions in the presynaptic


2:42whereas shank and syngap primarily

2:45function in the postsynaptic compartment

2:48and shank and sengap

2:51are involved in synaptic plasticity

2:54mechanisms whereas sdx bp1

2:57is uh primarily involved in release of


3:04soClinical Features

3:05we know a lot about the clinical


3:10of all three disorders just in in

3:12general we know that they are

3:15certainly associated with complex

3:17clinical phenotype that will include

3:21global developmental delay intellectual

3:23disability autism and epilepsy

3:26and we know that sleep is a common

3:30feature in many neurodevelopmental


3:34um in individuals with uh syngap1 it’s

3:38reported to occur

3:40in about 62 percent of individuals and

3:42then in individuals with feeling my

3:45dermit in anywhere between 25 and 50

3:48percent of individuals and i think from


3:51previous speaker slide i think we had

3:53probably 62 percent if if i recall or 56

3:58percent if i recall

4:00now although sleep difficulties are

4:02reported in

4:03patients with intractable epilepsy and

4:05we see

4:06uh significant epilepsy in individuals

4:10with sdx bp1

4:13the prevalence of sleep disturbance in

4:15that population is not entirely clear

4:19so the the focus of our uh conversation

4:22um is really going to be uh related to

4:26shank and um syngap1

4:29so why steady sleep wellWhy Sleep

4:32you know it’s it certainly is an area of

4:34on that need and uh we know that

4:38sleep is critical and good quality sleep

4:41is critical for

4:43many physiologic functions it supports

4:46neurogenesis plasticity

4:48brain development and behavioral


4:52and any parent of a child will tell you

4:55that uh poor sleep negatively impacts

4:58behavior and there is this bidirectional

5:01association between sleep and mood and

5:04certainly sleep and cognition


5:08thus uh

5:10poor sleep not only impacts the child

5:13but also impacts the caregiver

5:17sleep is not just a common problem in

5:21neurodevelopmental disabilities but it

5:24is pretty prevalent in the general

5:25pediatric population and approximately

5:2725 percent so one in four

5:30uh children um who are otherwise

5:33typically developed

5:34have sleep problems

5:36and depending on the

5:38the nature of the neurodevelopmental

5:40disabilities the prevalence of sleep can

5:43be anywhere between 50 and 95

5:46uh sleep difficulties may manifest

5:49either with difficult difficulty with

5:52sleep onset

5:53sleep maintenance

5:56problems with

5:57having increased daytime sleepiness

6:00or breathing challenges

6:02occurring during sleep

6:06so uh work from

6:08several groups in preclinical models of


6:13shows that

6:14the shank protein is involved


6:19circadian rhythm of um


6:23these studies are actually done in


6:25um but the

6:27synaptic level of shank protein

6:30varies over the course of the day


6:35the the changes uh correlate with

6:38changes in serum melatonin

6:41now mice lacking

6:44exon 21 in shank


6:47are shown to have

6:48less sleep

6:50during the dark period dark period

6:53and this disruption in

6:57shank 3 expression

6:59is also correlated with

7:01disruption in

7:03expression of many of the genes

7:05that regulate the circadian rhythm

7:09so based on this we know that shank 3 is


7:13for the regulation of sleep and

7:17just a note i want to make the exon 21

7:20in shank 3

7:23is actually one of the hot spots for

7:25many of the pathogenic variants that are

7:27seen in individuals with pmd

7:31uh like shank three same gap one um is

7:35also an important regulator of sleep

7:38and uh syngap1 is expressed in the

7:41suprachiasmatic nucleus which is the

7:44brain circadian clock

7:46its levels vary over

7:49the course of a day

7:51um and the indiv in rodent models that

7:54are haploid insufficient for syngap one


8:00increased activity

8:02during the dark phase relative to

8:05wild type miceWhy Synapse1 Sleep


8:09why why did we compare sleep in

8:12singapore and philly magdermoth well we

8:15opted to look at these two disorders

8:18because one they have

8:20shared clinical features

8:22and their genes converge on

8:24shared molecular pathways and share and

8:27have shared physiologic consequencesSleep Study

8:31we studied sleep in this population and

8:34the the patients were

8:36recruited from three sites uh two in the

8:40u.s and one in the uk

8:43we uh

8:45recruited patients with singapoand

8:47felimit dermot and typical developed


8:50we took

8:52all comers

8:53from as young as

8:56uh three years old uh uh on up

8:59um what we noted was that there was no

9:02significant difference in the number of

9:03males versus females for either of the

9:05three groups

9:07that were included in this studySleep Medications

9:12i shared earlier that sleep is a common

9:15uh problem in both singaporean and

9:18filament derma then so it’s not


9:20that many of the patients were

9:24taking at least one medication that is

9:27routinely used to treat sleep you can

9:30see that melatonin is by far

9:33the most

9:35common medication that’s used in both

9:38groups of patientsSleep Habits Questionnaire

9:41we used the

9:43child the children’s sleep habit


9:47to evaluate the sleep profile this is a

9:49parent reported a screening measure

9:52and it evaluates


9:57or sleep

9:59difficulties that are both behaviorally

10:01mediated as well as medically mediated


10:08cshq has been validated in kids between

10:11age 4 and 10

10:13but it’s been used in

10:15children younger and children older

10:19and a total score total

10:22score that is greater than or equal to

10:2441 suggests um clinical significance of

10:29uh disrupted

10:30sleep not only do we look at the total

10:33score but we are also able to parse um

10:37sleep features along eight uh subscales

10:41looking at certainly resistance to

10:45going to sleep delayed sleep onset how

10:47long the child remains asleep

10:49anxiety parasomnias and breathing

10:52related difficulties

10:53as well as


10:56sleepinessSleep Features Questionnaire


11:01using the uh cshq

11:04we first asked is there a difference in

11:06the total uh score

11:08and then the sub sales scores between

11:11all three groups

11:13and we show that

11:14individuals with uh syngap1 and

11:16individuals with filimide dermoth

11:19both had

11:21more severe

11:23sleep problems when compared

11:25to their typical developed siblings

11:28however individuals with singapoand had

11:31more sleep difficulties than those

11:35with filament derma and that’s indicated


11:38the higher total mean score

11:42um this uh difference between philly

11:45mcdermott and singapoand seems to be





11:53differences both in bedtime resistance

11:57and a difference in daytime sleepiness

11:59where you see that sync up one


12:02had higher scores on both

12:06we also

12:07noted that

12:09nighttime awakenings parasomnias

12:12sleep disordered breathing


12:15sleep duration

12:16were common problems in both

12:20singaporean and fellow mcdermott


12:26because there


12:28in general thought to be an age

12:31difference in the manifestation of sleep


12:35we divided our cohorts in those who were

12:39younger than age 11 and those who were

12:41older than age 11 and another motivation

12:44for doing that is again because the cshq

12:49was validated in those younger than age



12:55we asked you know is is uh sleep

12:58difficulties in

12:59uh these disorders age dependent

13:03and so

13:04we looked at this pattern and we can see

13:07again that uh

13:09individuals with uh syngap1 had a higher

13:12total sleep score so a worse sleep

13:15profile than individuals with feeling

13:18like dermot and we we saw that pattern

13:21um in those who were younger

13:24um than than 11 years of age so those

13:26who were


13:29and that’s consistent with what we saw

13:31when we looked at the

13:33larger group

13:36we also see that

13:38the the difference in


13:43the the difference between these two

13:45groups is

13:46driven in this case by

13:49uh sleep anxiety and also

13:52by daytime as sleepiness

13:55and the difference

13:56in parasomnias between individuals with

13:59syngap1 and siblings as compared to

14:05philip mcdermott and siblings were

14:10there was no difference between

14:12those with uh synched one and those with

14:14pmd and both disorders

14:17had a


14:20increased severity of parasomnias as

14:22compared to typical developed siblings

14:27weSleep Differences

14:28then ask well

14:31what is the profile of

14:32sleep differences that we see in the the

14:35older groups


14:38we can appreciate immediately that

14:42there was a severity of uh sleep uh


14:47in both singaporean and filament derma

14:50when compared to typical developed


14:53in many of


14:57sleep subscales

14:59and that there was no

15:01um significant differences

15:03between um

15:06individuals with older individuals with

15:08syngam1 and a pmd



15:14in in summary we see that sleep is a

15:17common problem in ndds in general

15:20uh both the shank iii and the syngap1

15:23protein are

15:24important regulators of of sleep

15:28um we see from our data that there is uh

15:30greater sleep difficulties in

15:33individuals rising gap one when we

15:34compare them

15:36to those with uh filament derma then we

15:40believe that this is dependent on age so

15:42the younger sin gap kids have more sleep

15:44difficulties compared


15:47younger individuals with shank three

15:50whereas the older individuals with pmds

15:52seem to have more sleep difficulties

15:55than their


15:57the the younger individuals

16:00parasomnias nighttime awakening and

16:02disordered breathing are common features

16:05i think you know this uh data suggests

16:08that both the total and subscale scores

16:11in the cshq

16:13uh can be useful measure for evaluating


16:17i think that it’ll be important for us



16:22look at the the utility of this and

16:25natural history study and what it tells


16:28about the sleep profile over time



16:35with syngap1 or other synaptopathies

16:38one of the questions we

16:40we often wonder about is how does the

16:43chsq or any other measure that we use

16:47how does that change over time when we

16:50think about


16:53and that’s something that we are

16:55looking into i mean we generally put

16:58many of our patients on

17:00medications that

17:02treat sleep and so this would be an easy

17:05thing to do

17:06at least in the clinics

17:09so i want to stop here and acknowledge

17:11um certainly the families and and

17:13children of syngap1 uh and shank iii

17:17the parent advocacy foundations the work

17:20was done in collaboration with jimmy’s

17:22group in texas

17:23and andy’s group in the university of

17:26edinburgh and certainly all our

17:29funding organizations

17:31so i think i have um probably two

17:34minutes for questionsQ A

17:45okay um and i see a question here in the

17:48q a that says do you see a wearable

17:50tracker as being a way to follow

17:52sleep habits over time

17:54um absolutely um that’s actually one

17:57thing that we are embarking on and we’re

17:59in the process of

18:00analyzing that data i think um wearable

18:04tracker we may be able to correlate




18:11delayed uh

18:13sleep onset

18:14or latency just to falling asleep with

18:17the cshq

18:19some of the other measures i think that

18:21might be challenging but yeah that is

18:22something that we are we and others

18:25are are doing and we just don’t have the

18:27data yet to share


18:38and um

18:41do you think that sleep could improve

18:43with treatments

18:45um so


18:48oh genetic treatment

18:49so do you think that sleep could improve

18:51with genetic treatments


18:55absolutely i think you know if we are

18:58there there are many approaches that are

19:01being proposed for


19:05genetic treatments whether it’s

19:06antisense oligonucleotides



19:12modalities whether it’s read through or

19:14many other approaches

19:16and if we are

19:18able to get


19:22targets up parts of the brain that

19:24uh certainly are involved in in

19:27regulating sleep

19:29um then it would be my expectation that

19:32sleep we should be able to improve sleep

19:34and sleep generally in my opinion at

19:36least is is a low-hanging fruit it’s

19:39one of the things that we are

19:41able to

19:43um treat to some degree in many of our


19:48um i

19:50i wonder

19:52in the data that we showed you may might

19:54have noticed that


19:58sleep onset delay was there was a lower


20:04score subscale score


20:07although significant when compared to

20:10typical developed peers but i wonder if

20:13that lower subscale score and


20:17less impairment in delayed sleep onset

20:20is related to the fact that many of

20:22these kids are on medications that

20:25their their role is to


20:31to increase

20:33sleep so


20:36targets delayed sleep onsets and so i

20:39wonder if we are

20:41being effective in in

20:46shortening the latency to falling asleep

20:48in many of the patients with the with

20:50the current medications we use

20:54my expectation is that a targeting sleep

20:56will improve

20:58behaviors will it be a cure i i don’t

21:01think so


21:04it’ll be one of the

21:06the um

21:08the treatment interventions that we

21:10would likely employ

21:13in in as we think about how we



21:18uh patients with syngpuan shank three


21:23s txbp1 and other similar disorders

21:28thank you so much dr smith hicks um

21:30sleep i’m glad to hear you say

21:32low hanging fruit i hope that will be

21:34the case it’s obviously something that

21:36can really impact quality of life