87.a – SYNGAP1 Conference 2023 – New insights in the DEEs

Event Time

November 30, 2023 at 8:00 am


:05hello my name is Professor ingred

0:07Schiffer I’m at the University of

0:09Melbourne and Austin and Royal

0:11Children’s Hospitals in Melbourne

0:13Australia um I was uh fortunate to be

0:16invited to speak at the recent SP Gap

0:18one conference at the American epilepsy

0:21Society in Orlando in Florida um and

0:25they’ve asked me to re-record my talk

0:27due to some technical difficulties

0:30my topic is new insights into the

0:33Developmental and epileptic in copath

0:36with an emphasis of course on singap one

0:40and here are my

0:42disclosures so in this talk I’m going to

0:45go through uh four major areas I’m going

0:48to start by defining what we mean by the

0:51term Developmental and epileptic and GAP

0:54opies I’m then going to turn to some

0:57very recent data we have on the EP

0:59epidemiology of different Developmental

1:02and epileptic in copath or

1:05Dees I’m going to talk about a study we

1:08published this year examining the rates

1:11of convulsive and non-convulsive status

1:13epilepticus and the mortality rates and

1:16suep rates in different genetic

1:19Developmental eptic and

1:21copies and then the final section is on

1:24our talk which is just coming out now in

1:26the journal Neurology on movement

1:28disorders in patients with genetic

1:31Dees so let’s start by defining what do

1:34we mean by this complicated term

1:36Developmental and epileptic inal opathy

1:39well here we’re putting together three

1:41different concepts the eyology or

1:44cause the uh whether a child has

1:47developmental slowing or regression

1:49developmental abnormality and whether

1:51they have epileptiform activity on their

1:54AG ellip epileptic activity and we’ll

1:57start with the concept of just epileptic

2:00in copath and here the idea is that you

2:03have this very frequent epileptic

2:05activity which causes impairment of

2:08development and really the uh prototypic

2:11form of this uh epileptic in copath is

2:15infantile epileptic spasm syndrome there

2:18you see a little spasm uh in a little

2:21Indian girl like careful who’s an

2:23identical twin and both twins develop

2:25this and you can see a spasm there this

2:27little series of very subtle seases and

2:31these EP infantile epileptic spasm

2:34syndrome are associated with a

2:35classically a very abnormal e called

2:38hips arhythmia and the the baby

2:41typically shows developmental regression

2:44with loss of skills so that’s what an

2:47epileptic in copath is and then we

2:49expanded this term to Developmental and

2:52epileptic inil opathy the reason for

2:55this was that we realized many causes

2:57and in particular when we think of caus

2:59as you think of genes cause development

3:02or abnormalities or impairment in their

3:04own right and as well as that they cause

3:07this epileptic in copath which actually

3:10further affects development so one of

3:14the uh prototypic forms of this of

3:16course is drav syndrome which is due to

3:18an abnormality of a sodium Channel and

3:21here you see the Alpha One subunit of a

3:23sodium Channel which forms the pore or

3:26the the Gateway into the cell through

3:28this channel through which the sodium

3:30ions pass and this is the cell membrane

3:33in which the sodium Channel sits and uh

3:37in drv syndrome which is due to uh

3:40mutations or pathogenic variance in

3:43scn1a uh you get this cause causing

3:46developmental slowing and then later on

3:48the child develops very frequent

3:50epileptic activity and has further

3:52developmental slowing and goes backwards

3:55and this is an example of what the gene

3:57abnormality is doing not the the

3:59epileptic activity a little girl here of

4:02six with normal gate and a man here of

4:04about 28 with very abnormal Crouch gate

4:07with distonia due to scm1 so it’s the

4:11developmental enal opathy as distinct

4:13from the epileptic enal

4:15opathy so just to conclude this

4:18definition session section when we talk

4:21about developmental an epileptic

4:24incopy we’re talking about a child who

4:27has developmental uh impairment

4:30then gets this superimposed epileptic

4:33enval opathy and here you see a little

4:35girl with singap one having a very nasty

4:37myoclonic atonic seizure but the problem

4:41is that the more we understand about a

4:43specific Gene and singap one’s a good

4:45example of that the more we see a

4:47spectrum of presentations of which we

4:49call a phenotypic spectrum and so when I

4:52see a child or an adult it’s important

4:55to try and understand their cause so

4:58their Gene name s Gap one Developmental

5:00and epileptic and galopy as well as

5:03their syndrome because they both uh

5:06reflect or both impact on my treatment

5:10choices so now let me share some

5:13interesting data about the epidemiology

5:15of Dees and there been a lot of debate

5:18about how common they actually are and

5:20together with my New Zealand

5:22collaborators this year we actually

5:24published the cumulative incidents to 16

5:27years of all Dees and found that 169 per

5:32100,000 children have a Dee and this

5:36this point is very useful one in 591

5:39children will have a de and this is

5:41important for government to ensure we

5:44get adequate resources and enough uh

5:47multi-skilled uh dis uh multi-skilled

5:50Workforce to care for these children who

5:52are so sick so the while epidemiology

5:55may not seem that relevant to a family

5:57with a child it is relevant in terms of

6:00helping the the community to care for

6:03children with these

6:05diseases now when we talk about the

6:07developmental epileptic and epileptic

6:10envelopathies we’re actually talking

6:11about a whole range of different


6:15syndromes um and these syndromes um are

6:18more common ones such as infantile

6:21epileptic spasm syndrome lenx gasto

6:23syndrome dra epilepsy with my clonic

6:26aonic seizures much rarer ones including

6:30a whole group of very severe ones that

6:32begin by three months of age but there

6:34are also many individuals with

6:36developmental an eptic and kopies who

6:39may not fish into one of these n

6:41syndromic boxes but still clearly have a

6:44dee so it’s a very important concept to

6:47understand and with our epidemiology

6:50well actually just before I get to that

6:51slide with singap one these are the main

6:54uh Developmental and epileptic and

6:56copath syndromic boxes that we see

6:59epilepsy with my clonic atonic seizures

7:02and that’s like the little girl I just

7:03showed you who had that very dramatic

7:06drop attack epilepsy with eyelid miconia

7:09as where you have very rapid eyelid

7:11fluttering and you’re often

7:13photosensitive and then gastos syndrome

7:15which is characterized by nasy Tonic

7:18seizures which can also cause you to to

7:21fall to the ground now in this recent

7:24epidemiological study we looked at the

7:26frequency of many of these syndromes and

7:28you can the infantile epileptic spasm

7:31syndrome occurs in 58 per 100,000

7:34children whereas uh epilepsy with my

7:37clonic atonic seizures which is present

7:39in singap one or common presentation is

7:4216 so it’s sort of the second most

7:45common out of these syndromes that we

7:48see so now I’d like to move on to the

7:51first of two studies and this one uh

7:54examines the rates of status epilepticus

7:57now this is defined as 30 minutes and we

8:00look at both convulsive and

8:01non-convulsive Status epilepticus the

8:04mortality rates and suep which stands

8:07for sudden Unexpected death in epilepsy

8:10in people with different genetic

8:12developmental an epileptic in copath and

8:15this work was led by a very talented uh

8:18pediatric registr called alist

8:21donin so in this study we decided to

8:24only take cohorts or groups of patients

8:27where we had at least 10 individual

8:29with that particular Gene and we study

8:32both children and adults so the study

8:34involved 510 patients and you can see

8:37all the different genes involved in the

8:39study s Gap one was the second most

8:42common after SC1 a which was mostly

8:45drave children and adults 203 but

8:48there’s also SC M1A non-ra and singap

8:51one included 60 individuals with singap

8:55one and what we found was the median

8:57agent study of the co H was 10 years but

9:01notably almost 80% was still under 18

9:04years so the age that we Define as

9:06childhood and Adolescence and the range

9:09though was as broad as one month of age

9:11to 79 years of age we found that the

9:15median onset of convulsive status

9:18epilepticus where the child ceases for

9:2030 minutes was 8 months this is partly

9:23skewed by the fact we have so many D

9:25children in this study but what was very

9:27interesting for me was that the

9:29non-convulsive stages epilepticus began

9:32at a median age of 5 years and this is

9:34where you spend 30 minutes not being

9:36very aware you might dribble you might

9:39be unsteady you might be um just not

9:42with it and that’s called non-convulsive

9:44status epilepticus and when when you do

9:46the EG of the child or an adult you find

9:49constant epileptic

9:52activity so starting with the different

9:55uh forms of status epilepticus in

9:58different genetic d is well you can see

10:01the drave syndrome 90% have convulsive

10:04status epilepticus which we would guess

10:07and about a quarter have non-convulsive

10:08status epilepticus here are the other

10:11genes which have more convulsive status

10:15and nonconvulsive status epilepticus and

10:17here are the whole group that we studied

10:19and notably sing Gap one is seen here

10:22and nobody had convulsive status

10:24epilepticus which is wonderful news for

10:26singap one children and adults because

10:29uh convulsive status epilepticus is

10:32definitely life-threatening but it

10:34doesn’t mean it’s impossible it just

10:36means it’s not frequent because it

10:38didn’t occur in our 60 patients so it’s

10:40a reasonable size but we did have some

10:43with non-convulsive status

10:45epilepticus turning now to the death we

10:48found that 8% of our cohort had died by

10:51the time we studied We performed the

10:53study and the median age of death was s

10:56years and you can see here the age at

10:58which different individuals died and in

11:01blue here you see those who died due to

11:04sudden Unexpected death in epilepsy

11:07which was accounted for almost half the

11:09deaths and the median age of suep was

11:12aged 10 years and you can see that some

11:15of the deaths occurred due to convulsive

11:17status epilepticus and again in some of

11:20those individuals then developed Cal

11:22edema and

11:23died and their causes of death were uh

11:27others such as drowning withdrawal of

11:29care respiratory infection in six uh

11:32which we know is always a bigger risk in

11:34this type of

11:36disorder so what about the genes well

11:39the biggest issue uh the big most

11:41important Gene in this mortality rate

11:43was SCM 1A uh and it accounted for 16

11:47out of 20 suep deaths in individuals uh

11:51for 12 of the 20 scm1 a deaths were due

11:55to DV syndrome which accounted for 6% of

11:58the cohort

11:59when we looked at those with with the

12:01nrav de so the early infantile the

12:04mortality rate was much higher over

12:07quarter of the patients had

12:09died so what about the genes associated

12:12with suep well scn1a scn2a we had two

12:15individuals scn ha we had one and we had

12:19one with scx

12:20bp1 now unfortunately I can’t tell you

12:23this means that children with th Gap one

12:26w die because they could die I have had

12:29adult die with a respiratory infection

12:31but it just means that their risk of Pep

12:34is fortunately not high compared to the

12:36other genetic

12:37Dees so in this study we found that

12:40different genes put you at risk of

12:42different complications such as

12:44convulsive status epilepticus

12:46non-convulsive status epilepticus and

12:49sudden Unexpected death in epilepsy and

12:52I I don’t think this is you know tells

12:54you definite facts for everyone but it

12:56certainly gives us some leads about when

12:58we should worry about what particular

13:01complications so understanding these

13:04risks invs clinical care it helps

13:07doctors to manage and counsel parents

13:10about these risks and what to look out

13:12for and it certainly has worked for me

13:15many times that my Angelman syndrome

13:17parents parents of a child with Angelman

13:19syndrome will be much quicker to

13:21recognize when that child has

13:23non-convulsive status epilepticus and

13:25present to the emergency department so

13:27we can diagnose and give treatment and

13:30the earlier you give treatment the more

13:32likely that’s going to uh prevent the

13:35child having developmental regression so

13:37very important to recognize it people

13:39often recognize convulsive status

13:41epilepticus because it’s frightening but

13:43non-convulsive status ticus can be slow


13:48recognize all right now the final talk

13:50um I wanted to the final discussion I

13:53wanted to have was around a paper that’s

13:54just coming out now about defining

13:57movement disorders in patients with

13:59different genetic development toward

14:01epileptic and copath these and this was

14:04work was led by a very talented medical

14:06student at the time from the Netherlands

14:08called stra vavine she’s now training to

14:11be an adult neurologist and Gabby say is

14:14also an adult

14:15neurologist so what happened here was

14:18that I realized in clinic every day that

14:20a lot of my patients with genetic Dees

14:23had movement disorders and we’ve been

14:25spending so much time worrying about the

14:28seizures we had really looked at this in

14:30in detail and you can say well why does

14:33it matter well we need to distinguish

14:35epileptic from non-epileptic uh

14:38movements because they have different

14:40management they may need medication and

14:43if it’s seizures obviously antic seesion

14:45medication but if it’s a movement

14:47disorder they might need movement

14:48disorder medications and there are also

14:50other strategies we can employ such as

14:53deep brain

14:54stimulation so in this study we

14:57hypothesize that specific genetic

14:59Developmental and epileptic in copath

15:03are associated with specific types of

15:05movement disorders and then that the

15:07patterns of the movement disorders

15:09reflect the undering neurobiology of the

15:13disease this study began by uh me and my

15:18collaborators who were both um Pediatric

15:22otologists and we worked with pediatric

15:25and adult movement disorders in Italy

15:27and in Australia Australia and we

15:30identified patients who had a known

15:32genetic de so we knew which Gene was

15:34involved and we saw them in clinic and

15:37we or the ward and we saw that they had

15:39a movement disorder and then we

15:41characterized the age of onset of the

15:43movement disorder the ca of the patient

15:45their epilepsy syndrome their severity

15:48of intellectual disability we use videos

15:51to classify the type of movement

15:53disorder and then we classified them as

15:55hypokinetic which meant stereotron Korea

15:59M clonus and Tremor hypokinetic or axic

16:04and then went on to analyze the patterns

16:06of movement disorders with different


16:09diseases now this is really a pilot

16:12study to get some understanding of this

16:14because it’s a very complex field and we

16:16need more patients but we started with a

16:18healthy 77 patients who at the age of

16:21study had a median age of 9 years but

16:24were aged from 1 to 38 years and three

16:27had sadly p away the median age of onset

16:31of movement disorder was 18 months which

16:33is interesting because the median onset

16:35of seizures was actually four months so

16:38we had a very severe group of patients

16:40here with seizures early mostly in life

16:44and here you see the seizure types

16:46epileptic spasms my clonus and tonic

16:48clonic seizures the subgroups of

16:51Developmental and epileptic and copath

16:54with over half having early infantile

16:57which means it begins by months um about

17:0030 having infantile and only 10 having

17:03later onset and here you see the

17:06epilepsy syndrome in our cohort with

17:09eight having Leno gasto syndrome four

17:12infantile epileptic spasm syndrome five

17:14drave four epilepsy of infancy with

17:18migrating focal seizures three epilepsy

17:21with my clonic atonic seizures and one

17:24with the progressive M clonus epilepsy

17:27it’s also very important to recognize

17:29that this group of patients these 77

17:32were severe with severe intellectual

17:34disability in

17:3572% and a further 15% had profound

17:39impairment and 70% did not walk so what

17:43do we find well we found the most common

17:47movement disorder was stereotypies

17:49followed by distonia Korea M clonus Axia

17:53Tria hypokinesia and other and distonia

17:57was more common in non-ambulatory

17:59patients and more common with moderate

18:02to profound intellectual impairment and

18:05a taxia was more common in ambulatory

18:07patients which is partly because we can

18:09diagnose it then and those with mild


18:13disability so here you can see the genes

18:16that were involved um and there were one

18:18or two with singap one but mostly other

18:21genes were

18:22involved so here you see uh the first

18:25the most common movement disorder which

18:28is stereotropism

18:30of 21 months and occurred in more than

18:34half the patients and here you can see

18:36three individuals with potassium Channel

18:39kcnq2 DE and the little guy that you can

18:42see is having some

18:44stereoptic um

18:46stereotypic um rocking and arm and leg

18:50movements as has the next little guy and

18:52then this big girl is a bit higher

18:55functioning and she has this backward

18:57stereotypy that almost causes her to


19:00over the second type of moving disorder

19:03is distonia with a mean onset of 14

19:06months and he used see the same boy at

19:08two different ages with distonic

19:10movements of his legs and arms um and

19:14you can see he really doesn’t find it

19:16very comfortable in the in the image on

19:17the left and this occurred began at 6

19:21months to 13 years in different

19:24individuals the next group is Korea and

19:27this occurred in 11 with chosis and

19:30seven with ballismus these three boys

19:33all have the early infantile profound de

19:37j1a and you can see this very prominent

19:41career as well as mouthing movements

19:43that are part of the career that you see

19:46and here you see another disease Dynam

19:48in one de and here you can see a brother

19:51and sister two with a similar sister of

19:54different ages here um and you can see

19:57that they have this

19:58very um sort of little movements which

20:01are called Korea which had a mean onset

20:04in our cohort of 12 months that couldn’t

20:07be begin from four months to 13 years

20:10and you can see just how severe it is in

20:13uh the brother when he gets a bit bigger

20:15fact it’s so severe they cannot take him

20:17on an airlane to visit me for a

20:20consultation so what about the biology

20:23well we could begin to make some

20:24correlations but uh as I mentioned

20:27earlier we need much better dangered to

20:29be able to do this well the

20:32channelopathies sodium and potassium

20:34channelopathies and synaptic physical

20:37trafficking genes were most likely to be

20:40associated with theonia seen in the


20:43green transcriptional defects were most

20:46likely to be seen uh in the purple

20:49associated with

20:50stereotypies and then other different

20:53mechanisms were associated with mixed

20:55pictures and these include post

20:56transational defects

20:58Transporters and signaling disorders and

21:01this is where singap sits down

21:04here so in conclusion for this study the

21:08uh we found that movement disorders are

21:10underrecognized in patients with genetic

21:13Developmental and epileptic and copath

21:16these differentiation can the movement

21:19disorder from aesia can be challenging

21:21and sometimes um you need video EG

21:24monitoring to distinguish whether it’s a

21:26movement disorder or a

21:28but more often the smartphone is our is

21:31our tool here so I ask P families to do

21:35me three examples of each movement

21:37disorder and that way I can look at the

21:39context in which it occurs what’s the

21:41child doing are there any triggers and

21:43how stereotyped it is which means how

21:45much does it look the same every

21:48time um we need we found some

21:52correlation with specific genetic

21:54Developmental and epileptic and kopies

21:57but we need larger cohorts and my dream

22:00and I think will be reality is that one

22:02day our treatment will be tailored to

22:04the genetic

22:06ideology so in concluding this talk

22:10understanding what a Developmental and

22:12epileptic en en opathy is is critical so

22:16that patients can be diagnosed with

22:18these diseases the cause can be found

22:21and we now have 825 genes that lead to

22:25Dees and then treatment can be targeted

22:28to the genetic disease which today might

22:30just mean choosing the right

22:32anti-seizure medicine but in the near

22:35future hopefully will mean gene

22:38therapy the epidemiology of Dees has

22:41found one in 591 children have a de and

22:44this will guide investment policy ma

22:47policy work and Drug

22:49development we can now fund the genetic

22:52cause in 50% of patients with

22:54Developmental and epileptic and careal

22:56opathy but these different genetic

22:58diseases differ with regard to their

23:00risks of status epilepticus mortality

23:04sudden Unexpected death in epilepsy

23:06rates and so understanding the gene

23:08informs your management and uh

23:11counseling for families and movement

23:14disorders in patients with Dees need to

23:16be differentiated and may require

23:18treatment in their own right I’d like to

23:21close by thanking the fabulous team that

23:24I work with in Australia um also my many

23:27intern National collaborators and most

23:30importantly of course patients and their

23:32families thank you very much for