82 – Behaviour, Cognition and Sensory Processing in People with SYNGAP1

Andrew Stanfield, MB, ChB, PhD

Dr. Andrew Stanfield is a Senior Clinical Research Fellow at the University of Edinburgh’sDivision of Psychiatryand an Honorary Consultant in the Psychiatry of Learning Disabilities working in hospitals in Edinburgh.  He is also Co-director of the Patrick Wild Centre for Research into Autism, Fragile X Syndrome, and intellectual disabilities.

Dr. Stanfield’s research interests primarily relate to the autism spectrum, intellectual disability, and related neurodevelopmental disorders.  


hello everyone and welcome to today’s webinar my name is Olga Bothe and I’m part of the team here at Syngap research fund our presentation today is behavior
cognition and sensory processing in people with SYNGAP1 and I have the pleasure to introduce today’s speaker Dr Andrew Stanfield from the University of Edinburgh
Dr Stanfield is a senior clinical research fellow at the University of edinburgh’s division of Psychiatry and an honorary consultant in the Psychiatry of learning disabilities working in
hospitals in Edinburgh he’s also co-director of the Patrick Weil Center for Research into autism
fragile X syndrome and intellectual disabilities Dr stanfield’s research interests primarily relate
to autism spectrum intellectual disability and Related neurodevelopmental Disorders
recorded version of this webinar will be available on our srf website under the resource tab
and by the end of this presentation you’ll have the opportunity to get the answer to your questions and we’d love to hear from you so please put those questions in the Q a below and for those
of us for those of you just joining us welcome and again our speaker is today is Dr Andrew Stanfield
from the University of Edinburgh to discuss Behavior cognition and sensory processing in
people at SYNGAP1 it’s now my pleasure to turn things over to Dr Stanfield thank you
okay thank you very much Olga I hope you can all see and hear me fine and and can see the slides
do let me know if you can’t the um uh so it’s a pleasure to be speaking to you
um I I’m going to start off with an apology well two apologies actually tomorrow’s the first is
that I I currently have covered so um if I appear to be a bit spaced out or maybe more spaced out
than usual that’s that’s my reason and the second is that there’s there’s quite a lot of data and
things in this presentation um because what I’m going to do is present you some findings from research that we’ve been conducting over the past few years and which indeed I think there’s some of
the UK families are watching here which I’m sure there are them you will certainly recognize some
of the um some of the questionnaires and some of the the tests and things
um before I get on with the um the actual presentation just is that people know up
front me have received me and my research group have received funding from various pharmaceutical companies for for clinical trials and and also for um doing consultancy um over the
last 10 to 15 years and and particularly for trials autism and another condition we work in for fragile X syndrome and I work um at a place called The Patrick wild Center uh at the
University of Edinburgh and I as part of that I work um we work alongside a really with another
Center called the symes initiative for developing brand we describe these as being Sister centers
um at the University uh and what they do our whole kind of idea and this is taken from the
Sid B website is that we’re trying to understand the brain basis of under Test new therapies but
really single Gene conditions which are associated with autism intellectual disability and you can see from um you know as I say this is team from the city website SYNGAP1 is right there uh as one
of the uh the big genes that we want to understand and uh the big conditions that we are are working
on here in Edinburgh the work that I present today is one aspect of of that um but these are all the
different group leaders from from SIDB um and each of these individuals Works to some to a greater
and some to a lesser extent on various genes associated with neurodevelopment and each of them
runs a research group so I suppose I’m just trying to get over to you that there’s a lot of people uh
you’re working on this field here in Edinburgh a lot of them based on sort of laboratory scientists
and then some clinicians like myself so I’m going to present kind of one aspect of the SYNGAP1 program in Edinburgh but there are um lots of people here who are working on SYNGAP1
I mean you can see at the top Peter kind is the head of SIDB um he’s done a lot in SYNGAP1 of the
years and many of the other people here some of whom may have indeed spoken to you before
um the other thing about the centers I want to get across before I I start is that they are
you know they were started by families really you know that that’s been at the core uh of what we do
um since the beginning you know the Patrick wild Center started now you know something like 13 14 years ago um and it was this found me the wild family here this is Alfred Wilde
um who you know left money in a legacy donation really to to set up the Patrick wild Center
um named after his brother Patrick who had severe intellectual disabilities on autism but actually
more so in memory of his parents who cared for Patrick at a time when there was little
or no understanding or support available other families have been involved um you know and some
of whom are pictured here throughout and then in the bottom this is from one of our family uh the syngap family Meetup in the UK from from last year which weirdly I also had covered for
um so so I had to talk online at that but it’s um we have another one coming in a couple of weeks time so I’m hoping well I will definitely attend them um
okay but the um what I’m presenting today what I’m going to present is findings from this the
neuro GD study which is really a large study and it’s SYNGAP1 is one of the main genes or
one of the main conditions that we’re looking at in this and we were also looking at another one called fragile X syndrome but obviously I’m going to present mainly this in gap results today
and I’d say some of you may recognize um some of the some of these tests Damien and Ashling
here were the two people who did a lot of the work traveled around the UK um you know some families
came to us some we went to see in other parts of the UK and to take part in this in this study
and what we’re aiming to do in Euro GD was was this um you know we were trying to really
understand behavior and to describe behavior um in detail and people listening at one and to describe
um a bit about cognition a bit about sort of how people think and how people um you know kind of
um reason and work things out we were looking at whether or not we could do research level eegs
um in people listing out one and I’ll present a little bit of that data that
um and we were looking at whether or not we could use some of these measures things like the EEG things like the cognition uh whether or not they might be suitable for future trials um to think
about tracking response to treatment objectively so rather than just using measures of behavior which are inherently subjective again these other sort of more objective measures to see about
whether we could attract and sort of progress and response to treatment and then we were also
interested in basically establishing cohorts you know getting in contact with people getting to know people you know with the idea that at some point you know what what we aim to do are trials
um in SYNGAP1 as we have done in other conditions so that’s one of one of our big games is just
around sort of them developing those cohorts developing those contacts through all of this
so when you’re interested in behavior um what what we decided to do first and I have to thank
Mick Parker for this he’s one of the geneticists who did some of the early studies in SYNGAP1 in the UK you know Nick said well the first thing you should probably do is just go and ask the families
um you know and I think that’s maybe something that that we don’t do quite enough um so we did we we did some of these clinical interviews with families we started them at our
first family Meetup and we went then you know we’re basically looking for themes you know of
when we’re asking people about you know you know how are your children and we’re mainly focusing
on challenges I have to say I think that’s a gap um in what we do generally speaking but
you know we were mainly focusing on the kind of behavior behavioral challenges that people um are faced with and so we did these interviews in about 27 people mainly children
um we asking families about how they wear and you can see the kind of things that came up will not be a surprise I guess to any any of you but these sort of um repetitive behaviors
difficulties with change people struggling with transition and getting very focused on things
um combining that with some of the social difficulties and things here is these are kind of classic sort of autistic like traits um often Associated and I’ll talk about this
in more detail things like distress related behaviors becoming aggressive towards themselves
and other people these three of us people sometimes call them challenging behaviors um we’re quite commonly brought out and then struggling with daily living skills
struggling with emotional regulation and then I’ll talk more about sensory differences later on but it was one of those things that came up um quite commonly and people very concerned about
this lack of danger awareness being unaware of danger and you know not really being able to pick out would run into the road not knowing kind of the general life or social dangers
so this just gives us a bit of a handle on which to start to think a bit about what more we want to try and measure well you know what we want to get into in in a bit more detail
and we were doing that um through these kind of more quantitative measures of
behavior so things that we can actually you know count and allocate scores and this is very common in this field I’m sure most of you are very familiar with it you know
um looking at things like um you know we did a whole load of questionnaires anyone who took part in this study will remember probably doing a whole load of questions
um you know we we looked first of all at this adaptive Behavior so the kind of things that people need for day-to-day life we use various skills the thing called the violence for that we
looked at I’ll talk more about these skills in a bit we look more into these behavioral emotional difficulties we looked at autistic traits and ADHD trades and we looked at sensory issues as well
so I’ll show you some of some of the findings and some of the results from these oh yeah we did this
in a similar kind of group same sort of group these were all recruited are mainly recruited from the UK not entirely but mainly recruited from the UK um about 30 people um 30 with
syngap and just slightly less TDC means typically developing controls that’s like a comparison group
um we had a few adults almost all of the data I’m going to present though relates to the children
because we didn’t really have enough adults to make great sense I think there was only three people above the age of of 18 requirements studies so everything I’m going to present here is
um going to be about children um the of the 30 people in Syngap 40 had a diagnosis of autism that
means that they’d actually been seen by somebody and being formally given a diagnosis of autism
um only two had a diagnosis with ADHD which is important and again I’ll come back to and
about 60 had epilepsy which I was surprised at I thought that would be higher um to be honest
given that a lot of this in gap research has come out of the epilepsy field um and then the
main kind of non-verbal IQ was about 60. um again I’ll come back to talk about some of these things
so starting off with the Adaptive behavior um on the Vineland this gives you you can get all kinds of scores from these things indeed
one of the difficulties is sometimes trying to reduce their mind that you’re actually measuring um the so that you can make best sense of it but so basically what the Vineland does it gets people
to answer loads of questions and then it gives you scores for different demands communication
consists of three sub demands daily living skills socialization and then motor skills so fine motor
and grow smoother importantly about this the scores are all age normalized to a mean of a
hundreds like a bit like IQ so you know the level of communication a four-year-old has to
show to get a score of 100 is much lower than the level of communication a 15 year old would have
uh you know when you expect a 15 year old to do more in terms of daily living skills looking after themselves getting out and about in the community then you would do for say a
three-year-old so they’re Age normalized and and that’s important what I’m about
um lots of graphs lots of data coming up um I will try and just explain the important points
basically the the key takeaway here which again is not is not a surprise is that you know in our
syngap group we see difficulties really across across the board in terms of daily living skills
and and adaptive kind of behaviors uh singer you know the syngap group will be in red and most of
the slides I present what’s I guess important you know is that I think the most marked differences
are seen done in communication so you know even compared to the the other scores uh the the
children’s show kind of receptive and expressive communication difficulties which are probably
um more pronounced than one would expect given some of the the other difficulties
motor was a bit less spared um than the others but still you’re quite there’s
still quite a lot of motor difficulties that people have and that we know about um one of the interesting things that comes out from this is that you know the older
people in our cohort have got lower is normalized scores than the the typically developing folk no
what that means I think this is important is that this is as I talked wait well two things one this
is cross-sectional data so you know this person here who’s you know quite 12 13 14 years old is
different from this person here who is four years old the way you want to look at this
um to show what’s actually true is to look at it longitudinally so to see this person here you know
four years old and then to track them up to you know eight years old 10 years old to see you know how these scores change um so first of all it’s cross-sectional so it may just be that some of
the older children have got more difficulties you know and that could just be coincidence um the the second thing that’s important about is these are kind of age normalized course as I say
that doesn’t mean that so what I’m not I’m not saying that people are declining per se this isn’t talking about regression or the children have um get worsened or lose skills
what it is more is that um you know some of these more complex skills particularly things
like learning how to write going out and about in the community you know you see that these are
non-age normal life scores these ones I should say no um you know in the controls you see these pick up dramatically between the ages of four and fourteen you know and that’s again to be expected
and that’s not what you see you see you do see improvements you do see development in in the and
you know our Singapore but it’s not to the same extent that you see in kind of control and it’s
in particularly these kind of advanced skills that people would normally pick up as as they get older
the other thing that was interesting about this um is that it was most marked this kind of not
keeping up with skills or not developing things in those with epilepsy as well um you know though whether or not that is holds whenever we look longitudinally I don’t know
um and what that means is also something that you know we we don’t know I don’t you know
it’s possible that some of the older children were more likely to be epileptic and that’s
how they got diagnosed 10 years ago um with singap one and so that’s why this relationship is there it is also possible that you know people who have untreated or or you
know lots of seizures and things it would be understandable if maybe they didn’t manage to develop the same kind of skills as those people who seizures or maybe kind of well
so um you know this is stuff that we need to look to look more into
um longitudely the the next thing that we looked at were these kind of Behavioral difficulties
um you know and this was using a thing called the cbcl awful questionnaire 113 questions quite small
writing takes it’s a good very good question here lots of detailed information but just when you’re the person filling it in it can take a long time it covers lots of different demands it looks at
kind of um what are called internalizing problems that’s things like withdrawing into yourself being
anxious or depressed sort of somatic complaints or physical health aches and pains and things
like that it looks at externalizing problems things like aggression and Rule breaking
um you know other um kind of important parts but and I think of things often
that cause the most difficulty and then it also looks at things like attention and social difficulties and difficulties with people’s thinking and processing of information
um which are associated with intellectual disability autism and ADHD
um if you look at this in in this sort of set of scoring the the controls again are in blue
and we see particularly high levels um you know I I was surprised actually I thought we would score
higher levels on things like anxiety and things in this in gap group and I wonder if maybe we’re just not capturing that that well but we do see quite high levels of attentional problems
particularly interesting and I’ll come back to this later not lots of our group do not have diagnoses of ADHD and and um high levels of aggressive kind of behaviors
these social difficulties associated with autism and the thinking and thought difficulties are most likely related to the uadhd or not to adhd2 intellectual disability but
um you know that that holds when we look down at the kind of if you look at this scale at the items
that were endorsed by over 50 of our population Lots coming out in the attention hyperactivity
um and quite a lot coming out in aggression and agitation sides of things but these are you know
relatively common uh within this cohort and cause cause difficulties and stresses
again we wanted to look at age because when we speak to families there are some families who’ve
come to us instead but you know that they they perceive that things can get have been
getting more difficult through adolescence um and certainly within our childhood cohort we do see
this kind of some of these difficult behaviors become a bit more marks um over the course of
over the course of adolescence again this is cross-sectional Behavior a cross-sectional data
so we need to look at this longitudinally to see whether this this actually holds
the the next set of things uh that we looked at were autistic traits and and ADHD kind of traits in terms of behavior
and um you know what what we find in terms of autism so this is a thing called their social
responsiveness scale and we find really quite high levels of autistic traits according to the scale
in in singaporeon Waits eighty percent of people are scoring in the moderate and above impairment
um and on this scale now this is not a diagnostic scale this is a screening scale for autism
um what’s interesting about it doesn’t relate to age so this is not something that changes with age which fits it’s with autism and the traits really aren’t supposed to change
it is very much Associated though with non-verbal IQ and it’s possible that some of these artistic trips might actually really more to the difficulties
um the the broader difficulties with intellectual disability and so forth rather than autism per se
what is interesting though is that about 40 of our population had actually a diagnosis of autism
um so you know we that is either under diagnosis you know that actually there are more people with
Autism who aren’t for whatever reason getting a diagnosis and there’s lots of things that affect whether you get an Autism diagnosis certainly in the UK there’s very high waiting lists for some of
these things and it depends who you’re seeing and you know these things autism diagnoses might be
more likely to be made in certain disciplines and so forth and it depends whether or not um you know it’s been felt you know some some doctors will say well you know what’s what’s
the point of giving an extra diagnosis we know that this is related to this genetic change so you know there’s lots of things that that affect it um the but it is possible that
people are being kind of under diagnosed or or the autism being under under recognized
it is also possible though that at least some of these traits are more related to to the sort of more Global intellectual difficulties as opposed necessarily to autism per se
what is important is when we look at why are there not autistic traits how they might actually relate
to these measures we looked at earlier things like adaptive Behavior more that Yeah the more artistic
somebody is in terms of their social communication the lower their adaptive behavior is so
um uh that means that people generally speaking more autistic people are going to struggle more
with the kind of things that um allow you to get out and about in the community to manage yourself
um to communicate with others and to your kind of daily living skills and things what’s interesting
is that social communication skills autistic aren’t really related to externalizing behavior
so these these kind of aggression these behavioral challenges there’s a slight relationship here it’s not statistically significant but it’s not a big driver of these kind of things
um for repetitive behaviors we see a slightly different picture you know the levels of
repetitive behavior and this is things like resistance to change problems with problems with transitions relates a little bit to Adaptive Behavior you know um but it’s not super strong
um and or but it does relate to these externalizing behaviors to aggression and so forth but these sort of things like resistance to change and repetitivity
um you know are associated with higher levels of aggression higher higher levels of
um uh you know frustration lashing like and things at other people and I do wonder if I mentioned
earlier on that you know the we didn’t score particularly highly on levels of anxiety in some
of our groups using the scales we looked at but I suspect that at least some of these sort of things
like the resistance to change and struggling with routine these are anxiety related um or these can
cause a lot of anxiety and agitation children who who struggle with changes to routine can become distressed and and stressed maybe rather than anxiety distressed um more often and that can then
lead to these kind of externalizing behaviors they’re things like aggression and so forth
ADHD traits were slightly different I was particularly interested in this because I was surprised that you know I don’t find a surprise the relatively low rates of ADHD diagnosis in this
sample are the seven percent only two people now this really it’s possibly the two things one this is mainly a UK sample and in the UK we do diagnose ADHD less than in some other parts
of the world particularly the us although it’s not that much less than it used to be
um the second is that I think broadly speaking across intellectual disability
um we don’t we under diagnose ADHD there’s a tendency to attribute things like inattention
hyperactivity to IQ you know too though it’s part of a global impairment these Global IQ differences
whereas actually some of them you know might actually be a similar process to what leads to
ADHD and the general population you know if you’ve got a general population rates of ADHD which
can be between five to ten percent depending on where you measure them there’s no reason why you wouldn’t see that within our syngat populations within our learned populations
and we’re likely to see it more um the yeah so they ADHD was was particularly interested
didn’t relate to age so it doesn’t change with age and it didn’t relate to non-verbal IQ so
it’s not a bit different from the autistic traits this is not in this cohort anyway it’s not the people who have got lower IQ have more ADHD it seems to be something the um okay
so in terms of ADHD traits the other thing that’s really interesting about them
is that they are associated with adaptive Behavior you know because you don’t pay attention as much
you know do you struggle a bit more with adaptive Behavior don’t do you struggle a bit more with behavioral difficulties but the hyperactivity impulsivity side of things the part of the ADC
hyperactivity impulsivity part of the ADHD is very much associated with difficulties
with adaptive behavior and very much associated with difficulties with externalizing behavior
the um um okay I should say sorry I can hear at times that I am there’s various noises going on
but I’m not quite sure whether those are related to to what’s going on the webinar I’m unable to see the chat on things at the moment so if there is questions and things we can
um we can come back to them or someone’s able to kind of I’m happy to be interrupted if they wished
um the but yeah particularly this hyperactivity impulsivity component
of ADHD seems particularly important to determining how well people get on with their adaptive Behavior and the levels of Behavioral difficulties that they show
so lots of graphs lots of data um I’ll there’ll be more to come I’m afraid but um you know going back
just trying to summarize some of these behavioral findings that we have we have high levels of autistic traits and high levels of ADHD trades across all age groups despite you know diagnostic
rates of these conditions are relatively you know seven percent for ADHD 40 for autism
may be under diagnosed I think particularly important to consider this for ADHD because ADHD
might you know there are treatments for ADHD they probably don’t work quite as well in
folks with intellectual disabilities and that you know attentional and hyperactivity in the kind of more Global cognitive impairment sense but there are treatments and they
they are things that could be tried and that could have some you know significant benefits
um I think it’s important to point out I think everybody here knows communication is a particular
problem and that is important and I think you know having access to speech and language therapy uh to
look to develop functional communication skills you know I’m not saying necessarily people will develop lots of language but better ways of communicating and supporting communication are
are really important I think that think about the behavioral difficulties which is obviously
one of it’s one of my main interests being a psychiatrist you know focusing on anxiety the kind of things that maybe drive some of these difficulties with routine and so forth
um and focusing on ADHD would seem particularly important if you’re looking at trying to treat
or manage some of the behavioral difference the behavioral difficulties that that occur
um and then the last thing I I’m very tentative about saying this because as I say this was
cross-sectional data there’s some idea that some of our older adolescents are maybe more
affected than than the younger other than the ones in our cohort where where this holds true for you know as we study people over time you know whether whether we see changes in these
difficulties we we need to work out so we need to do long achievable studies and see if this
is true and then to look at the reasons as to why that might be and what might become
okay um that’s most of the stuff from behavioral questionnaires I’m going to very briefly mention
sleep this is not work that I have done particularly I was um although we did data from neuro GD was we contributed to this paper with funny Constance with hex and Jimmy holder
they’ll be familiar to many of you um looking at sleep because sleep is obviously one of
those things that families you know struggle a lot with and it can be particularly difficult and we
really want what we can see is that you know it’s like as families and said children will sing out
one do struggle to sleep and they’re actually probably more severe sleep difficulties than are seen in some other forms of genetic intellectual disability um so this paper was comparing sting at
one to Phenom McDermott syndrome which is another um genetic form of intellectual disability in autism and find that the singap kids you know had similar or greater difficulties with with sleep
um colleagues of mine Lindsay mizzen again will probably be known to some of the UK families went out and did some sleep studies using actigraphy watches
um and did some sleep studies where they actually went to people’s houses and patched elect you know various electrodes to measure brainwaves and things like that to people
um yeah to try and get a handle on what these sleep difficulties are and what they um what they
may be caused by or what the parents are Lindsay I’m sure would be delighted to come and talk about
this with you at some point um you know there’s some of our early findings that she’s looked at and has presented elsewhere showing that yeah we can measure we can use this actigraphy these
watches kids managed to wear to actually quantify the Sleep difficulties to to actually measure how
much people are awake after they go to sleep and then how efficient their sleep is so if you spend time in bed versus time of sleep basically a sleep efficiency and this is important because if you’re
doing studies of medicines either to help sleep or to help uh you know other aspects of singer using
these active graph watches could be particularly useful the other thing that Lindsay is doing is
looking at some of the um findings from the more detailed sleep studies and comparing those to um findings that colleagues of ours in um Patrick wild Center and then Sid beehive in the laboratory
models of Singapore to look at these kind of translational biomarkers as they are called
so I won’t go into that in any more detail but it’s just to let people know
um okay where am I for timing um cognition then we we wanted to also measure cognition you know
this we a lot of the behavior things we had looked you know we had some ideas of the kind of things that we might see from popular parents but we wanted to try and understand you know
um quite thinking was affected in Singapore and this is this is quite difficult to do because one of the main ways that we access people’s thoughts as they say um we wanted to
be able to understand how the brain works why people think and how that might be different we also as I said earlier on we wanted to look at more objective ways of capturing difficulties
I’ve talked about social difficulties attentional difficulties and so forth but we wanted to look at
um whether or not we had ways that we could measure these that were not just you know rating
scales which are affected by how things have been that week what’s going on in the child’s life they’re affected by how you feel they’re affected by how the child feels and they’re
infected by actually what the investigator says to you whereas what we wanted to do in measuring
cognition was to try and tap something a bit more objective um using these measures we use the
non-verbal IQ measure which I’ve already referred to um a little bit um called the lighter three
um and then we used um measures of social attention and inspection time which is a kind
of more Global cognitive measure using a thing called eye tracking and I’ll talk about each of
these [Music] um so the lighter three first of all I I don’t have a huge amount to say about
this this is this is basically a non-verbal IQ test again it’s age Norms to about 100 to 100
so you know a child who’s three has or childish 15 has to perform better in a childhoods right
um on it and it is entirely non-verbal so it’s not the idea of using this was to try and get at you
know the the population of children that we saw how what their IQ was if you took away some of the
communication it’s not I don’t think it’s possible to entirely divorce findings from communication
you know there is a level of communication even in administering a non-verbal IQ test
um but you know it’s just it probably represents a bit more people’s underlying cognitive abilities
so most IQ tests I should say I guess people might know this are a combination of verbal IQ and non-verbal IQ one of the concerns really is that you know when you do that if you have
a population who particularly struggle with communication that’s the thing that one group too you’re maybe your score that you’re getting in an IQ test maybe it doesn’t reflect someone’s
actual abilities and understanding uh and an ability to think and reason
um and so so whereas non-verbal-like you might be a better measure
um of of how people actually function and then what was interesting to me and this was was the
spread really more than anything else you know the mean IQ was in the uh non-verb like he was above 60. it was just above 60. that’s higher than I expected to be quite Frank
um you know uh the and it stretched up we had one person with Nike of 100 IQ of 90 down to 80. I
mean you know and and they did go down to the to the lower end of the range but it was it was the
spread of IQs and to be honest I think uh higher IQ as we expected which I I think is probably
I mean you may well as parents probably May well know this that people aren’t seem to understand
maybe or pick up more than maybe their levels of communication actually um uh allow them to
demonstrate and I I suspect that’s what we’re tapping here and we can see that nonverbal IQ
is is important I mean it is um it all it does relate to people’s adaptive Behavior those people
who score more highly on this IQ measure tend to have a higher level of adaptive behavior
um than those who who score less well um so you know I’m I think it’s just interesting and
it speaks to the idea that actually you know that there are perhaps skills and abilities
that that children just maybe aren’t able to show because of their levels of communication questions
um eye tracking um we used to look at particular um as I say this inspection time and social
intention the reason for using eye track I mean basically what it is is you you have a computer
and sat at the bottom of this screen here is a little device that tracks where people look at
and you can use that to measure various cognitive abilities um because you can
look at where people are looking at and you can look at how long people are looking at it for and it’s passive the nice thing about it is it doesn’t require communication it doesn’t require
you’re not telling the children okay you know look at this screen and find the find the o or look at
this screen and do this it is literally you’re showing them the screen and you can see where
they look at [Music] um and because it’s passive it’s quite suitable for non-grabberable groups
and then because it’s objective we’re not telling people to do things um and we’re not asking people
to measure things we’re just measuring what is actually a behavior that’s occurring it’s it’s
potentially useful as a measure you know to tap this cognitive thing as a measure of um possibly
response prediction to medicines and things and trials possibly for users as a medical project um
so what did we do with the eye tracking we looked at we looked at a few different things um we were
particularly interested in so there’s a lot of eye tracking work in this sort of field of social attention um in autistic groups and so you know we wanted to see could we tap and could we look
at these some of these artistic traits measure them objectively and maybe look at so you know I
it can also give us some idea about mechanism and things we did a few different tasks and the first
one is uh well there’s three of them the first one was this kind of social the one on the right
of the screen which is you know you show them two scenes one with a social stimulus usually a person
or it is a person who’s in it and a non-social scene where there’s there’s no person in it and you just look at how long people look at one versus the other you show an array of pictures and
you look at how long people look at the face which you know most people will Orient towards the face
and be more interested in the face than they are in the other things and then in faces themselves
people typically are more interested in the eyes and then to a lesser extent the nose and the mouth
feature parts of the face but particularly the eyes than they are in other parts of the face so
so what we’re doing is just we’re looking at where people attend to we know what what people’s eyes
are drawn to what they’re looking at and we’re also I should say it’s looking at relative times so we our singap kids do not look at the screen as much as the typically developing controls
because they are more distractible so they would be looking away but what we can do is look at the relative point of time that each person you know so that somebody is looking at the whole screen we
look at the proportion of that time that they are looking at the eye say for example so the
first one the social versus non-social thing what we see is that actually the syngak group performed pretty much the same as our our typically developing controls they were more interested
in the social scene than the non-social scene so more interested in looking at uh scenes of people
and none van scenes without people in them in the same way exactly the same kind of pattern that you see in the controls so on the left of this group it’s a social scene it’s engapping controls and
the right non-sources instant government rules and there’s no differences between um the the singer group and the controls here and both tend to look at the social scene more
so they’re interested in these kind of social scenes more generally and things with people
in them it gets a bit more interesting when we look at these what folks look at in these pop-out tasks as we call them so there’s lots of things on the graph there but
the interesting things we find is that the syngap group look less at faces they fixate
Less on the face than they do on the other items they also look a bit less of the phone
um it’s a very old phone in this picture uh I don’t know where that is because um people are
less interested or whether the controls were looking at are thinking what on Earth is that um but you know they were yeah they were particularly less interested I mean the
singap group should lessen client inclination to look towards the face than the controls did
um and that’s interesting because that’s in a bit of contrast to the previous one where actually both looked equally at the um at the social scene and then this gets more marked when
we get to this more intense social stimulus this is a kind of zoomed in picture of someone’s face
um and this is the one on the left is what the child sees and then the one the right is how we Define non-feature faces known feature Parts the face which is the white oval then the red red is
how much people look at the eye region purple than those the like and broadly what’s what
we see is that kids are saying Gap look less at the face the more looking at other parts
um of the the picture and they look less at the eyes when they are looking at the face
they are looking at other parts of the face rather than the eyes so even when the when the the proportional looking time for the eyes is actually compared to the whole face
so when they’re looking they don’t want to look at the face and when they look at faces they don’t particularly don’t want to look at the eyes whereas they you know
the controls show that bias towards eyes and towards faces we just don’t see that biased
so when we take these kind of social attention things together we do see social motivation and families will tell us that the kids are pretty social at times and want to you know want to be
social but they look when they when you get these more intense social stimuli which is
what this is how we are interpreting this and you know those social scenes the kids the people in them aren’t usually looking at the camera there’s lots of other things going
on they’re not an intense social stimulus but if they get more intense you start to introduce faces that people have to look at in their eyes and so forth that becomes more
difficult certainly less appealing than it is for control and it might be that
it’s actually stressful you know that that there’s a kind of aversive nature of these kind of more intense social stimuli which is something we see in some other other conditions
um for whatever reason that this these sort of social these more intense things can be stimulated
can be quite um aversive or cause degree of stress and the other thing that’s interesting and and
good about this is that you know the eye tracking does seem to be able to objectively quantify some social differences I didn’t mention it there I thought I had a graph with it actually but um the
difference in time of looking at faces was much less or was Associated you know the ones children
who are more autistic showed the greater aversion to looking at faces when we looked at comparing these kind of eye tracking findings to our um our measures of autism we we find that they related so
that they are indexing these eye tracking findings seem to be objectively indexing these sort of
autistic type Trails or social communication part of the artistic traits in in our case is Singapore
um the other thing we looked at eye tracking and I will just mention this quite briefly because I’m a bit aware of time it was a thing called inspection time reason for looking at this is
that in typical people the quicker you find and out an odd object in an array or a group of other
objects relates to your overall IQ basically um you know and um this was we thought might be an
interesting way of actually trying to pick out well hi you know could we index IQ or
um objectively using our eye tracking so what we ask children to do is we don’t ask them to do this we show them a picture put up a nice attractive stimulus in the center some
little cartoon fire character or something like that that attracts people’s eyes to the center when we display these um this array of uh shapes which are letters here um right all of them the
same apart from one these circles aren’t there I should say so these circles aren’t actually part and you look at how quickly people find the odd one out and you could how often they look
at the original and and mostly typical people will look at this you know relatively quickly
and we’ll fixate on it more than the others um importantly for this to be able to do it you have
to look at the center and and there were six of using Gap Kids just didn’t look at the the nice attractive thing in the center of the trial so so we had to exclude some people from the analysis
um and what we find that that you know of the trials number of trials that people actually do
the kids this thing got one are less likely to fix it they’re less likely to look at this old
one right so we only show this for a very short amount of time uh typically developing controls are more likely to you know locate and find the odd one right um the speed at which they find
the overnight the ones who manage it it’s a bit slower in our singact group it’s not
significantly slower but it’s a bit slower but we do see a relationship between this no between non-verbal IQ and adaptive Behavior we do see a relationship between that these measures and
the speed at which people think safe so those people who have got a higher non-verbal like
you are hired after Behavior within our singap group find this odd one-eyed object quicker
so it would suggests to us that we this again it might be an objective way of kind of indexing
cognitive abilities which might be helpful or suitable for for um clinical trials okay
so I’m hoping you’re all still with me hoping people haven’t haven’t turned off from all of the stuff I’m too much data um this is the the last set of things I want to talk about which
is sensory processing last few minutes um we we know we knew from talking to families we
knew from seeing children that that there are sensory processing differences in Singapore
um and we use this measure or called the sensory profile and it’s a good measure because what it does is it allows you to look across different senses so hearing Vision touch movement body
position and a mouth sensation what to me so it gives you scores across all of these
um it allows you to have sensory behaviors which I’m not going to talk about but some of the stress type behaviors that might result from sensory things I’m not going
to talk about here because we’ve not really looked at this in great detail yet um and then it allows you to kind of um you know look at these scores within this
um so theoretical model of sensory behavior and sensory sensitivity
um basically this has an idea that there is hypersensitivity and hyposensitivity
uh if you look up and down this this Arrow here and then that’s affected by how much people
actively try and self-regulate their sensory systems so well how much they use their behavior to regulate their sensory input and how much they self-regulate using more passive measures and then
it gives you these scores in different domains so somebody who is hypersensitive and actively
self-regulating they’re hypersensitive to stimulus stuff they will they will move they’ll avoid sensory stimuli they’ll try and reduce it by kind of withdrawing and hiding away
or they’ll be very sensory sensitive if they possible so you’ll notice that they are you
know particularly reacting to certain senses somebody’s hypo sensitive if they’re active
they might seek out sensation they try and increase their sensory systems responses
um whereas if they’re passively self-regulating they just don’t notice um sensory things so they just don’t seem to register themselves
you don’t really need to understand the kind of whole model to sort of think about the results but
um I guess the key thing here is that we find this this contains data from fragile X syndrome
I should say as well listen got one side of these slides but all we find is our singap one groups show clearly you know high levels of sensory sensitivities across the auditory
domain less obvious across the visual demand um but certainly with auditory touch movement body
position and and oral Sensations you know there is differences in sensory sensitivity
um and this is both High sensitivity if we look at these different domains
both hypo and Hyper sensitivity so both you know seemingly low registration so this is one of
those classic things that people have talked about not picking up pain stimuli not seeing to respond to pain that would be something that would come in here this hyposensitivity sensory
seeking is associated with like seeming to enjoy things so the kind of stuff families talk about is like wanting to touch water and so forth um and and that’s it meant you know that could be
an example of someone who’s hypo sensitive but they’re seeking stimuli and then this hyper sensitivity avoiding appearing senses of getting very distressed by by very sensories all of them
in our group you know we saw these differences in singap one um across and they’re similar to those
that we see in fragile X and fragile X is another condition you work in where actually these are
very well established these sensory differences one of the kind of core parts of fragile X this is
um these sense three differences so to see we see similar levels in in Children of Singapore
and then what’s important to remember as well is that the same child can be both hyper and
hyposensitive so that sounds a bit contradictory you know how can you be hyper when hyper sensitive
but but they can this is a dysregulation of the sensory system rather than an over sensitivity
or an under sensitivity so it is um and that’s what this graph on the bottom left here shows
you know the children who are more hypersensitive are also likely being more hyposensitive and that
that’s a really strong relationship so you can think of just one or the other
but High bar sensitivity is the thing which is most associated with these difficult behaviors
so I’ve talked about earlier these sort of aggressive or or distressed type behaviors are most associated with this um people’s level of sensory hypersensitive
would suggests that it’s particularly important to try and understand those in terms of when you’re thinking about what might be causing sort of behavior
we then went on to have a look at sensory processing using EEG um so seeing if we could
again quantify this then these sensory processing differences and look at maybe what might be some
of the things that underlie them um we did this using what’s called an auditory Oddball Paradigm
so basically you have this EEG cap on and we play lots of tones 600 tones beeps basically and then
some of them are a certain frequency and some are a higher frequency so it’s really like people
and the reason for doing that is it allows you look at how sensitive somebody’s brain is to there’s their auditory system is to these terms but also what’s different whenever they’re
hearing the same tone over and over and hearing a different tone and that’s what the graph in the
bottom right sort of shows the this is the kind of response electrical activity in the brain that you see to you know a um a these repeated tones and then the Oddball so the odd one out there
the higher tone you get a slightly different one and we’re interested in that because this is a thing this difference is a thing called mismatch negativity and that’s interesting to us because
it’s possible indexes a few different things but one of the main ones is it’s thinking about a thing called prediction coding or protection error so your brand ability to look at these um
our brains rely on basically being able to predict things about the world and what is predicting when
it’s hearing the beep beep beep the repeated tone is that that’s what I am going to hear and then when it hears something different it goes oh something different has happened so
it’s it’s having to change its predictions it’s having to change adapt in terms of um you know
how it is working to a change in the sensory and that that’s the thing which is called mismatch
um and what we see basically in our in um the children with singer
I don’t necessarily is that there are differences in the mismatch negativity so it’s a bit hard to see in this graph but the green or the the blue is the typical developing control just listening
to the repeated tones the green line is then when they hear the standard or the Oddball term so you get a difference occurring at this point 200 milliseconds after stimulus onset
syngap group are the black and the red and you don’t see a difference at this at this
point they’re not reacting differently to the Oddball tone as they are to the standard tone
and that that suggests that this projective coding mechanism in the brain just it’s it’s not it’s not
processing the sensory stimuli in the same way and then what’s really interesting about this
is that when we take this EEG derived measure and then we correlate it to sensory hypersensitivity
measures a card is quite strongly so the the more hypersensitive kids are the ones who show the
um the biggest difference from controls in their mismatched negativity so the basically it’s it suggests that this lack of um you know the the difference in the way that the brain is
processing this audible stimulus is in some way associated with the degree of hypersensitivity
that people show and it’s also really strongly Associated albeit numbers are pretty small at
this point you know that we’re looking at um with the levels of difficult behaviors
that this predictive coding difference in the brain that’s mismatch negativity is associated
with differences in uh sensory processing uh and increases in these aggressive or agitated
so pulling pulling that bit together um aware I’ve gone over my my time
um that you know we see high levels of sensory hypo and hypersensitivity and they can occur
in the same children across different senses they’re probably really important for Behavioral challenges particularly with hypersensitive um you know and it’s one of those things that you
know we increasingly think about in clinical practice uh it’s getting you know it’s usually
an occupational therapist who would be able to look measure sensory processing differences and things and then try and give some strategies to try and manage them it’s not like you can
get rid of these things but how you might be able to manage some of these sensory processing things but optimizing the sensory environment to try and reduce these levels of different
then we have some idea and it’s preliminary data in small numbers so we need to we actually need
to analyze this more to check that it’s it’s it holds and but this sensory hypersensitivity might
relate to high differences in the way the pro sensory processing system kind of codes
um predicts stimuli that are coming and then Alters itself to new stimuli and that we might be
able to I mean we can capture that using EEG and that in itself might again be another a biomarker
or another way of tracking things in the interests okay this is my second last slide promise the
um what are we doing now and so the biggest single thing that we’re doing uh related to these data is
that we are going to try and follow up lots of people who’ve taken partner so as I said
before we need to do longitudinal studies to look at high Behavior changes over time
um a to try and look at you know to help people understand you know what
they might expect what are the things that we might need to look out for um and B Because having this what we call Natural History type information gives us to if we’re
gonna have interventions and trials and treatments and things you need to have some idea about how the condition changes and progresses and this is one way of looking at it um you know the there
are other ways and I know that that srf funded the citizen uh data to look at Natural History and I
that’s a way of trying to look at it with some of these quantitative management we’re going to do this this we’re starting it in about two weeks time Sydney who’s
um the person on the right of this is going to be running this study um we’re going to repeat the measures and we’re going to recruit new people and we’re going to
be aiming the follow-up people over time in this we’re particularly also they’re going to focus on some of these aggressive and difficult behaviors because that’s one of the things that
causes a lot of distress for people so looking at sort of what are the causes what are the markers what might be things that um might be able to be targeted I guess for for potential treatments
um and things around these sorts of things um and so she’s also going to look at things like
autonomic arise the nervous system arise on using each and so that I’m going to start seeing the
first groups of people in a few weeks time out at a family day uh and then Lindsay is expanding
her sleep study hopefully she’s awaiting some funding uh decisions around that but um we are uh the hope is that she will be able to to go and to look in more detail at some of this message
and that is me just thanks to everyone who’s been involved in the research all of the
families who’ve been involved thanks to the syngap research fund we’ve been a great supporter of us
as well as singap UK and syngap Foundation um and then this is uh this is Damian who did a lot of
the work Ashling is over here in this picture this is our kind of family day um you know and
This Is Us showing our stripes for rare disease day I should say we don’t normally have labels
um but yeah most of all thank thanks to um people who’ve Taken part because we can’t do clinical research without picking oh thank you that was epic um
no it’s good and it’s good you have covet I’m sorry you have covet I hope you get well but it’s good if you slowed down enough that we get actually absorb it I think if you’d been
in usual clock speed we would have lost those but um there’s a number of good questions in the
chat but I want to abuse my position and just go through my questions quickly because I fear that
what you’ve just done in an hour really should have been a day of of a tremendous amount of work
um before I jump in though some of these things said right that Al submitted some of them didn’t
so I I’m assuming that the write it out submitted is coming to publication whereas the ones that
didn’t say that on the bottom of the slide are still works in progress and we can look forward to a future publication right I want to make some broad observations about the Bible I said at the
beginning before we do all the cool sensory stuff you referred to autism and ADHD and I think even
in the U.S I find that singapians noting the eye tracking and the preference for faces right
yeah the average younger singapian tends to walk into a clinician’s room for an Autism assessments
and does what they’ve been trained to do since they were two they stare they lock eyes with the clinician and they smile beautifully and the clinician says not autistic right
they then get through the assessment go home and break everything so you know even in the U.S
I’ll observe that if someone needs to hit mute I’ll observe that um it’s hard for our kids
to get an Autism diagnosis and I guess one question for you is is it do you do you get
the sense that it is also hard if not harder in the UK to do the same so that’s that’s question
one is how hard is it to get that diagnosis in the in in the in the UK I mean question
two it’s I also point out that until recently and it is changing because I’m starting to see
two-year-olds in the U.S you got a syngap diagnosis because you were having eyelid myocolonia or Worse seizures right whereas in the UK because of the NHS and the triple D you guys
have been sequencing people with ID so it follows doesn’t it that your percentage of patients with
epilepsy is lower than we would expect from the literature which is not not all from the UK
and it then does it suggest then that syngap is it supports the hypothesis there’s a lot more
than gappians out there we’re not finding them and maybe there’s a lot of them who are just not seizing but are delayed so that that’s question two related to the epilepsy
this is a slow-moving phenotype right so some of our very severe cases start having drops in the
early years but generally I would say it’s absence eyelid myoclonia progression over time drops
so as you’re observing the behavior and all these things getting worse over time before we even talk about adolescence and hormones would it make sense that as seizure frequency
increases and if early seizures or absence and mist and therefore untreated just the the noise
in the brain gets greater and then that would it’s a plausible hypothesis that that would explain a lot of these things we see getting worse over time let me let me stop with those three
okay cool I’ll try I’ll try and remember them all my my brain is not functioning as well as normal so the first ones but the autism diagnosis that yes I think it is it can be
challenging in the UK in the same way that you describe as in the US and I think it relates to
I mean I think there’s there there’s a few things I mean there’s the kind of as you say you know if you’ve got people who are you know a socially motivated individual you know and in
the way that we describe sometimes there is society about you know how autistic are you Etc and that that then pushes people away from the diagnosis I do I think as well though there is
a tendency and it’s hard to know what you know it gets very difficult when people have got quite
marked communication difficulties and impairments in the kind of IQ and intellectual abilities
there is a tendency not or has been intensity not necessarily to give an additional autism
diagnosis to say well look it’s what you have is singer what you have as intellectual moderate to
severe intellectual disability what you have is we see this in projects and other things you know
and actually you know your social communication and so forth is what we might expect for somebody
with this level of of intellectual kind of impairment and I think that that I don’t think is
that’s always going to be very hard to tease out that’s in part diagnostic Trends and habits you know um I think it’s maybe a bit more likely that people get autism
diagnoses now with these difficulties and would have been the case 20 30 40 years ago
um and it’s important this kind of odd and almost unsolvable thing to say well what what exactly is
autism in this sort of context uh my view is very much if it adds to the understanding of
a child and the clinical picture you know these sort of particularly if you think about we think autism yes social communication differences but repetitive Behavior sensory issues and so forth
like those are things which are important for people to be aware of and to highlight
and I think having an Autism diagnosis helps in terms of highlighting those things so that that’s me on a very pragmatic way I think itself what about tonight yes so the epilepsy yes are
these cohorts derived primarily from uh research these This research cohorts that were based around
um developmental differences occurring earlier on so they’re not so you’re you’re right if you look at a bunch of people with epilepsy you’re gonna and you identify
syngap you’re going to come up with the idea that all singapians have epilepsy and that’s
you know whereas if you look at a bunch of people with intellectual disability some of whom have epilepsy and some don’t and you identification you come up with a different idea so it is I think
where you select from as you know gives this thing our findings are definitely consistent with the idea that there is people out there who either don’t have epilepsy or you have such mild
seizures or whatever that they’re not noticeable you know what I mean that that you know that this more severe if being a type is not is not that um you know but I I would say I could say 60
of our group has seizures so 40 didn’t have a noticeable epilepsy um so yeah it does and as
the I mean so every single parent will smart when you say mild phenotype because a mild subclinical
storm in the head times 100 in a day you’ll still mess up your day right especially if it’s every day but sorry I shouldn’t use it I’m not being difficult I’m just advocating no no no I know but
um I wanna I wanna make I want to I want to push forward a little bit because I there’s a lot of great questions in the chat but you’ve just triggered that that webinar was epic and I will be
sending it to every industry partner and every clinician because you covered you you touched so
the tops of so many icebergs and I just wish you had a bigger end on everything not a criticism
just a just a supportive comment so on the as the end grows though I think a fair question will be
can you sh can you break that data down by medication and phenotype a genotype Pardon
Me Right was it a Miss sense was it a protein truncating so I think even if you don’t have that
being able to share the genotype of the of the of the subjects might be interesting um even if in a
table and I want to talk about drug for a second I just get anecdotal reach outs from parents right
but parents call me when things are blowing up generally and the first question I ask is what drugs is the kit on I will observe that in the U.S kids generally are on more drug
and in the and I what I say I’m not a doctor I don’t get medical advice but I do say [Music]
I find generally singapians do better when they are on anti-impulsivity drugs like guanfacine
and anti-anxiety drugs ask your clinician for those in the U.S anecdotally patients go and have
those meetings in the UK patients tell me no I’m on one epilepsy drug and my doctor said I’m good
so I I just wonder if like so there’s two questions there one would it be reasonable
to assume that this cohort is generally on less medicine say a U.S cohort and two
how would we globally speaking effectively suggests to the clinical community that hey
your kids got syngap maybe in addition to asms we should be thinking about anti-anxiety and other behavioral meds not to make this kid more manageable
but to reduce the suffering of this child who is going through a world that is I think you’re exactly right my personal hypothesis having done nothing to think about syngap for five years is
the world and I learned this from Jr who’s asked a lot of good questions that we should get to the world is incredibly anxiety-inducing for our kids and I think that triggers both seizures
and behaviors yeah so so you’re right they will be unless medicines than than those in the U.S
I mean there’s both good and bad things to being you know you can I you know we we don’t want over
medication but we don’t want under medication you know and and I I think that there is
a uh as I think I you say and I agree with you and I touched on my tour I do have some concerns
that people would benefit from medicines that maybe they’re not having you know and and not um you know often for things like agitation people end up getting prescribed antipsychotic
medicines and things in the you know and stuff and you know whereas actually it is possible
that medicines like guanfacine as you say um or anti-anxiety methods which are probably a better side effect kind of profile are likely your heart May potentially have effect you know how do
we how do we change that partly I think getting information out there and saying you know these
are behavioral problems which are pretty marked and cause issues and you know that yeah even say
seven percent of the kids and we still were diagnosed with ADHD whereas they all showed high levels of hyperactivity and impulsivity and things that is a message that we we need to get
out there from from this kind of study I’d love to do I think we need to try and start you know
there’s trials that need there’s tons of traffic needs done you know isn’t there but there’s trials needs on targeting things you know hopefully we’re going to hit stuff like gene therapy and
Asos and these things but there’s also questions about well what are the medicines that might be helpful bumper scenes are really interesting one um you know I would you know where we are there
are colleagues of mine who are looking at it in some of the laboratory models and things like that as well to see what other medicines that we have that we should be suggesting might be particularly
helpful for this these groups so yeah and so okay so I wanna I wanna go to eye tracking I’m trying
to move really really fast I will observe by the way there’s there is as the phenotype broadens
there are certain sub-phenotypes of our kids the c33 Dells those kids are a step function
higher on ID right so if you have one of them in your cohort it’s worth calling that out
um there’s also another subcohort my son included who is oddly verbal
and what I’ve learned from Tony the verbal is there’s some kids out there on Trazodone Tony on Trazodone is so hung over the next day he can’t complete a thought
kids who are non-verbal you wouldn’t you wouldn’t catch that but just to just to continue my confusing commercial only when we put Tony on guanfacine ER did he sleep through the night
so it was an impulsivity drug that actually ended up working for sleep right so the the holistic view here that you’re forming is beautiful um I want to just make a point on sleep and then
go to eye tracking sleep you reference the the Smith Hicks paper very good paper I agree with it
completely they don’t cite in that paper Sullivan 2020. and maybe I’ve got my years mixed up but
I think they could have and in Sullivan 2020 what you see in those human eegs and mouse eegs
was it seizures cluster at sleep wake and wake sleep and I’ve always wondered if that is one of
the reasons for sleep resistance because these kids know they’re heading into a seizure storm
um but I want to go to eye tracking so Tom Frey you guys are doing everything you said makes sense
Tom Frazier is also doing a tremendous amount of eye tracking work and I hope you guys are in touch and if you’re not we’re funding it and I want to connect you because it you guys are barking up
all the same trees um okay that was I want the only other thing I want to ask you and again
that was just a beautiful review of so many things we could use as biomarkers I didn’t hear you talk about GI and I’m wondering if in the forward-looking stuff
you may want to are you planning on collecting any data on that
um GI like the gut well I don’t want to head you down the gut brain axis and microbiome and all that stuff but I I the plot I love to see is behaviors against how often does your
kid poop every week yeah it’s interesting so we we’re not interested of Ashling he was the ra he
was working in this study is now doing a PhD about the microbiome and premature birth and things like that so you know there’s it’s an area which is really of increasing interest we’re not collecting
any data around that at the moment but it you know yeah it there is definitely GI issues uh you know
that I don’t need to tell you guys that occur yeah again like we’re just a civilian observation when
kids stop pooping seizures and behaviors go up and and when go ahead uh I was gonna say I work part
of my clinical job which is just more generals NHS kind of thing I work in an inpatient board for
people others with intellectual disability um one of the first things that we think about when we see behaviors changes is how they open their files you know and it is it’s one of those things that
gets reported and it you know it first and there’s lots of different things there both about just
discomfort and so forth but also there is there is broader gut brain access and stuff questions yeah
all right I’ll head I’ll head it over to the Q a you’ve got 11 more questions good luck with this
um I I I want I’ll call out the people I know so Jr has a few asking about the um ADH that
second question do you want to read it because it’s pretty long and so I’m very interested in the ADHD associations uh looking more closely thread systems hyper focus and inability to
switch attention is one side but another issue is the reward pathway a strange addiction cycle with
preferred activities and objects combined with access let’s start to something interesting can become a favorite then a requirement then becomes a painful while screaming for it and I wonder if
the addiction Type S Lane behaviors are based on a reward pathway and if that is part of of hbhd
so that that yeah I mean that’s that’s a really interesting kind of formulation of some of these
kind of difficulties um I the addiction cycle is something that you see in children who with
ADHD more broadly sometimes you know these sort of the whatever these dopamine hits that people get
um and that there is a difference in the way that the brain experiences reward and reacts to things and then stimulant medicines which are the ones that are
used mainly for ADHD different than guanfacine but you know guanfacing probably also affects dopamine stimulants protect the effect of I mean unlikely do affect some of these kind of reward Pathways
and things so you know the answer it is you could do a whole you could sit and do a PhD a number of
things about based on that question um but broadly speaking that yes it’s it is possible that these
kind of reward Pathways function differently as we think they do an ADHD and as we we are interested in other and autism and other things too and that that need for dopamine almost is
what driving that requirement and that painfulness and things about them that they’re talking about
these are all good you wanna you wanna just go down just to keep going going down them someone’s
asked if we look at Behavior difficulties between males and females um we we didn’t
find much in the way of differences um between males and females in this group uh you know the
that’s not to say you wouldn’t in a larger group you see the same kind of patterns of behavior and basically in our in our um the cohort that we have um I think sometimes and I’m just thinking
clinically more broadly you know as they get older males are bigger hormones change you some
of the behavioral consequences of these behavioral difficulties become greater for people well I know
lots of people with female children who struggle with a lot of the same kind of difficulties
um and like I say we didn’t see any clear male female difference there um okay someone says how early can the diagnosis be made for autism ADHD and anxiety uh earlier
than the average population and how to get around the a typical autism of this and gappians that are
more social you kind of touched a bit on the last part of that you know um and I think it
is highlighting the difficulties that you guys experience with this resistance to change with
these repetitive behaviors you know labeling what is typical social behavior for some of the global intellectual impairment that’s really hard massive struggle with sensory differences massive struggle
with change resistance you know routine etc those are those are things which are a bit more
quantifiable and can be pointed out how early the diagnosis is is difficult it’s probably actually
not that much you know other difficulties are likely to be noticed first and that can
lead you into diagnostic Pathways earlier but it’s not like you can pick these things out I
guess necessarily earlier anxiety is a really tough one as well because so much of anxiety
you know relates to how you express it and if it’s expressed differently
um because people don’t communicate they don’t say I’m stressed I’m worried you know they act differently picking out what is anxiety and what is not is is difficult to say I
think a lot of these distressed behaviors are associated with stress and stress is a precursor kind of anxiety anxiety is a kind of higher construct but it’s stress and distress
yeah um someone’s asked about hormones in adolescence you know hi do some of the behavioral
difficulties in adolescents could they come uh are they hormone related does it platoon at a certain
age and maybe wins or does it continue to increase in severity throughout adults I don’t know the
answers sometimes they’ve said you know is there an age that families feel okay we made it to the worst and it should level out or get better from I would say that we don’t have studies we need
to know more about the adults we we just do need to know more and and more adults will be getting
diagnosed the sequencing widens out but it’s all you know children are the people who get diagnosed
first uh you know when you these new tests when I think they’re prioritized for the younger populations but there’ll be lots of singap adults out there um I would say that you know adolescence
you know is a time of difficulty for all parents where changes in Behavior as families grow people
change resistance to hormones sexual feelings behaviors very difficult for people to understand even harder for someone you know a singapian you know actually to understand and process
I my our general experience is that these there is a sense you know that you can make it through
the worst and it should level out or get better as you say we don’t know that for sure but that
things you know are likely to be more people adolescents are more emotionally available they’re more volatile and they’ve got a whole lot going on and that should improve a bit as
people move into adulthood not for everybody if I think of other conditions that we work in might be
different like things like fragile X and stuff adults are much calmer than the kids kids have much more marked ADHD type features and things and they do the anxieties are still there but they’re
not as prominent in the ADHD stuff does settle down a bit so so yeah we need to look at it more
but I would say that yes and I hope you don’t that was one of my worries if I presenting this I don’t want people to go away and thinking oh goodness it’s going to get harder and harder that’s not
what I’m trying to say is to say what can we think about what do we need to look out for and maybe it’s those things that we can do that might make adolescence easier is the important right
it also allows you to go to clinicians and say look things are getting more difficult we know
this happens in this population please take us seriously don’t just dismiss us you know I think that’s the other thing yeah I want to like I don’t want to break your flow
but I don’t know I want to underline what you just said I I for the first few years we were
very nice and gentle with the newly diagnosed parents and I have taken the gloves off because
I think I mean I just about just 10 seconds I had a newly diagnosed family who was in the process
of moving to a new state that was very hot and about to buy a new house and they’re holding
a two-year-old and they’re like my baby doesn’t seize yet maybe and we’re not going to seize and I’m like hate to be a jerk but pretty good odds your kids are going to seize I’m looking at a
protein truncating variant here and I think it’s important that families walk in two points one
clear-eyed these kids will get more complicated and become bigger for the next 15 years and then
at adulthood I think this is what’s sort of behind explicitly in the end of Jackie’s question they do
tend to level out so I think I don’t think it’s a message of Despair I think it’s a message of Hope like hang on love this kid get them to adulthood they’re going to be okay look at Karen she’s 65.
these kids this is not a terminal disease and I think your point is probably the most important
walk in waving whatever publication hopefully your next one is needed and it insists that
these clinicians find the time or give you another employment take this seriously and help us reduce
the suffering of and increase the manageability of these patients because they are complicated and I think sync app enjoys a huge wealth of cool science but we’re really suffering from
a dearth of clinical work and I think your work and andrade’s work and Connie’s work and all the other good stuff is helping us close that Gap but it’s desperately needed because the families are
struggling mightily okay buckle up you got another um you got another Jr question it’s a PhD um so
I think it’s more of a comment uh it’s you know the about high you know the idea of older people
having more severe phenotypes seems like a reasonable observation based on who gets the genetic tests and when they’re likely to get them so that’s that my in this cohort the older kids
you know where people who ended up getting exome sequenced early you
know and and that’s not offered to folks you know that that’s maybe more likely to be done to people with you know more inverted commas severe kind of phenotypes and things
um I think as we expand exome sequencing we will find more singer variants in people with milder
forms and milder I’ll do my inverted commas again but you know of intellectual disability and things that doesn’t mean they won’t have other difficulties but I think we will see a
kind of expansion of this I think the people who get diagnosed are the ones who are ending
up in research studies ones we’ve got pretty severe epilepsy and sometimes in people who
for whatever reason have managed to navigate their way through a system and to get these things exome sequencing will increase and we will see more you know and and I think adult sequencing will
tell us a lot and hopefully answer and reassure probably some of the questions that people have um about what’s what’s the future going to be like you know as you say Karen is 64 she was 64
times 65 you know as we can as we can describe people that’s gonna that’s gonna be helpful oh
so some of these other one of the smoke alarms has gone off in my house I don’t know if that’s coming through it is strongly it is not not too strong do you need
to make sure there’s no fire there’s other people in the house survival get told I expect dinner as
being cooked here at 6 30. sorry to push sorry to push you but that next question is non-verbal IQ
um so it is measured with um a test that’s later I
um basically it’s getting people to match they’re looking for specific pictures uh you show them
things and you’re indicating in terms of things it’s about recognizing shapes finding things in
larger pictures and you use a lot of gesturing and things it still involves communication
um but it is it is less reliant on that than kind of verbal IQ but it’s a lot of matching sequencing
things like that I wonder I wonder if those scores would go up if you gave them more time because I
I mean Tony I mean I can only speak for my own case but my kid will give you the right answer if you give him an uncomfortable amount of time to respond but it’s it’s always the
the processing speed is just low I have literally said to therapists in my house you would be more
effective if you came to work stoned like please go get stoned and then come work with my son if
you were slower you would be more successful with my kid and they think I’m kidding but I’m not anyway next question hyper hypo um doing different domains are changeable hyper and hypo sensitivity
going together do you mean in different demands are changeable in the same environmental situation
um so even within the same domain I don’t think they are particularly changeable
and but you guys may say different in terms of I if somebody is hyper sensitive to something it’s a
noise it’s unlikely that in other situations they would be hyposensitive to light noises you know
um but within a domain they might be hypo and hypersensitive so certain light noises they might
be hyper and they might be hypo to them certain touches or feel of things people might be hyper to
the touch of something but hyposensitive to pain so the it’s a really complicated and it speaks to
you and I don’t think we really understand this very well how can you be both hyper
neurologically how you can be hyper sensitive to touch and maybe hyposensitive and other things so
um so it can be it’s not it can be within the same sensory domain and it can be within um the
you know that it can be the same across different situations that makes sense we need to know more
about sense hypers I think sensitivity sensory stuff is so important and there’s been so little looked at over the years in this sort of field and it’s only really in the last five ten years we’ve
started becoming really aware that actually these things are key to behavior key to people’s ability
to process the worlds and key to anxiety and things like that as well if we can tap into and
work out ways to help some of these sensory things then that I think to go a long way towards you
know improving people’s quality of life which is ultimately important but let me add to that list
temperature control not all but many of our kids tend not to sweat very much and I think that is
the tip of another Iceberg like self thermal self-regulation right when I have if I look
back over summers are hard for our kids summers are hard for our kids because there’s no school
Everything Changes blah blah blah summers are also hotter and if I look back over some particularly challenging behavioral incidents it’s generally on hot days and I think our kids are
uncomfortable but their body is not managing it in part maybe because it’s not they’re not doing
self-regulation on the temperature side that’s something we cannot find in the literature but anecdotally is popping up like crazy okay Aaron’s throwing the dullman paper at you
yeah I’m not a zebrafish scientist but I do I have some familiarity of some of these things they
um you know I work a lot with people who do most of the work in in edinburgh’s I think you guys probably know is done using mice and rat models and things but um you know the so
you know this this idea I mean the the quote you have that at this cause of right activity
associated with elevated Enterprise especially pronounced in lower rival environments you know
um I don’t know that we have it fits with the idea that people are in some way trying
to regulate something by some of their activity you know the arousal levels if somebody is in
a lower original environment they might then get more hyperactive I have to say
you know that then feeds them into ideas about just distraction and other things and and you know ideally what we tend to do is reduce arousal if somebody is very arised you know we try and
bring them down so so I don’t know how much that would hold across in humans one of the
big problems with any clinical kind of research is a lot of what we do is very um artificial in
a way we do these things in Laboratories you know we um we we see people we’re not actually seeing people in a home environment and across multiple different environments you know
um so yes I I I don’t know it’s the simple answer I suppose overall um I’m very interested more
broadly in Translation between our laboratory models and and people and as like that that’s
going to be key going forward and I’ve not touched on that but we are doing some work we are a number of pieces of work actually to look at translation between some of the models uh of
um Singapore one in Edinburgh and some of our clinical findings which which have not presented today but um okay the next one is the Oddball tune test
um they I wonder if you could try a more complex test for one listen to a simple song with a strong constant beat and then also part of it in an unexpected way but keep the same rhythm
this is because of the background we’re slowing I wondered if having a beat is helpful for listening
I’m going to say possibly I don’t know I think I would need to speak to somebody
you know perhaps Damien who did some of this work but with someone who’s a more
auditory processing scientist you know the the um you know I don’t know about the effects of kind of the Rhythm and what that effect
has on all of these are played in the same Rhythm that we have you know there’s literally you know um and so I don’t and it’s a very again a very artificial thing having a more complex
thing with a song and a Beat yes I don’t know I don’t know you end up with so many variables
so to try and control you know that’s the thing that starts becoming quite difficult um okay and then little I think the last question is why isn’t additional autism diagnosis
beneficial in the UK is essentially processing difficulties and the consequences are much to overlooked so going in with a singap one diagnosis gives us more opportunities to push practitioners
to understand this part of the puzzle better and then get this OT SI referrals yeah so uh I think
an Autism diagnosis can be beneficial it’s it’s beneficial in terms of things like understanding
social communication I think it is beneficial in highlighting sensory issues I think if you go with
a syngap diagnosis to most clinicians they’re they’re not going to know anything about it and
the best they might go away and look at something you know they might go they might because they
should go but they might go and look something up on the internet if you can if getting a you know
an additional autism diagnosis it does highlight this sort of routine sameness sensory kind of
things you know um which I think that that is what is beneficial I mean I there’s always caveats to
these things what you don’t want is people going like oh yeah cool they have autism so we just need to think of this with an Autism lens you know um because that’s and I see that in other conditions
it’s not quite the same as whatever typical autism is you know um but I think it’s a label that
Society is familiar with and that care workers and things they will think more about sensory issues and think more about this kind of need for Shameless and stuff with these kind of diagnosis I
agree I think you get I think you get the baggage and the opportunity with autism right you get the the opportunity for more services whatever drugs and then you get the baggage of oh it’s just
autism some people are growing I mean it’s such a big umbrella whatever in the U.S it’s essential for services so it’s not it’s a no-brainer I tell people to go to their clinicians give your
child Red Bull Snickers take away their iPads send them in tell them to break things because otherwise they go in they smile and then they come home and then they break things and that doesn’t
help anybody right because that that appointment took six months to get yeah I’ll get off that so thank you so much for delaying your dinner and for giving us all your time and indulging all of my
editorial comments um I really think your work is critical and we we’re grateful yeah well thank you
very much it’s been really interesting to speak and great questions and things like that’s yeah delighted to come and talk and my house hasn’t burned down so that is a good thing that is a
reliever yeah yeah okay excellent okay thank you very much bye thank you Andy thanks cheers