Scientific Questions & Answers
Presentations at the 1st World Conference IASO - Tampere, Finland, 4-8 July, 2000
Presented by: The International Angelman Syndrome Organisation.
This Session was held from 09.45-10.30 on the 7th of July, 2000.
Q: How can all these different areas and differing levels of ability ALL be categorized as Angelman Syndrome? I understand (sort of) the genetics, but have I lost perspective on the broadness/rarity of it all?
Dr. Ellie Smith: This question - deletions, UPD and so on - has been covered pretty well in the previous sessions, particularly in Dr. Jill Clayton-Smith's summary.
Q: Are there more redheaded angels than you would find in the general population?
Dr. Ellie Smith: In Australia, we have actually got a few more red heads than you would expect, and I think you have, too, haven't you?
Dr. Jill Clayton-Smith: Certainly in the UK, red hair is not that unusual, but I don't know if anyone has a hypothesis for why red hair should be more common in Angelman Syndrome. Or do we know whether it's more common? This is something that we could perhaps do a little survey of to find out.
Dr. Ellie Smith: Does anybody in the Italian or Spanish group want to say, do you have redheaded Angelman people, too? Would anybody like to answer that?
Audience: I think we haven't got red-haired Angelman children in Spain.
Dr. Ellie Smith: You don't have any in Spain? We definitely do in Australia. It's been a noticeable thing in each of the families, it's in the family as well. So, it's not a de novo red hair.
Dr. Charles Williams: In the United States, I don't recall any obvious increase in redheaded children. We have some, but it doesn't seem to be impressive, in my experience.
Dr. Arthur Beaudet: I think that it's possible it's a smaller factor at the P locus in the deletion patients, so that in people who might have been sort of light brown, you see them reddish more in the face, of those with a deleted P locus.
Michel Marcotte: The Italians say no, we don't have any. Usually the kids are just the same colour as parents.
Dr. Jill Clayton-Smith: I think the consensus of opinion is that usually we probably don't see more than we see in our usual, general populations.
Dr. Bernard Dan: Yes, that's the point, really. I have a Turkish and an Algerian patient with AS and red hair, but there's a family history.
Dr. Ellie Smith: I wonder if Bernhard Horsthemke would like to comment that, in this family history, if you have a deletion, maybe there is a mutation on the other chromosome so that you could have a double dose.
Dr. Bernhard Horsthemke: Well, I think the red hair locus is not on 15, as far as I know.
Q: With regard to the Human Genome Mapping Project, what can be expected from the genetic advances gained particularly in the gene of Angelman syndrome? Is there a possibility of finding a cure? Or, would there be a possibility of improvement in the clinical manifestations of Angelman syndrome as a result of this?
Dr. Joseph Wagstaff: I think that if you ask 10 or 15 different geneticists, you would get 10 or 15 very different answers. From my point of view, I think that the Human Genome Project is going to give us a great deal of information that's new, about how genes are turned on and off during development, in different cells, in different tissues and in different organs of the body - information that we've not had prior to this. All of the manifestations that we see in Angelman syndrome come from the very peculiar behavior of UBE3A and from how the gene is turned on and turned off, so from that point of view, I think we'll get a great deal of insight into the underlying mechanisms behind Angelman syndrome from the Human Genome Project.
On the other hand, with any attempts to introduce a normal UBE3A gene into the brain, it's going to be very important to have the new gene working to produce the right amount of UBE3A protein. It's possible that not only too little UBE3A but also too much UBE3A might cause problems, so there again, the information from the Human Genome Project about how this gene is turned on and off is going to be very important, as far as any work on gene therapy of Angelman syndrome, but I think it's very difficult to predict what the outcome is going to be.
Dr. Arthur Beaudet: I think that had the Human Genome Project come 20 years earlier before the discovery of UBE3A, it would have had a big impact on maybe finding the gene sooner. In some sense, having already known the major gene involved, some of what the Human Genome Project might contribute for other diseases has already been accomplished for Angelman syndrome. On the other hand, it might be quite helpful, for the group of patients that we can't find any defect yet, to figure out what's going on in that group.
Q: The next question, which is a rather long and complicated one, deals with UBE3A, the ubiquitin mediated proteolytic systems and their relationship to prion disease and Angelman syndrome.
Dr. Arthur Beaudet: Prion disease, I guess in lay terminology, is best known as mad cow disease, that's one version of it. So the British will have to take some of the credit for popularizing the familiarity with this. But it's a group of unusual disorders that involve serious brain deterioration from a protein and not from a virus. Prions are virus-like protein molecules.
It's currently the case that there is an increasing sense that perhaps many different neurodegenerative diseases are so-called protein misfaulting diseases, which would include the prion disorders, but also perhaps Alzheimer's, Parkinson's and a group of genetic diseases with a polyglutamine repeat.
It's interesting in this regard that breeding the UBE3A mouse to a mouse with one of these polyglutamine repeat disorders has provided some interesting information about that process. It's quite likely that there is a lot of interaction here and out of research in ubiquitin and its relationship to Alzheimer and Parkinson. There are many more research laboratories working on these disorders who might have things come to light that would be very helpful for Angelman syndrome. So I think there is a substantial relationship between ubiquitination, prion diseases, Alzheimer's, Parkinson's and other neurodegenerative diseases that might help research in Angelman syndrome.
Professor Dick Swaab: If you look in brain sectors from patients with prion disease, the most pronounced alteration you see are little holes in the cells and around the cells, called plaques. They haven't been seen those two autopsies [of AS patients] by people who have looked through a microscope to the tissue. So there's no indication that it is a prion disease, from those autopsies.
Q: The subject of the next question is this substance called secretin. Many of you will be aware that some children with autism and with Angelman syndrome have had treatment with secretin. Results have been reported anecdotally from those studies. But basically, to summarize the question, what is the state of play with secretin in regard to Angelman syndrome?
Dr. Charles Williams: I think that most of the information about Angelman's relationship to secretin is anecdotal, with people's personal experience. I haven't seen any reported series of Angelman children treated with secretin. On the other hand, we have a fair amount of information from its use in children with autism, or with autism spectrum disorders. The experience there is that in large groups of children there is no obvious difference between the control group and the treated group, if you look at various clinical parameters. But there may be a subgroup of children who respond, and this is something that is seen in a number of other treatment ideas that have been applied to autistic children.
At the University of Florida, we attempted to fashion a trial for human synthetic secretin, but that got tied up in some ownership of the company and availability of secretin. My personal experience whether there is a treatment, while I haven't done that yet, is that I don't know of any definite benefit in a series of Angelman children.
Q: This question is about the commonality of body awareness. Is one-sided weakness more prevalent? Are there more left-handed or right-handed? Some kids cover their heads and complain about feeling cold.
Dr. Bernard Dan: It's an even broader issue, because I suppose when people talk about pain threshold, it also goes into that, because people ask the question. The child doesn't seem to be sensitive to a thing we think should be painful. Is it because he doesn't feel it? Is it because he doesn't understand it as pain? Or is it because he can't express it?
So, if you compare body awareness in general, or specific aspects of body awareness with that of unimpaired children, there's certainly a problem, mostly as a global delay, harmonic delay. But if you compare the body awareness of children with Angelman syndrome with children at a comparable level of development and with other conditions - non-specific cerebral palsy, some children with Rett syndrome, some children with Down syndrome - children with Angelman syndrome seem to to a lot better, and to be comparable to children with cerebral palsy, with an otherwise similar level.
This can be taken - why they are covering their head and so on - as a way of communicating. That's what can be said at this stage.
Dr. Ellie Smith: Any parents who would like to comment? The temperature differences, for example, and is left-handedness or right-handedness more prevalent?
Audience: I don't know whether you could say that it's more prevalent, but I'd suggest perhaps that it is what they learn to use, that they learn to use their left hand, or they have been taught to use their right hand. So it just becomes a matter of repetition. If you keep giving them objects to their right hand, they will learn to use their right hand. That's my experience in any case, because my daughter would use both hands, but with physiotherapy and OT she's been encouraged to use the right hand, and this is what she does. So I don't know if it just becomes learned behavior.
Audience: I just wanted to mention that we discussed this on the Internet, and a lot of parents felt that their children had a weakness on one side or the other. And I've noticed in my son that he's right-handed normally, but when he has seizures, when the seizures come out, he starts using his left hand, and my possible feeling is that the seizures are centered on one side of the brain than the other and that might affect. And the same thing with pain on his arm: the neurologist just explained that it could be that if he's having seizures, he just misses sometimes, when he bumps himself he doesn't feel it, just because he's in whatever his brain is turned off due to the seizure. Although we don't see a lot of overt seizures in my son, he's well controlled, it's constantly happening and I'm sure it affects him in that respect.
Dr. Bernard Dan: This is a very good and very important observation. The question, in general, of hand preference in Angelman syndrome should not be posed in the same way as it is posed in the general population. There are genetic determinants to right-handedness and only to right-handedness, as far as I know. There are some right-handed people and not-right-handed people. It's not a complete mirror image. And that's the alternation of the hemispheric dominance. There's a lot to say about it with language. But again, speech - that's the area that Professor Swaab talked about yesterday - in most right-handed people, these areas are inter-dominant, that is, by the left hemisphere.
In Angelman syndrome, as it is a developmental problem, the question is probably much more complex. So, preferential use might be prompted by experience, as you suggested.
Weakness: there's no reason in the basic brain structure of patients - children or grown-ups with Angelman syndrome - for having a weakness on one side of the body. It could of course be related to seizures. It could, in some instances, not be reversible, so it could be because of seizure activity affecting one side of the brain. So, after the seizure, there is sort of an exhaustion of the brain cells on that part which you can find as difficulties on using the other side, for moving, or even for sensation, as you mentioned. If the seizures are very important, have been very prolonged, or the patient has had great many of them, these asymmetries can sometimes stay. So that's an important observation.
Audience: We assumed for 25 years that our son was right-handed, because we gave him his spoon on the right hand etc. We trained him that way. When he became 25, he started to do facilitated communication. He did it with both hands, but when we asked him which hand he preferred, he let us know that he preferred to use his left hand.
Audience: I just would like to mention that I believe it's true in North America that we were all warned by Dr. Spark or someone that it was a terrible thing to do to try to direct a child's handedness, because you might confuse them. Therefore, I was very careful not to do that, and I suspect that it's true with most North American moms. My son seemed ambivalent at first and then clearly had a left-handed preference. So at least in some cultures you probably get a better idea of whether they really were left-handed.
Audience: I have a comment to what you said about temperature tolerance. Our experience is that our son has less tolerance of hot and cold extremes, so that his bath, for example, would be significantly cooler than what you would think would be comfortable. He has his dinner at a lukewarm temperature and also, he can't tolerate ice cream or ice desserts.
Dr. Ellie Smith: That's really interesting, because the Prader-Willi people also have a temperature intolerance, and there seems to be some interaction there. I think that could be something that we could talk about further. I would be interested to know how many other people have children with temperature problems.
Audience: My comment is, I agree, I think is is a learned behavior. My son burned himself, and now he is very wary of hot objects, including hot food. He would not take a hot food near his mouth until you've assured him in several different ways that it is cooled off.
In addition, as far as handedness, he would prefer to use his right hand. If you obstruct him from using his right hand, for some reason, he would reach around with his left hand. If you obstruct his both hands, he might take his foot, reach and pick it up with his foot. I think that he just knows in his mind what he wants and it's only a means to an end. Now, I don't know how that goes with the long term potentiation that Dr. Beaudet talked about the other day, but he certainly has his wants, likes and dislikes, and he's wary of some objects.
Audience: Our son, 22, has a trait which is similar to a few others, which is why we have asked the same question: he sweats abnormally when he's exercising. And I'm wondering if anybody else has seen that.
Audience: When my daughter was an infant or toddler - close to one year of age - her hands would turn purple and her feet would turn purple sometimes in relation to the bath water and other times just sitting in a highchair, and we really checked to make sure that no nerves would be cut off while she was sitting. It would just come and go. And she also is very sensitive to warm foods, the bath water...She doesn't seem to have any sensitivity to cold foods, she would bite ice cream, so she doesn't seem to have a sensitivity there.
However, in Michigan, most of our families that I connect up with say that their children have very much difficulty in the heat in terms of being able to tolerate and release - I don't know if it's accurate, releasing the sweat, but releasing the heat. They get overheated very quickly.
Audience: We are from Sweden, and we have two sons with AS, 20 and 24, and they both get real tired when they're walking, but we believe that's because they are walking in a very uneconomic way, with their knees bent. And they are not so fond of the heat, they prefer the shadow. But still, yesterday we tried the sauna with the younger one: he stayed until I put some water on it, and then he ran out. The younger one is left-handed, but my grandmother was left-handed, and Inga-Lill's grandfather was left-handed, so I don't suppose it's abnormal.
Dr. Bernard Dan: Sensitivity to heat is one of the associated features in the consensus criteria. There hasn't been any systematic research into the autonomic nervous system in Angelman syndrome. The autonomic nervous system is the part of the nervous system which is responsible for maintaining our function, or adapting our function, like heart rate, breathing, body temperature and so on, That's why, what makes us feel nervous when we're nervous, our heartbeat quickens and so on. The only report I know of - this is a very recent report by a French group - said that three patients with Angelman syndrome, when they had an intense emotion, fainted. They could relate that with dysfunction in the autonomic nervous system. Now, it could be that adaptation is not quick enough to high temperatures, extreme temperatures, and that goes in the same context, but that needs further research.
The other comment you made about your sons getting tired when they walk. Again, it's a very fine observation, and as I said before, children or adults with Angelman syndrome seem to trade economy for safety, and they pay the price, obviously. And they get better, they invest then, because they can walk.
Professor Dick Swaab: About the sensitivity to temperature, becoming aware of the temperature is of course a cortical function, and one might see the hypersensitivity as an hyperactivity of cortical function, so a lack of inhibition by GABA. In that sense, it might be one part of a general phenomenon seen in AS.
About the left-handedness, or not-right-handedness, there are two factors important. One is an hereditary factor and the other one is an early developmental factor. In all early developmental disorders, you can see more non-right-handedness, or left-handedness. So it's a general phenomenon.
Dr. Jill Clayton-Smith: I would just like to mention that when we looked in our UK study, of just over a hundred individuals in the end, we actually looked and specifically tried to test handedness. We are also a population where you don't force children to use their right hand, they're given the free option. And in fact the incidence of left-handedness in that population was about twice that of what you would normally expect. Nearly a quarter of the children didn't really show any hand preference. But I think it fits in very well with what Professor Swaab said with other populations of children with learning disability.
Audience: I am wondering if there is a link between temperature and the feeling of the skin. Tristan, 8 years old, shows all the typical aspects of the phenotype of Angelman syndrome, but we still don't know what causes it. He's hyposensitive everywhere in his body. For example, he can pinch a finger on the door, and he won't know whether to cry or laugh, or he won't even say anything. He was very sensitive under the feet and in the face, and it was especially worst in the wintertime. In the summertime, when there is wind on his face, he kind of liked it, actually, but as soon as it's in the wintertime and the weather is cold, he hates it. It's like slapping in the face, really, he has a very adverse reaction.
Dr. Ellie Smith: Does his temperature go down, or does it all go up, in the winter? Does he get cold?
Audience: No, that's something funny also, because I would say that his normal temperature is probably below normal, compared to his brothers. Tristan would play hours in the bath, even if the water is cold. When he was younger, he slept all nights on the floor, and in the wintertime, the floor could be a little bit colder than usual. And he didn't mind, just laying there. But at the same time, he has a hard time controlling temperature. Usually, we did at Tristan's illnesses, with a temperature hike, the temperature rises, it actually skyrockets. Every time he has something. At one point we were in a hospital, and it reached 41.5, which is about 105 Fahrenheit. So, we tried baths and everything, and it's kind of an art to get it lower. Quite often, it's the risen temperature that brings us to a doctor, and at first, the doctors don't see anything. It's usually a day or two later when they discover that there is a pneumonia, or a throat infection or something. But it doesn't show up in the regular, typical kids' test.
Dr. Ellie Smith: I think that's interesting, and correlating that with what Professor Swaab said about GABA, that could be why both Prader-Willi and Angelman seem to have this problem. It's definitely recognized in Prader-Willi. In Australia, we had a few children who died when they got very cold. They just could not bring their temperature up again. I really think this is an interesting and important issue.
Audience: My son is 12 years old. The cause is still unknown. He pretty much shows the same temperature resemblances as Tristan. When it's very hot, he sweats very little. He's not very sensitive to pressures or pain. When he does have temperature, it rises very, very fast, too.
Audience: I have two questions. They feel very tired when they're walking. For example, my son feels very tired when walking. Is it a good idea to stimulate walking even though they feel tired, or not?
The second question is, if the level of the pain is less than normal, or is it normal? Because we have checked it, and they endure it, and they don't cry at all.
The third one is about hydrotherapy in the swimming pool. Is it better that the water is very deep, so that they can try to swim without any help?
Dr. Jill Clayton-Smith: I think the first question is very much the same as the one from the Swedish family: with your child who gets very tired when walking, should you still persist with encouraging him to walk? As Bernard has mentioned, probably the reason why they get tired is that the way in which they walk, the way in which they can walk most safely and efficiently, isn't in fact very efficient, and they have to work quite hard to do this, and this is why they get more tired than another individual, because they're working very hard at it. And I guess one has to be sensible and say that you shouldn't push a child beyond the limits at which they're clearly uncomfortable when they're walking, at the same time encouraging mobility generally.
The question as to whether the threshold of pain is higher in Angelman children, do they not feel pain as usual? Would anyone have a comment on that?
Dr. Charles Williams: I think this was something that was raised earlier. It's not uncommon in a number of children with other genetic syndromes, where this observation is also raised: they seem to have more tolerance to pain, particularly in blood drawing. I think, though, that there are a number of children who don't seem to mind having blood drawn, so that's my clinical experience. But, on the other hand, I don't see a lot of self-injurious behavior which is often an indication that either there's an increased tolerance to pain, or some sort of unusual relationship to pain. So, my general thought is that while there may be a little bit of different sensitivity, I don't think it's very impressive.
Audience: I have a question, not a comment. It's a little convoluted, but may I try? I have been wondering about it for many, many, many years, and I don't think I've got a good explanation. Is there any scientific explanation for Angelman syndrome behavior on object permanence? Is that a familiar term for everybody? It's a testing term they do when children are little, to measure their intelligence, and they use natural objects like a ball or a block. And they put it under a napkin. My daughter was 1½ when they did that, and when they put a ball under the napkin, she didn't pay any attention to it, but when they took her bottle that had the rubber nipple on it, and they put that under the napkin, she went right for it. So, my thought is wondering, is there a way to harness our children's preoccupation with certain things that are mostly just very relevant in a limited way, like their food, to get them interested in more important things? I'm raising this as a sort of a neurological question as well as a behavioral question. Is there something in their obsessive elements that can be harnessed to get them to do more things?
The session ended because its time ran out.
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