Prader-Willi Syndrome: A journey from clinical observation to research explanation
Interview with Professor Tony Holland by Lorna Rouse
Could you briefly describe the main features of Prader-Willi Syndrome?
Prader-Willi Syndrome is a genetically determined disorder, there's an abnormality on chromosome 15 but there are two main abnormalities, both of which that lead to Prader-Willi Syndrome and then two much rarer genetic forms of Prader-Willi Syndrome but they have much in common. I think the first thing to say is that the phenotype, the characteristics of people with Prader-Willi Syndrome, evolve over time, so they're not the same at birth as they are in later life. At birth they're very, very floppy - so they're very hypotonic, as a result they can't feed normally so often they need special help with feeding: tube feeding or spoon feeding. It's a great worry for parents early on and they fail to thrive, they don't grow normally. Usually around two to four years of age you see the emergence of the characteristic phenotype. First of all the child with Prader-Willi Syndrome will often have some developmental delay as with most neurodevelopmental disorders, but any intellectual disability tends to be mild so they will usually develop good language but the most striking change is that around that time they start developing this overeating and what the parents will often describe is that from a struggle to get their baby to eat, now they'll just take anything you give them and they won't stop unless you stop on their behalf.
So why does it happen at that age?
We don't know about that switch that happens then. What we do know is that if you look at it later in life the way we conceptualise the eating problem now is that they fail to satiate. So the the feedback mechanism between the gut, the hypothalamus and the brain generally seem to malfunction in some way. They're clearly hungry so they eat but they don't lose this feeling of hunger or develop a feeling of fullness as they eat. Now, it's not that they don't feel full at all, it's just that they need to eat much more than you and I would eat for that to happen.
So they do get some feeling of fullness?
Some people at least, seem to get some feeling of fullness and some loss of hunger, but in the very first study that we did in London, we found that they had to eat three times more food to do that. Of course that's a problem because inevitably they must put on weight because they're eating far too much food for their energy needs. Whilst Prader and his colleagues, the Swiss Paediatricians who first described the syndrome, saw it as a syndrome of obesity, more recently we've seen it as a syndrome of what we've called starvation. By that we mean it looks as if the brain is fooled into thinking that the person hasn't eaten when of course they have, so in a way the whole behaviour of the person is the behaviour of someone who is constantly hungry and that makes a lot of sense because the biggest difficulty for many people with Prader-Willi Syndrome is not only eating all the food available on the table, but it's food seeking behaviour; so there are stories of stealing food, perhaps eating rotten food or pet food. It must in some way, we believe, relate to an abnormality at the level of this small nucleus of the brain, the hypothalamus, but brain scanning studies both here and in the states have suggested that there may be some kind of abnormality or some abnormal response of the reward pathways in the brain so food carries with it a greater reward stimulus than it might ordinarily carry. At present I think that what these studies show with great clarity is that this is a biologically determined abnormality and therefore, in a sense you can't expect people with Prader-Willi Syndrome to get complete control over that. It's not as if they're being lazy or stupid - they are genuinely feeling hungry and like any of us if you are feeling hungry you seek out food. In terms of the developing phenotype what you also have the evidence of the low growth hormones and low sex hormones so unless they're given growth hormone they're short and they don't get the growth spurt before puberty and nor do they get puberty. So very rarely do women with Prader-Willi Syndrome have periods, men don't develop the secondary sexual characteristics of men like a beard, pubic hair, broken voice. Another characteristic that seems to be quite striking as they get a bit older is a continuation of a number of behavioural and psychiatric problems, so they may have rather repetitive and ritualistic behaviours a bit akin to what you see in people with autism and they also get quite significant temper outbursts which for the parents can be one of the most difficult things. If you can control the food environment you can prevent obesity but managing the temper outbursts is another matter.
Do they go along with say being kept away from food?
It may occasionally be associated with that but interestingly it looks like it's more associated with change. Work in Birmingham has suggested that people with Prader-Willi Syndrome have particular difficulties with set shifting with cognitive change. if they're fixed on one task or have one expectation of what's going to happen and it can't any longer happen they have real problems with that. There are many, many examples where parents of people with Prader-Willi Syndrome will describe how they start getting a bit irritated and begin repetitive questioning; why is it that the bus isn't here? You promised me that the bus would come at this time and that we would go here, and they're getting more and more worked up and parents will say this can sometimes go on for hours, so it's a major difficulty. Some can develop also quite severe skin-picking, usually it's picking at a particular spot or a scar, but it can be quite a problem for some people and also as they get a bit older they may develop mood problems, depression, and people with one particular genetic subtype of Prader-Willi Syndrome also have a very high risk of developing a psychotic illness in the late teens or early twenties. So that's the sort of evolution from failure to thrive - a floppiness in infancy, to this over-eating, developmental delay, the emergence of behavioural problems and the growth and sex hormone deficiencies to risks of psychiatric illness developing in later life.
Are the causes of all these symptoms known or still being investigated?
It's still being investigated. One of the great debates about Prader-Willi Syndrome is whilst we know it's an abnormality on chromosome 15 and it's a rather unusual genetic abnormality because it involves genes that are what's called imprinted. What's striking about Prader-Willi Syndrome, if you take the commonest cause of Prader-Willi Syndrome people have the loss or the deletion of a small bit of chromosome 15 and it's referred to as 15q11 to 13, which is the marker for that little bit of chromosome that's missing. If that bit is missing from a chromosome 15 that is inherited from the father they get Prader-Willi Syndrome but also if you have a similar deletion but it happens to be inherited from the 15 from the mother you don't get Prader-Willi Syndrome, you get a completely different syndrome called Angelman's Syndrome. This indicated that, either the single gene or several genes that are involved in Prader-Willi Syndrome seem to be only active when they're expressed in terms of the chromosome from the father but the chromosome from the mother are, quite normally, switched off so the problem for those with the deletion is that they've lost those chromosome, those genes that would normally be expressed from the father because they've been deleted. The ones from the mother are there but they're not expressed because they're switched off so they have no expression of those chromosomes, of those genes and that's what's referred to as gender specific genomic imprinting. Now what we don't know is whether to get the full phenotype of Prader-Willi Syndrome it's because there are several genes that are not working, or whether one gene is the key gene and that's the debate at the moment. Most people think it's several genes, we feel a bit differently about that but that's a problem because until you can tie that down a bit it's a little difficult to sort all this out really, but it seems very likely that the absence of the expression of a particular gene or genes, we would imagine affects the development of the hypothalamus in the brain because the hypothalamus is what controls eating behaviour and it controls other things that are also abnormal in Prader-Willi Syndrome like temperature regulation and sex and growth hormone secretion, so can you see that the cluster of symptoms in Prader-Willi Syndrome point to the hypothalamus. That doesn't explain the learning disability and it doesn't probably explain the mood disorder or the psychotic illness. So there's much more to tease out yet. Whilst we know a lot about the genetics, we don't know everything. We know quite a bit about the brain, but we certainly don't know everything and we know quite a bit about the behaviour but we haven't really been able to put all those three together. You can't quite yet go from these genes to this effect on the brain to this behaviour, that's the challenge.
What does living with Prader-Willi Syndrome mean for people's day-to-day quality of life?
I think the interesting thing about Prader-Willi Syndrome in terms of quality of life is that our advances in understanding have potentially transformed quality of life, but it does mean having the right environment. The thing that was so problematic before was the severe, and by that I mean really severe and life-threatening obesity that would develop because parents had no idea what was going on. Those that became severely obese had so many other problems. They got to the stage where you couldn't walk well, their skin was in a terrible state, they couldn't breathe normally, you got conditions like sleep apnoea and diabetes. So now at least, whilst it's not a treatment, parents can control the food environment and prevent the consequences of the failure of satiety that is obesity. Just by keeping weight controlled you improve quality of life and I think there's increasing evidence now that people with Prader-Willi Syndrome feel more comfortable when the responsibility of eating is taken away from them. Some people say, well doesn't that make them worse? But actually no and I think the way to think about that is that if you or I were having to starve because we were having an operation say, you're better off being nowhere near food because if you look at food or smell it when you're already hungry, that makes everything even worse and so for people with Prader-Willi Syndrome, if they know the kitchen or the fridge is locked, they know there is no choice. The problem comes a bit more in adulthood of to what extent do you have the right to control someone's access to food and there's quite a lot of debate about the ethics and legality of that, but by and large I think you can make life better by managing food and preventing the obesity and if you combine that with growth hormone treatment and the general improvements, one would hope, in services for people, with mild learning disability, I think quite a lot can be offered to people with Prader-Willi Syndrome. Many would be able to lead independent lives if it wasn't for the risk of overeating.
You mentioned some psychiatric conditions, so does Prader-Willi co-occur with other syndromes sometimes?
Well I suppose it would be slightly more correct to say other psychiatric conditions co-occur with Prader-Willi. There's no question that rates of mood disorder are really quite high and then those with the disomy or UPD subtype have a risk of psychotic illness that is probably about sixty per cent in adult life, so very high. The deletion group is not as high as that, which is a very interesting observation, but may be as high as perhaps fifteen per cent. So psychosis of really quite a problematic kind; they get hallucinations and delusions and their behaviour often deteriorates because of that. It may have a cyclical nature to it, which makes it a bit like a bi-polar disorder, a manic depressive illness and they clearly have episodes of both depression and over-activity. The picture doesn't quite neatly sit into that but it's probably quite similar and there are treatments that can be quite effective. There are medications that will help the mental state to stabilise and help the person stay well but the onset of psychiatric illness in late teens or early twenties is pretty dramatic and really presents with marked changes in behaviour and underneath that changes in mood, delusions and hallucinations.
Can you tell me about some of the research that you're doing at the moment?
Our research here in Cambridge really started with a population based study and that was really assessing the characteristics of everyone with Prader-Willi syndrome we could find in one particular geographic area. We didn't want to take a selected group that had been in hospitals for example. That study really allowed us to really establish clearly the common features of Prader-Willi Syndrome and led us to the observation about the high risk of psychotic illness in the disomy subtype. We went on and did a brain scanning study, done by Ella Hinton, that helped to establish the abnormality of satiety. Most of our focus at the moment is on a proof of principle study in which we're using something called a Vagus nerve stimulator to see if it reduces the eating behaviour. This is something a bit like a pace maker that's inserted surgically under the skin with a wire that's attached to the Vagus nerve in the neck. The Vagus nerve is one of the ways in which the gut tells the brain that the person has eaten. It's part of the feedback loop to the brain. Vagus nerve stimulation is sometimes used to treat very poorly controlled epilepsy and there'd been this incidental observation when it's been used for epilepsy that if the person happens to be obese they just lose weight. So theoretically you might imagine that over- driving the Vagus nerve might switch off appetite and this incidental observation suggests that this might be the case. Three people with Prader-Willi Syndrome agreed to have the Vagus nerve stimulator implanted, two who've had it switched on for quite some months now and a third has only recently had it implanted and is about to have it switched on. The work on epilepsy suggests that its effect only emerges after many months, so we don't expect much early on and so far we really haven't seen very much but we're still doing the observations.
Did the people with epilepsy report having a low appetite?
Because it was such an incidental thing which wasn't directly relevant to the epilepsy no one has really looked at that. Our assumption was that their food intake must have gone down because there was no particular reason to believe that their exercise might have gone up, but I suppose if their epilepsy was better controlled they might have been able to go out more, but no we don't know the answer to that.
Are there any particular challenges to research involving people with Prader-Willi Syndrome or learning disabilities in general?
I think that first of all there is a history of very unethical and inappropriate research going back to the Second World War and afterwards that engaged people with learning disabilities and other vulnerable groups into unethical research and that's soured the atmosphere. I think it's much less the case now than it was, but there was always a certain suspicion about research in this field. There clearly is the particular issue of consent because research is only lawful if someone is properly informed and consents to it and most people with Prader-Willi Syndrome are able enough, but for some people with learning disabilities that may be a problem. They may not be able to understand what it is that's being asked of them and therefore not be able to properly consent to it. I think in terms of Prader-Willi the other difficulty is that it's a rare disorder, so if you needed a hundred people to get sufficient power for your study that might be quite difficult, particularly if you wanted them between certain ages or if you wanted to control for gender. I think we would wish to look to better collaboration with other countries and we've done work through the European Union and developing a common database to try and do that because there are certain groups like the very young or the very old where the numbers are so small in any one country that you can't really do meaningful research. I think, going back to research with people with learning disability more generally, research requires people's cooperation. For example, if you want to do a brain scanning study someone has to lie still for over an hour in the scanner and that may be problematic for some people. People with Prader-Willi Syndrome were just wonderful when we did it but for some it might be a bit scary, they may not fully understand, so I think there are quite a few extra hurdles of doing research in this area.
What are the main questions that you think still need to be answered around Prader-Willi Syndrome?
I think first of all it would be very important to really try to tie down the genetics properly and be certain about what the gene or genes that are really crucial in Prader-Willi Syndrome because then you can begin to ask questions about what that or those genes do. The second thing is if you take the eating disorder, whilst we believe it's an abnormality of the feedback mechanism, we don't know why that should be the case. Is it because the genetic abnormality of Prader-Willi Syndrome directly affects the various mechanisms in the hypothalamus so they don't work normally or is it some other mechanism? We're beginning to argue that it might be some other mechanism which sets a very high threshold for satiety but we don't really know, we can't readily move from the genetics to the behaviour at the moment. There's been work done mainly in Amsterdam looking at the hypothalamus at post-mortem and they've tried to look at whether the control pathways in the hypothalamus are abnormal or not and, with some exception, essentially not finding anything very striking, so that's a bit of a mystery. I think that's the dilemma with the eating disorder, we still don't really understand the mechanism or why they have a shift at two to three years of age. There are things beginning to be excluded but there's no obvious explanation for that. We don't know why they have a learning disability, that's never been properly explored. Then I think there are more general things like trying to understand the cause of the mood disorder and the psychotic illness in more detail. In terms of therapeutics I think growth hormone therapy now is fairly standard. There's a lot of debate about whether you should continue growth hormone therapy through adult life because obviously once they're fully grown, from the point of view of height there's no point continuing to give it but many parents want it to continue because they think it helps muscle bulk and so on, so there's work to be done as to whether growth hormone should continue or not. Relatively speaking there's been little research on sex hormone supplementation and that may be increasingly important as people with Prader-Willi Syndrome are living to an older age because both growth hormone and the sex hormones are important for things like bone strength so and are clearly at risk for osteoporosis and it may be that these hormones ought to be given for these reasons as well as for sexual development or height and we don't really know if there are particular risks much later in life that may have their origins in the failure to treat these various things in childhood or early adult life.
Is there any research happening at the moment that you think is quite exciting for the future?
We have increasingly sophisticated neuroscience technology, scanning being the obvious one, but I think it may be possible to begin to tease out some of the underlying brain mechanisms that may be important and may explain, not only the eating disorder but the learning disability and the risk of psychiatric illness. I think in terms of the eating disorder we are moving into a phase where therapeutic research is beginning to happen. Drug companies are frantically trying to develop appetite suppressant medications because of the general problem of obesity in Western society, so it may well be that medications will be developed that could be shown to be effective and if the eating disorder could be controlled or if something like the Vagus nerve stimulation was shown to be effective it could transform the lives of people with Prader-Willi Syndrome. So I think we have moved into that phase now where therapeutic studies are just beginning to be a reality.
Thank you very much.
This interview originally appeared in News & Views February 2011.