I.A.G.S.A. – Meeting with Parents – 29.5.2001

Lanzi – Let’s start today’s meeting. Our speakers are ready to listen to your questions. Who would like to ask the first question? I think Mr Oriano deserves to be the first.


Oriano – First, I would like to thank all of you – Prof. Aicardi, Prof. Barth, Prof. Lebon, Doct. Kuijpers, Doct. Crow, Doct. Stephenson, Prof. Lanzi, Prof. Fazzi, Doct. Fischbeim – who could not join us today – for their dedication and, especially, for being so kind as to accept the invitation of our association. For us it is very important to meet them, because they in them we place the greatest hope and expectations for the future of our children. Certainly, our children live in the present and not in the future. We are well aware that the timing of medicine and research is very different from the stringent needs of our children. However, at the same time, we do hope that your work and your commitment may soon lead to concrete results and may give us an opportunity to get out of the tunnel where we are at present. I don’t refer to us as parents, but especially to our children, in terms of hope for them.

We have many questions and we hope you will be very patient to answer all of them. Unfortunately, A.G.S. is still a disease that is poorly known internationally. Consequently, there are still cases where not only the first child is born affected by the Aicardi-Goutierès Syndrome, but also the second child is affected. Still today this disease, at first, gets the wrong diagnosis and is seen as a possible consequence of a viral infection. In order to prevent these cases, I’m asking whether an international protocol may be recommended in order to allow for a prompt diagnosis whenever such an unfortunate event occurs. I repeat, these wrong diagnoses still occur and there are families that, in the year 2000, have an affected child aged perhaps 3 or 4, but also have a second affected child; maybe he is only one year old, he was born in the year 2000, but nonetheless he is affected by the A.G.S.. I think that an international protocol would help. Please consider that, in the United States – perhaps the most technologically advanced country in the world – the A.G.S. is practically unknown. They know the Indian Cree, but they do not know or know the A.G.S. only partially. What do you think about the drafting of an international protocol?


Aicardi – It is true that the syndrome is not yet widely known, despite the efforts that have been made in order to make it better known. I think that it is true that there are still misdiagnoses and especially the confusion with infectious disorders which we actually made with our first family and which is easily understandable. It’s obviously not a common disease and it raises the problem of all rare diseases. In France, for instance, there is a Registry of Rare Diseases which is diffused to the physicians by the INSERM, by the organ of investigation, which I think is an interesting thing to do. On an international level, I can’t see what we can do. We can try to publish in journals which are widely known. And that we’ve done with Françoise Goutières and myself, quite recently in fact. And I think this is the one thing we can do and which is likely to improve the recognition of this syndrome.

Lebon – I think it would not be very practical to propagate knowledge about the Aicardi-Goutières Syndrome for the large paediatric or neurological population because each message decays. Whenever you get to the broad public with such a message, it will be in their minds for a few months, a year, then again it fades away. But there is another option and it is that, in a general sense, paediatricians and neurologists should be critical about the diagnosis that they make and they should not refrain from going back on the first diagnosis and consult colleagues when they have doubts whether it still applies. In my country, it is not unusual that, in Aicardi-Goutières Syndrome, usually the first diagnosis is wrong and then it turns out usually to be wrong on several criteria. For instance, you may have fever and you may have cells in the cerebrospinal fluid and the paediatrician may think that it is an infection and when that infection lingers on for months and months, he or she may get second thoughts about whether it is an infection or something else, or what kind of an infection it should be and then consults a paediatric neurologist. Most paediatric neurologists in my country are aware of Aicardi-Goutières Syndrome even though some of them have never seen it. So my main illusion, if you may call it like that, is that, by second thought, the proper diagnosis will be eventually made and hopefully mostly within the time that is necessary to give the parents a good genetic counselling and to prevent a second birth with the same diagnosis. So I completely concur with professor Aicardi that it is a very difficult message to propagate but I think that, in a general way, a disastrous consequence of medical ignorance may be prevented.


Question – Yesterday, you told us that, at present, researchers are heading towards considering interferon alpha as one of the factors that cause the greatest disorders connected to this syndrome. However, we still don’t know whether interferon alpha is the primary cause or whether, upstream of its increased level, something else has occurred. Do you already have a hypothesis in terms of research and of possible results? What direction do you intend to follow?

Aicardi – I think that all physicians who are dealing with this syndrome are perfectly aware of the fact that interferon is not the be all and the end all; clearly there is something behind that. Interferon at the moment is the convenient marker for the condition in terms of diagnosis. Whether it is a cause for the disease, not necessarily the only one, or whether it is only another manifestation of the syndrome remains to be established firmly. I’d like to turn this question to the basic physicians who are more competent than I am in this field.

Kuijpers – I fully agree with the remark of Professor Aicardi. I think that interferon alpha, at the moment, cannot be judged as the cause of the disease. It is something that goes hand in hand. But as of course you all know, the levels of interferon alpha drop in time, whereas there is no change in the clinical progression of the disease. So, I think that especially the scientists and the physicians and also the parents should not be completely focused only on interferon alpha. Probably there is something behind and as long as we do not fully understand what the pathogenesis of the disease is, then it is very hard to tackle this particular clinical disease. There are several things that should be sorted out in the near future and that is simply a matter of time. First of all, of course, see to find a kind of pathogenic mechanism – what is this disease caused by? – that’s one part, and the other part is see whether you can find the gene. Because these two ways will probably lead to understand the disease. And I think it is too early to speculate on.

Lebon – I think that interferon is not only one marker in this disease, but I think that it has deleterious effects on the central nervous system. It was shown by the experiment of Ian Campbell, but it was also shown by Jan Gresser 20 years ago in the model of infectious with virus in mice and in congenital infection in this mouse. When it read the mouse with antibody to interferon alpha the mice are better than the control. I am sure that interferon alpha plays a role in the development of some symptoms of the disease. It is another problem to explain why interferon is produced as I said yesterday, but it is not an "idée fixe" for me, but I think that a dys-regulation could produce the interferon without virus.


Question – I am a parent with 2 children with Aicardi-Goutières Syndrome. I would like to know why some families have 2 children and some families have only one child affected with this condition.

Aicardi – This is a problem of probability. The probability for parents who are carriers of the gene for this condition have a one in four chance, as was explained by doctor Crow, of having an affected child and three out four of not having an affected child. This obviously doesn’t mean that when you had an affected child you are going to have three normal children. It’s like throwing dice, you can get the same number several times, despite the fact that you have one chance in six of throwing the same number. That’s the way we explain that sort of thing. It’s not a very good explanation, but it is the one which is true.


Question – We understand the one in four chance of having it again, but as families we are aware that – and you know more families than we do – if you count up the number of normal children and the number of affected children, it seems to be skewed, to be higher than one in four and why does it look that way?

Crow – I wonder if the explanation for that observation comes from the discussion we were having earlier about the possibility for misdiagnosis of this disease, so only when you’ve had a recurrence of what you thought was a sporadic condition or was diagnosed as an undiagnosed congenital infection or an undefined congenital infection would you consider in some cases the diagnosis of AGS. I wonder if it’s simply a bias because of an under-recognition of the diagnosis. I’ve no doubt that this is a genetic disease and that there is a one in four chance of recurrence in each and every pregnancy. I think that if you took enough families and you had the right diagnosis in all of those families, it would be a one in four chance. That also means of course that you can both be carriers and never have a child with Aicardi-Goutières Syndrome, so there are many couples presumably or there are couples in the population who never have a child with AGS because there is a three in four chance that you will not have a child who is affected also. But I wonder if your observation is simply due to the fact that it may be not diagnosed unless you have a second case.


Question – One thing the families may be interested in and maybe you don’t think of because you are doctors – we need to know how to manage our kids day by day. Can you give your ideas on feeding, on positioning in wheelchairs, ----, possible surgeries, what the future is… the daily management that would help us take better care of our children. I do have like ten different areas I would like to ask about. Do you want one at the time or all at once?

First I’ll ask about feeding. All these children have problems with feeding difficulties. Some are tube fed and become normal in size, but there are many who eat just small amounts orally and are very small. Should these children be in the normal height-weight range, or is typical that they are small? Do you recommend tube feeding for the best nutrition and the best health of these children? Because some countries do and some countries don’t.

Aicardi – In the first place, there is no universal rule, because the cases are not the same. Some children do eat reasonably well, don’t need any special way of feeding but some, especially the early-onset cases, certainly do, because feeding problems are really quite often in the forefront of the clinical picture. In these cases obviously all the available techniques should be used, including tube feeding. This is certainly something that is quite helpful in severe cases in which it is impossible to maintain the infant in a reasonable state of nutrition which is obviously something essential and that can be done either by natural route or often by tube feeding.

There is no reason for rejecting systematically tube feeding. I have seen patients who really improved considerably when the tube was inserted, not only from the nutritional point of view which is obvious, but also from the general well-being and comfort.


Question (German family) – Yesterday, reference was made to the alteration of the white matter. We would like to know whether white matter is the same as myelin. We have heard that, for multiple sclerosis, there are some treatments aimed at strengthening myelin that seem to be beneficial to the patients. Would such an approach also benefit AGS children?

Aicardi – I’m not very well aware of the treatment of multiple sclerosis because I’m working exclusively in children in whom multiple sclerosis is not a common disorder. No, myelin is not the same as white matter. Myelin is just one of the major constituents of white matter, but not the only one. There are many other proteins and lipids and other substances which also are constituents of the white matter. If somebody among the panel wants to comment on multiple sclerosis, I would be happy of that.

Kuijpers – About multiple sclerosis, the pathogenic mechanism behind it is, to a very large extent, known. It is caused by the influx of inflammatory cells, white cells, T-cells to be exact, and these are causing the inflammatory lesions. What they exactly recognize there is still a puzzle. We have some clues there too, but they may be different from patient to patient. Nonetheless, if you take away these cells, so if you delay the influx of these cells, if you can dampen that inflammation, then the white matter is spared more than myelin production is boosted. So you just take away or you prevent inflammation. And that is why substances now widely used in MS seem to work. One of the things that is used in MS is interferon, interferon beta for instance, but you have other medical approaches that affect more or less the same type of cell, but in a different way, but all meant to prevent that inflammation to occur.


Question – My name is Nancy, I’m from Vancouver, Canada. I’ve a three and a half year old daughter who is with me. I have two brief comments and two questions. First of all, thank you for your work and, second of all, just a bit of information: my daughter received her diagnosis from a geneticist and the paediatric neurologist was not aware of AGS, so it was the geneticist who made the diagnosis.

My first question is: my daughter has bilateral basal ganglia calcifications, she has also had two positive results of leukocytes in the CSF over a 4-month period. The interferon tests were not easily available and the Canadian doctors did not really want to push to have this done. So, my question is: can this diagnosis be made based on those two symptoms? Should at this point still have this done? Is there an approximate age where the interferon level drops so low that perhaps at this point having it done may show nothing?

My second question is my trying to understand correctly from yesterday’s topics. Did I understand correctly that this disease can be static, that there were some children where this is the case, that in fact they do not increase in calcifications after the first to second year of life?

Aicardi – I think the best person to answer your first question is professor Lebon.

Lebon – Yes, at 3 or 4 years interferon could strongly decrease, as you saw yesterday in the diagrams. But what was the sensitivity of the test, what was the test for that interferon? – She was not tested –

Barth – If I may also make a comment, there are few places in the world where the alpha-interferon test can be done reliably and for us in Amsterdam, Holland, we use to send it to doctor Lebon. But until a few years ago we didn’t that either and we used to make a preparation of the cells in the cerebrospinal fluid to do electron microscopy on it and, by doing that, you can see peculiar inclusions that are specific for alpha-interferon. So, even though you have not easy access to the determination of alpha-interferon such as doctor Lebon has in his laboratory, there is an alternative route which is quite reliable and may be available in your local medical centre.

Lebon – But I am sure that in Canada you have teams which can dose interferon. Such teams working on interferon are present in Montreal; I can give you their address.

Aicardi – With regard to your second question about the late appearance of calcifications, this is certainly possible. I’ve seen it at least in one patient. It is not usual and when it does occur the calcification still appears early in life, not after the age of – I don’t know exactly, but I would say not after the first year of life or the first year and a half.

Lebon – I have another comment on that and that is some concern that we have. CT scan is excellent for exposing the calcifications, but nowadays CT scanning is replaced more and more by magnetic resonance imaging and magnetic resonance imaging is highly preferable to CT in all regards, except one: calcifications. So what seems to be a diagnostic hazard is that when a doctor is trying to make a diagnosis in a child with white matter disease and increased cells he may miss the calcifications unless he makes that jump in his mind. That of course is not basically your concern, but it should be ours.

Crow - Nancy, I think we don’t know the minimum diagnostic criteria for this disorder. If your child has a CSF normal interferon alpha level, it will not take away from the significant possibility that this is an Aicardi-Goutières Syndrome. So I think in a sense you have to make an individual decision as a couple about whether you want to put your daughter through that test, because a normal level would not make it less likely; a positive result would confirm up the diagnosis, but I don’t think there is not a should or a shouldn’t; I think you decide.

The other thing I was going to say is that there are some cases that are static, children that are not regressing, are not getting worse. I think professor Lanzi’s paper yesterday suggested that children sometimes improve.


Question – Would you recommend immunizing these children with routine vaccines that are usually planned in the first years of children’s life? What did you do with the patients that you personally follow?

Aicardi – I certainly immunize my patients; I think these patients are particularly susceptible or may be particularly susceptible to infections. It doesn’t help for these children to get measles or to get the sort of infectious diseases that can be prevented by immunization. I don’t think there is any definite contraindication to immunization in these patients, even though the small number of cases makes that statement perhaps a bit too absolute, but my feeling is that certainly these patients should be immunized like the rest of the children.

Lebon – It is an interesting question. I agree with doctor Aicardi about the non dangerosity of vaccination; but what is the efficacy of vaccination in these children? Because they produce interferon; interferon is anti-viral and when you inject the measles, or mumps or rubella vaccine, you inject live viruses, viruses that normally replicate in the child. The question is: have you tested immunity in children after vaccination against measles, mumps, to know if the immunization is present?

Aicardi – The answer is ‘we haven’t’.


Question – I have a question for doctor Crow. By the way, doctor Crow and doctor Kuijpers will have to leave sooner than the other doctors, so if you have question for them, it’s better to ask now.

Yesterday, in your talk you said that you have identified this locus 3p21. But we know that, also based on the results of DNA testing for many of us, this was not recognized in all cases, almost in half of the cases in fact. How do you intend to proceed also for those other children for whom the locus has not been recognized? How will you continue your research?

Crow – One of the grants we’ve applied for is to perform a genome search, the same technique we used the first time, using only samples that we know are not linked to chromosome 3p21. So previously we had 13 families available to us with enough DNA to use – because you need quite a lot of DNA for that kind of search throughout all the chromosomes. But now, of course, because of the results of our study and because of this organisation, there is more DNA available, and because of the collaboration within the group I belong to – Pierre’s group – there are many more samples. Where it is possible to say that a family do not link to chromosome 3p21, the idea is to use those families. So, one of the grants has been to an organisation called The Marshfield in America. It’s very good because it’s free; it’s a free genotyping service. They will do what we’ve spent a year doing for free and they will probably do it in two months; they will probably be better than anything I could do. So, I will be very pleased if they accept our proposal. That proposal involved collaboration and submission of the grant with Pierre. And you also have to have an American sponsor, so Ian Campbell sponsored that and sent a letter of collaboration for that grant. That is specifically to try and identify a second locus in families who are definitely not linked to the first. Previously I said that there are some families who may be linked to chromosome 3p21, of course they may also be linked to the other locus or the other loci. But I think that this is a sensible way to proceed, to use families which are definitely not linked and to try and identify a second locus, and then we can look at all of the individual families.

The second approach – and I mentioned it yesterday – is that if you identify the first gene, you may be able to quickly leap-frog jump to the next gene at another place, because if you understand gene function – you remember I showed this diagram of A, B and C – if you have a defined biochemical pathway already, that you know about, and you find that the gene is gene A and you know ‘Ah, gene A works with gene B and gene C’, you can go and explore those genes. So sometimes you can jump very quickly, sometimes not. But I think these are two sensible approaches to the problem.


Question – Another question on managing our children. In talking with other families, we’ve noticed the regression in this disease is not slow, it is episodic, it’s like… when a stressful time comes, then the child may rapidly regress and then stabilize. And then another stress comes… do you agree? For example, the stressful test we’ve noticed is if the child gets dehydrated, if the child gets overheated, if the child might lose calories for 2 or 3 days because they’re sick, they may regress. And a very noticeable one is sedation – for example for an MRI – or anaesthesia for surgery. Very often our children, when they wake up, they are not the same again, going through these stressful periods. Have you noticed that? Do you agree with it? And should we try to manage our children’s lives so that there is little stress? And, along with it, should they no longer have MRIs because they require sedation and should surgeries be limited because they require anaesthesia?

Aicardi – Yes, definitely there are periods of aggravation following episodes of infection or even episodes of fever without detectable infection, especially acute nutritional problems following any sort of stress – as you say, let’s put it that way, as it’s very broad. Clearly there is a relationship between the general health of the child and the evolution of the disease. I think that the aggravation is mostly temporary, but that needs perhaps further analysis.

What you said regarding the magnetic resonance I think is important, because this requires usually at least sedation and very often general anaesthesia, which is not desirable in these children. I would certainly add that in many cases I can’t see really the necessity of repeating the MRI investigation once you’ve got a clear-cut image that is sufficient for the diagnosis. I can’t really see any interest in repeating the MR, at least in the close range period. Certainly you can wait for years before repeating that because it doesn’t add very much, as far as I can tell.


Question (German family) – We have a question regarding the treatment of hypertonia, i.e. when children suffer from attacks and become rigid. Would you recommend to use botulinum? Another question: does it make any sense to cut the muscles before the hip is displaced? So, is botulinum effective and does it have any side effects? Could it be dangerous?

Aicardi – I think the botulinum toxin is not generally indicated in these patients, because the spasticity they have is diffuse and it’s difficult to use the botulinum toxin in very diffused contractures. On the other hand, in the case of a specific problem around a particular joint, then the indication of botulinum toxin is possible, and this could apply to the adductors, could apply to other muscles as well. But that’s a temporary effect and it has to be included into a general plan of treatment. Botulinum toxin is not a miracle drug, it can be used in certain definite circumstances, for specific purposes, but it should not be considered as being the answer or even an answer to the problem of these children.

For the second question, that also is a specific problem. In general, I would not think that it is a good idea to operate on these children, but if there is an immediate emergency threat on the hip, that can be one possibility that can be considered.


Question – I would like to comment on botulinum and doctors. My younger son had botulinum shots. The third time he went to severe seizures; his brain was swollen like encephalitis; he had very severe reactions, lost his eye-sight, couldn’t move any more and it took many months for him to get back to normal, although he has permanent vision loss from it. I believe doctor Lebon said that one other child with this syndrome had a similar reaction to botulinum toxin, so I would be very concerned about other families trying that. I don’t want it to happen to the other children if this may be something related to the syndrome.

As for releasing adductors and other muscles, if it can be done under a local anaesthetic, I think that would be better. My sons have had a local anaesthetic rather than a general anaesthetic, if it’s possible, and I recommend that.

Aicardi – I’m not aware of any sort of accidents like the one that you observed. There is now a large experience with botulinum toxin, not specifically in this syndrome obviously, but in the general population, and there are known complications, especially when related to large doses or excessively large doses which can produce weakness and lasting weakness – not indefinitely lasting, but for some time. I’ve never heard of convulsions precipitated by botulinum toxin. I certainly believe that botulinum toxin, like any drug or any surgical intervention, has to be included into a general plan of treatment of the child. It may be quite useful to reduce a specific contracture at one joint, but certainly not as a basic sort of therapy. That’s certainly not the aim of that. It has very specific aims if any indications exist; these are for specific problems and temporary problems, especially in the case of these children, who have a number of other problems and who certainly do not tolerate general anaesthesia very well. And if anything has to be done clearly it’s better to do it, if possible, under local anaesthesia.


Question – I have a question for both doctor Barth and doctor Kuijpers. Yesterday you talked about this new pilot treatment. We think we have understood the idea underlying this treatment. At present, we know that interferon alpha is not the main cause, but we know that it is responsible for a number of damages in these children. For this reason, we attempt to limit such damages. However, also based on our personal experience, we have seen that, usually, interferon alpha tends to decrease in these children while they grow older. Do you think that this kind of therapy may also help those children whose interferon has already dropped below 2 or is dropping – perhaps it is now around 5, 4, 6 – and is now very close to a normal level?

Barth – I think that you’ve quite well understood the message. The message is that it is possible to lower the alpha-interferon by the use of a certain drug, but you also understood that alpha-interferon is contributory to the damage, but we don’t know if it is really the origin of the problem. So we have the idea that it might help some patients who have a high level to get the alpha-interferon down, but nothing has been proved about possible results. So we have to rethink what we have found before we can take next steps that may be a reward to early cases. I think the IAGSA would be an excellent platform to discuss such an approach before we go to the next step and maybe go for a proposal. This is very preliminary, but it keeps our attention and I’m sure we will come back on it.


Question – My 5-year old boy is affected, but I have another 8-year child who is unaffected. First of all, I would like to thank you; second, we come from Rome and we would like to acknowledge that doctor Bertini helped us very much with this syndrome. Just before we went to see him, he had already diagnosed A.G.S. in a little girl. Our diagnosis is not confirmed yet, but it is supposed to be A.G.S. We were very well assisted and I would like to acknowledge this, because I know how painful it is when you realize that you are confronted with a rare disease.

My child is very nervous and, at times, he is also very stiff. Can these muscle contractions be painful for him? I would also like to add that my child underwent adductor surgery and has considerably improved after that. Before surgery, he could no longer open his legs, whereas now he can keep them apart and he has also become less nervous.

I have another question: do you have any idea about the life expectancy of these children? How long do they live? This is something I really would like to know.

Aicardi – Regarding the second question, we don’t have any systematic follow-up study, but we certainly know that there is a high mortality, especially in the first years of life in the severe cases with early onset. In the milder cases of late onset we have certainly seen patients – at least 2 patients – who are now in their 17-18 and are doing reasonably well. So I cannot give a complete answer, but certainly there is a possibility for at least part of these patients to live for a reasonable period of time as far as I can tell.

About the pain in muscles: muscles are not usually very painful; the hips may be, on the other hand. It’s certainly uncomfortable to have a marked abduction of the thighs and makes life more complicated as well in terms of care. As I have already mentioned, there are specific indications for a specific surgery with a specific purpose. That’s the best answer that I can give.

Barth – It does not apply just to your case, but I think it’s worth a general comment for the parents with AGS children: the rehabilitation doctors or their orthopaedic surgeons may come to think of the problem of those children as a kind of spasticity similar to cerebral palsy. In some of the cases, there is, in addition to spasticity, what we call ‘dystonia’. In those cases, you may have very painful spasms and I think it would be very important for parents to know that and, when they have suspicion of it, to specifically remind the rehabilitation doctor and the orthopaedic surgeon of that.


Question – Since the AGS seems to have some features of an autoimmune disease, have you ever considered the possibility to perform bone marrow or stem cell transplantation?

This is a question from parents and not by experts, but we would like to know your answer.

Kuijpers – That’s a very good question, but a good answer to that question is only possible if you know a little bit more about the mechanism and we just started thinking about a therapy. We did it with a kind of bolus infusion with methylprednisolone to limit the side effects of that steroid treatment. What we did see on one hand is a very steep drop in interferon alpha – that would be great if that was the cause of the disease, and on the other hand, the cells that we characterized were never seen before. And if we look then at what the treatment did on the number or the phenotypes – how these cells looked – that didn’t changed at all. Now the question we have to answer first is: are these the cells that we should direct therapy at? Those are the questions that we have to pose first and then come to maybe another proposal for another type of therapy. And if, at the moment, we stick to this kind of ‘basic’ autoimmune treatment – if it is already recognized that it can be designated as an autoimmune disease – if we stick to this disease, we can get more information on whether it can help or not, or on whether we should change or not.

The question you referred to was: should we give bone marrow transplantation or stem cell transplantation? That is a very difficult question to answer at this particular moment, because those types of therapy are in a way very cruel and should be limited only to those patients that do not have anything else to expect. And I think it’s too early to say that this is the case in AGS. So I should say: try to have a little bit more patience; it sounds silly, but I think that, before jumping to the most cruel therapy we have, I should recommend that.

If this disease turns out to be driven by something like a cell type which is not a leukocyte, which is not a white cell type, driven for instance by a brain-derived cell, you can put in a bone marrow from a perfectly matched donor or a healthy sibling, but you end up with a similar kind of mechanism. This brain-derived cell will cause the same autoimmune or immune attack, even if it is due to a new bone barrow. Then, in that case, the disease will be exactly the same and, on the other hand, your child has come through a terrible period – in fact, a false therapy.


Question – I would like to thank the Association for what they are doing for these children who are really suffering a lot. My little affected boy is 4 years old; the diagnosis was made by doctor Bertini when the child was 4 or 4 and a half months old. Mirco is suffering quite a lot and it is not easy to manage him, because he presents with a very intense dystonia. It is even more difficult to manage his disease when he is sleeping. When he is relaxed and sleeps, he suffers from sudden apnoeas, so that he must make use of oxygen. Is there a method you can recommend to manage his breathing. Consider that, sometimes, when his apnoeas are very severe, we have to rush to the emergency ward to get oxygen and other aids. Thank you.

Barth – The problem that you describe is not specific for AGS, of course, but it has to be analysed before it can be treated. In neurologically handicapped children, there are two ways in which they can get apnoeas - I skip the third one, which is seizures, I suppose these are not seizures. Either it is what they call ‘obstructive apnoea’ that means that, when the child is lying on his back, he may become obstructed because his tongue falls back or because his palate does not lift enough. In that case, the treatment should be directed at removing or at least relieving the obstruction. The other possibility is that the apnoea is caused by an abnormal steering mechanism of the brainstem (primary apnoea). In most cases, it’s obstructive I don’t know your situation, but in our situation usually the child is analysed before advice and treatment can be given. This is not a complete answer, but it’s a just the way you have to move to relieve the problem.


Question – I come from Rome and I have a 5 and a half year old girl. Going back to the 25% chance to have an affected child, I have noticed that there are families where the first child is healthy and the second is affected. And I have seen several cases where there are two brothers or two sisters, both affected. Do you know of any families where the first child is affected and the second is healthy?

Crow – The answer is ‘yes’. If you take a coin, heads and tails, you toss it once, it can come down heads once; you toss it again, it can come down heads again, but it doesn’t mean to say there is no tails on one side. It is chance, probability as professor Aicardi said. If you’ve had one child affected and the diagnosis is made, there is no way of saying that your next child will not be affected, then, for some couples, that is a strong reason not to have another child. So maybe this is the explanation why you haven’t met these families. I’m convinced that this is a genetic disease. It is an important observation, especially when we were considering the possibility that it may be due to an undefined infection. But, as I said to you yesterday in my presentation, there are families known where you have two affected children separated by the birth of an unaffected child, over a long period of time, and that is very much against the possibility of an infection that we haven’t been able to identify, that has been gone away and come back. I think this is very important evidence.

I’d like first of all to thank you. It has been a great pleasure to be here. The second thing is a practical issue. I have come across many of the samples from people in the audience and their children; those samples have been collected through your physicians and your doctors. The samples have been taken with your permission, of course, but there is now an issue with this kind of research that one has to make sure that we always have consent for the use of this material. In England in particular there have been some particular problems about this, so I was going to ask if – although this may be duplicating what has already been done – but I have a number of consent forms and if I give them to professor Lanzi, if it’s possible, if you wish to be involved in the research or to continue with allowing us to use the samples from you and your children, then if it would be possible to fill and to sign these consents as a couple or as an individual parent, that would facilitate, that would allow the research. It would just make it easier just doing it now as opposed to coming back to you when you are all spread across the world. So, if you do want to continue, that would be very helpful.


Question - My orthopaedic surgeon has recognized that my kids are not very spastic, but they are rigid and he says the difference is: spastic is - the muscles are more uneven in their strength and there are more spasms, and rigid – the muscles are more even and stiff and the arms do this, when you move them. Have you recognized in other kids that they have rigidity more than they have spasticity and is there any different way to control this rigidity , for example would the medication Baclofen help that?

And is there any specific treatment for dystonia as well?

Barth – First of all, in AGS you may have pure spasticity, you may have spasticity combined with dystonia and you rarely have only dystonia – I am not aware of cases with only dystonia. The hazards of both are of course dislocation of the joints and pain. Dystonia especially may cause pain. You ask whether there is a specific treatment for dystonia. Well, there are drugs that are specially designed to treat dystonia, but it’s an empirical treatment and it rarely completely relieves dystonia. On the other hand, there are some surgical treatments for severe dystonia, like stereotactic brain surgery, but as far as I am aware it is rarely done or not done in AGS. In this regard, I miss the opportunity to forward the question to professor Aicardi who has seen more patients than I. But I think that, in a general way, treatment is empirical – one should try to relieve pain, one should try to influence the dystonia by drugs, and it’s all a question of step-wise trying what is available.


Question (German family) – Going back to the treatment of rigidity – we said that botulinum may carry some risks and I am rather worried. Is there any alternative treatment to botulinum, should my daughter need it?

I have a second question regarding child feeding. With regard to tube feeding, can we give special liquid food to our children, also orally, as is usually done with terminally ill patients, for instance? Does this make any sense? When a child improves through better feeding, is this more connected to the quantity of food he receives through the tube or to the quality of that food? Could we use some similar food also orally?

Barth – For your first question: there may have been a little misunderstanding about the botulinum toxin, because as is given, it is applied very locally to the place where the nerve enters the muscle. By doing that, you paralyse the muscle for a few months until about a half year. The importance of that treatment is that you do not actually damage the muscle or damage the tendon or damage the nerve, you only remove its action for a certain time. The implication is that you can apply it to several muscles at the same time and see whether it works and, if it works, it can help in the decision for instance to cut the tendon. So, in a way, the application of botulinum toxin and surgery are complementary and usually there should be a good cooperation between the rehabilitation specialist and the orthopaedic surgeon. They should combine their efforts, ideally, to get a good choice of what to do. And there are other kinds of treatments for spasticity and dystonia, but they are not available in all the centres; so I think that it is perhaps not practical to debate very much about them. But botulinum toxin and tendon surgery are always available.

The feeding: when children cannot be fed in the usual way and have to be tube-fed for a prolonged time, then usually there comes a moment that you have to consider a percutaneous gastrostomy, which means that you make a small hole in the abdomen to feed the child. That relieves many problems, including problems of aspiration, problems rising from the tube being too long in place, etcetera. In our experience, we apply percutaneous gastrostomy more and more for children with prolonged severe feeding problems necessitating tube feeding for a very long time. We have the experience that most of the families are very relieved by this appliance.


Lanzi – I think that we can close this meeting with the experts. They have answered many questions and I think you may be satisfied. I wish professor Lebon and professor Barth to join the other doctors to discuss about future research plans, before professor Lebon leaves. Perhaps we have slightly shortened our morning session, but I think that, in the interest of all of us, it is also very important that they may discuss about future research. Thank you very much.

Lebon – I would like to express my deep appreciation for all of you, parents, and for the Association that you have created. This is very encouraging for us to continue to work on this disease extremely rare and mysterious disease. Many thanks to all of you.