AADCd Family Workshop 3; Clinical Presentation of AADCd - Understanding the Symptoms & Treatments

AADCd Family Workshop 3: Transcript Clinical Presentation of AADCd; Understanding the Symptoms & Treatments

Dr Roser Pons Greece

Transcript ...

Lisa Dr Roser Pons welcome and thank you for joining us.

Thank you all for joining my name is Lisa Flint founder of the AADC Research Trust and mum of 23 year old Jake who has AADC. Together with my colleague Julie and all of you we are celebrating 15 YEARS of this year of patient advocacy, raising global awareness and funding critical research.

I'm sorry because of time constraints we can't go round and introduce each and every one of you.

The subject about the clinical presentation of AADC and understanding symptoms and treatments is of extremely high interest and we hope you will find this workshop helpful.

Let's begin by welcoming and introducing our presenter Dr Roser Pons is an expert on AADC and has been working with our children for more than two decades. We first met Dr Pons in New York when we flew there twenty years ago with Jake to find out how best to treat his new diagnosis of AADC deficiency. We have collaborated on many research projects and been grateful to her commitment to our children and their disease.

Dr Pons is a paediatric neurologist and movement specialist at the First Department of Paediatrics Agia Sofia Hospital, University of Athens, Greece.

Dr Pons Thank you very much Lisa. It's already twenty years! I am very happy and very honoured to be here today and we can have an interactive discussion.

Slide 1 So AADC is a disorder of neurotransmission basically. Neurotransmitters are chemical substances. They are involved in synaptic transmission which is the way the brain cells, the neurons communicate, between them. The synapse is where the chemical compound neurotransmitter is liberated to work in the following cell. That way messages among brain cells occur. So as you can imagine Page 1

neurotransmitters are very important.

Slide 2 There are many neurotransmitters. Biogenic amines or monoamine transmitters, you are going to hear both things. The reason to call them this way is because they have specific chemical structure. So when we talk about monoamines or biogenic amines this includes dopamine, norepinephrine, epinephrine and serotonin. The first three are also called catecholamines.

Slide 3 I will give you the functions of these three neurotransmitters. Dopamine is important for movement, cognition, emotion and endocrine function meaning hormonal function. Serotonin is important for mood and sleep. Norepinephrine and epinephrine are important for what we call the autonomic nervous function which is the part of the nervous system which controls the function of the other organs. So this controls the autonomic nervous system that is called the sympathetic nervous system. Then the norepinephrine and epinephrine are important for the stress response, whenever the body encounters stress it has to react in some way. So these two neurotransmitters are important for this.

Slide 4 In general these neurotransmitters are produced in this part of the brain called the mid brain, the upper part of the brain stem. And then from there the neuronal cells, the brain cells, send projections to different parts of the brain and in that way can do all these different functions that the neurotransmitters have.

Slide 5 How are they produced, the synthesis/production? It is very simple. Dopamine is synthesised after two steps on the synthetic pathway. So there are two steps and then we have dopamine. The first step is tyrosine converted into L-Dopa then the next step is L-Dopa being converted into dopamine. For this second step we have Aromatic Amino Acid Decarboxylase that is the enzyme, the catalyst of this reaction produces dopamine. Then dopamine can be further converted into the other catecholamines; norepinephrine and epinephrin. Then serotonin, serotonin is synthesised in the two steps in the synthetic pathway. It starts with tryptophan.

Tryptophan is converted into 5 hydroxylase trytophan and then it is converted into serotonin with the same enzyme Aromatic Amino Acid Decarboxylase. So we have the same catalyst for synthesis of dopamine and then for the synthesis of serotonin. This means that if we have a problem with this enzyme, if it is deficient Page 2

and not working well, that is going to lead to a decreased production of all the biogenical amines. So only one enzyme but effecting all the biogenical amines.

That's important to keep in mind.

Slide 6 So the symptoms that we are going to see in patients with AADC deficiency are going to be related to the deficiency in the function of this enzyme, in the function of this neurotransmitters that are not being produced.

Usually the most characteristic symptoms in AADC deficiency are the ones that are related to movement. These are the most relevant but they are not the only ones.

Dopamine deficiency leads to these movement problems and developmental delay. Serotonin deficiency leads to behavioural problems and sleep disturbances. Norepinephrine and epinephrine deficiency lead to a dysfunction of the autonomic nervous system that I was telling you, the control of other organs.

Slide 7 As I told you the most important, or the most remarkable clinical manifestation in patients with AADC deficiency are related to movement. The first thing that the parents see is that their children are not developing. They also see that they are very floppy, they are hypotonic. When they pick them up the head goes to all sides and is not well controlled. They also see that the children don't move much and if they move the movements are slow. In addition to all that the little movements that they see, they are not normal. They have this twisting posture and this is called dystonia. So they see little movement and they see abnormal movements In addition to that they also see oculogyric crisis, these are episodes where the eyes go up intermittently or they are sustained up and this is very distressing for the child and can also be associated with lots of other abnormal postures of the limbs, neck or tongue. As you can imagine these events are often misdiagnosed as seizures because they look like seizures but the patients are alert and if you have an EEG at the time of these events, usually there is no epileptic activity. And the final thing that we see is that the patients, even if they do very little, they are much better in the morning after they have slept. They have this so called diurnal variation and sleep benefit. We might not see this but if we do it is very characteristic.

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Slide 8 Oculogyric events are very characteristic. There is eye deviation that is intermittent or sustained and they can be together with the stiffening of the neck, the tongue, the limbs. They resemble seizures but they are not and often times they resolve, the patient can put him or herself to sleep. Parents tell us there is a periodicity to these events. Sometimes you tell us it is going to happen every day or every four days or once a week. And it is happening in this periodicity which is quite characteristic.

Slide 9 Then there is the diurnal variation and sleep benefit which means there is aggravation of the motor symptoms late in the day and improvement of the motor symptoms with sleep. Apparently related to metabolic recuperation of dopamine during periods of inactivity. I insist it's difficult to appreciate this in children that are very very developmentally delayed. But if you see it is very characteristic.

Slide 10 Patients have other problems too. We said that because of the serotonin problem we have behavioural disturbances. How does this manifest? We see sometimes, in the little children, that they are very dysphoric, they get upset very easily and it is difficult to calm them down. They don't all do that but it is something that we see.

Sometimes when the kids are older, it might become more clear that they have a pervasive developmental disorder, it's not always there but sometimes. Sleep disturbances are also very frequent in these patients. So what we see here is sometimes the children sleep a lot or the contrary, they have a very disrupted sleep. So it can go either way. We are talking about patients that are neurologically very effected so they can have other problems that rely on this developmental delay or neurological impairment so they can have difficulty swallowing, they can have seizures too and they can have other movement disorders . The symptoms that I have told you about now are the symptoms that appear to be related to the neurotransmitter deficiency that we see.

Slide 11 I told you that we see autonomic dysfunction. I told you that the catecholamines norepinephrine and epinephrine are important for the sympathetic nervous system. That is the part of the nervous system that controls other organs. So they control heart rate, they control blood pressure, they control the movement of the bowels. So we often see that many of these patients sweat a lot, the temperature Page 4

is unstable, they have a fever but they don't have an infection or the opposite they can have low temperature. They can have a lot of secretions and it is not necessarily that they have an upper respiratory infection. Often times they have a lot of secretions in the nose. They can have gastrointestinal dysmobility. This can be very severe constipation. They can have hypotension, bradyarrhythmia, poor distal perfusion and they can also have apnoeas. They can have mitosis and ptosis because the sympathetic nervous system controls the way that the eyes open and the size of the pupils. So if we have a problem in the production of catecholamines the eyes are more closed and the pupils are small.

Slide 12 Dopamine effects the endocrine functions. We can see hypoglycaemia, growth retardation, we can see hyperprolactinaemia, we do see an inadequate response to stress and delayed bone age.

Slide 13 In general the symptoms that I have told you about up to now are symptoms that we see in all neurotransmitter disorders that involve the biogenical amines. We always say there is a spectrum of severity. Most are severely affected but we also have patients that are milder. In AADC deficiency most often patients are quite severely affected. There is a proportion of patients that can have a moderate severity but most often we will see a severe phenotype.

The severe phenotype is the most frequent. These patients have no or minimal developmental progress. They have poor response to treatment. And if we give treatment they have lots of adverse effects from the medication.

In the cases that have a more moderate presentation they do have some developmental progress even without treatment. They can manage to have head control and to have a little bit of hand use. And they usually respond better to treatment. And although they do have adverse effects from the medication they are usually less severe. So we developmental progress.

Slide 14 So how do we diagnose patients with AADC deficiency? The clinical history and physical examination aren't enough to confirm it. Many times with patients who have these types of problems the first thing that we do is a brain MRI. So in AADC deficiency in general the brain MRI is not going to show us anything. It is not going to help us with the diagnosis. Usually it is normal. Maybe more severe cases with a long history we can see some brain atrophy but in general it is not Page 5

going to help.

So what is going to help us here is the biochemical investigations of all the chemical compounds. As we said if the AADC is not working we are going to have decreased content of all these neurotransmitters. All these neurotransmitters, the same way there is a pathway for synthesis, there is also a pathway for degradation.

Many chemical compounds in the body are synthesised and then they are degraded. The cycle and the balance of this is necessary for the normal metabolism. That is also the case for these neurotransmitters. There is a system of degradation and this degradation leads to the production of some metabolites.

So we can measure these metabolites in the spinal fluid. We have to do a spinal tap and we measure the metabolites of these neurotransmitters. We can see that all the metabolites are low because they are not being produced as they should.

In addition to that because L-Dopa cannot be transformed into dopamine, LDopa accumulates and because it accumulates our body has a system to transform L-Dopa into something else and this is 3-O-methyldopa. So the spinal fluid, in addition to see if the metabolites are low, we can see that the 3-O-methyldopa is elevated. This is going to be the biochemical hallmark that is very characteristic of AADC. If you see that you have a diagnosis.

You can also check by assessing the activity of AADC in the blood. This can be done by a blood test but most of the time we don't do this step.

We confirm the result of the biochemical analysis and then we go directly to the gene. The gene that encodes AADC and then we see if there is a mutation that is pathogenic and explains this biochemical pattern and most of the time that is what happens.

Slide 15 How do we treat AADCd? We have a problem with neurotransmission of the biogenical amines and we have many symptoms that are related to dopamine. As I said before the most remarkable symptoms are the motor symptoms, they are not the only ones but they are the most remarkable.

So to improve dopamine function we have medication called dopamine agonists.

These are chemical compounds that act on the receptors for dopamine so we call them dopamine agonists. Fortunately we have many so we can try different types, depending on what is available in your country and how the patient tolerates them.

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We can do something else. As I told you all these metabolites are usually degraded so we could inhibit this degradation. So for the little neurotransmitters that the patient may produce stays longer in the system. For this we have the MAO inhibitors. The monoaminoxidase enzymes are enzymes designed specifically for the degradation of the biogenical amines. If we inhibit this degradation it means the little biogenical amines we have are going to stay longer in the system.

This is basically the main stay of treatment for AADC deficiency . Usually it is the combination of dopamine agonists and MAO inhibitors. In addition to that we can use Vitamin B6 because AADC, in order to function well, needs this vitamin. So sometimes, by giving a little bit of the vitamin that is necessary for the function of this enzyme, we might push a little bit more the activity of the enzyme that is deficient. So we usually give it to all the patients.

We also give Folinic Acid. I told you that the L-Dopa that cannot transform into dopamine, it's transformed into 3-O-methyldopa. This is something that our body does, we don't choose it. By doing that it takes away the possibility to activate the folinic acid, so patients become deficient in folinic acid. This is easy to rectify. We give them the folinic acid.

At the end of this list I've written L-Dopa, but it doesn't make sense to give LDopa when the problem is in the enzyme that converts L-Dopa into dopamine.

But there are some mutations in the gene that encodes this enzyme and what they do is they interrupt to some degree the interaction of L-Dopa with the enzyme. We know that of we give more L-Dopa this interaction might get better.

So there are a number of patients, not many, where it actually helps to boost the activity of the deficient AADC. So that is why I have put it in brackets because it can be given to some patients.

Slide 16 What is the response to treatment?

It is variable but in general it is what I already told you earlier. The severe phenotype, the most frequent phenotype of AADC deficiency, has a poor response, not favourable. And moderate phenotype response is favourable. There is a general concept that the earlier that we treat patients the better the prognosis. The later we treat patients, the worse the prognosis.

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Q&A Julie Which is the best dopamine agonist to use?

Dr Roser Pons This is a difficult question to answer because I do believe that we have to assess each patient. We used to give Bromocriptine because this was better tolerated by some patients but at the same time it was less efficient. But then when we went to other dopamine agonists like Rotigotine or Ropinirole patients could have adverse effects. So we had to find a balance. I don't think I can tell you which one is the best one. I do a trial and error with my patients in general and right now I have a patient with two dopamine agonists and it was the combination of both, I had to play with it but we found it. The same way we found it we can lose it. Anything might make us lose it, an infection, a bad day and that balance that you had you lose it. If you were to also ask me about the MAO inhibitor again it depends on what is available in your country and how you use it.

For example, I had my patient with AADC deficiency here in Greece, I had her on one MAO inhibitor that was very helpful from the beginning, it was perfect. At some point this medication just stopped being available in Greece, so I had to switch from one to the other. Of course for a while, some months we lost all the balance we had. So then I was playing with the dopamine agonist. I don't think I can give one medication I think it is patient and country and situation related.

Julie How would you immediately notice whether a child is severe, moderate or mild when you see them in the clinic?

Dr Roser Pons This is a very nice question. I think I can answer it but I may be wrong. If I see a patient with AADC deficiency at nine months of age, and by nine months of age the patient has some hand function and some head control, I think I would be positive that it might respond well to medication. But if the patient has not any function I am quite sure that he or she is going to be a severe phenotype. If it is very early on I don't think I can say. That is my theory because I had two very severe patients when I was in New York and I had a clear picture of a severe patient and then my only patient in Greece, when I saw her she was less than one year old, but I kind of knew she was going to do well because she wasn't as severe, also her OGCs were much less severe , they had started much later on.

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Not so much at the beginning of her life. So I think you can sense it but until you try the medication you don't really know.

Julie What is the best management for OGCs, how can we avoid them and are they dangerous?

Dr Roser Pons That's a tough question because what I have learnt is that every family knows what to do. Many times you tell us that if they manage to fall asleep the OGC event is going to finish. But also I have had families say that the next day when the patient wakes up the OGC continues. So I have heard both things. Families try different things. If you help them to sleep with chloral hydrate or benzodiazepine that might help. Some families like trihexyphenidyl. Other patients for example, are not so affected by OGC events, especially when they are older. They have this upward deviation of the eyes and they might be annoyed but it is not such a big deal. I think it is more of an issue for the younger ones, the severe ones, the ones that last hours and hours. You can see that they are very uncomfortable. Are they dangerous? There are descriptions of patients having done apnoeas during these events so in this regard one could say that they are. But in general it is not like status epilepticus, which is a seizure that lasts more than half an hour and we know that when you reach this level it is very risky to have apnoeas, hypertension and you know that the patient is at risk of dying. It is not the same. I don't think that the OGC event has this same equivalence in terms of severity but it’s true there are descriptions of apnoeas during OGC events. I don't think they are that benign but they are not as severe as the status epilepticus.

Julie Does gene therapy improve all catecholamines i.e. dopamine but does it improve norepinephrine and epinephrine?

Dr Roser Pons I am not sure I can answer this question. I would leave it to my colleagues. They have measured the metabolites in patients that have had gene therapy done and I know in some patients there is no big difference in the concentration but in other patients there is improvement in the concentration but in terms of function, if there has been an assessment of the sympathetic function in patients that had

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gene therapy, I don't think it has been done so I don't think I can answer that.

Julie Is B6 Pyridoxine better than the active B6 P5P (Pyridoxal-5-phospate)?

Dr Roser Pons I think that in the case of Aromatic Amino Acid Decarboxylase it is either thing.

Theoretically a patient with AADC deficiency does not have any problem activating B6 into the active form that is pyridoxal-5-phosphate. So theoretically it is the same. The only difference is that B6 is cheaper and more easily available.

Julie What is the difference between MAO inhibitors Selegiline and Parnate?

Dr Roser Pons They are both MAO inhibitor. Each one may have a pharmacodynamics, pharmacokinetics.

Julie How can we find which mutations may respond to L-Dopa?

Dr Roser Pons There is a very good group in Italy, Dr Bertoldi, she is the molecular biologist and she will answer this question. She has done studies on the genetic mutations that have been found.

Julie What medications should children start on?

Dr Roser Pons There are in general, if you follow the guidelines, the AADC guidelines, you can either start with a dopamine agonist or with a MAO inhibitor. It depends on your preference, the preference of the doctor and how comfortable the doctor feels. I myself start with MAO inhibitors. In my opinion they have less adverse effects and Page 10

are better tolerated by the patients. Once I give the MAOi and I see the patient tolerates this, then I can add the dopamine agonist and I can go slowly, increasing the dose, maybe combining with another dopamine agonist. The dopamine agonists have more room to play with doses whereas the MAO inhibitors doses that we give are stricter, so I go with something I know I have a clear protocol to give it and it is better tolerated. But if it is the opposite it is also officially accepted and of course all patients are put on Vitamin B6 and Folonic Acid.

Lisa Can I just elaborate on that Roser? Normally B6 and melatonin are the first things that families try. I agree the MAOi worked great for us followed by the dopamine agonist. Would you think it's unusual to start with an anticholinergic, trihexiphenidyl, is that an unusual start medication?

Dr Roser Pons I think I would use it the same way you use melatonin. You use it to improve the sleep. Usually I would wait to see how the sleep is. You give it as a symptomatic management. The same that you do with trihexyphenidyl. It would be like you give a painkiller for a headache, but the headache is due to a brain tumour. It causes headaches, so I give the medication for the headache but I don't treat the tumour. So the same thing I would say, by giving trihexyphenidyl. I treat the dystonia, I treat the symptom but I'm not improving the transmission.

Julie We have used bromocriptine and my daughters mood became very unstable.

Dr Roser Pons The very first patients I met with AADCd were all treated with bromocriptine. It was the one we knew. It wasn't bad in general but some patients, let's say I saw five or six patients, two or three had no problem, they had no measured problems, but there were two or three patients that couldn't tolerate it at all. But then they couldn't tolerate the other dopamine agonists.

Lisa Can I again elaborate on that Roser? Can you say really it is trial and error for the dopamine agonists and can families switch from one to the other easily?

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Dr Roser Pons I think it is possible to switch but it is not something you do with AADC patients. It's not something you do quickly. You think a lot about it. If a patient tolerates poorly one dopamine agonist it's very likely they'll react poorly to another one. You can switch around, sure no question, I have done that. But you have to keep in mind that if they don't tolerate one dopamine agonist, its likely they will have issues with another one too. But if I have a dopamine agonist that I can play better with the doses, because this is possible for a specific one, I will use it. Or for example, the Rotigotine patch, it is very helpful. They are better tolerated and have less adverse effect. But there is something about the patch that you don't control. If it works fine, but if it doesn't and you want to increase or decrease, you are a little bit limited, whereas with tablets it's easier.

Lisa Do you also think that with the dopamine agonist the patch particularly, families are constantly asking about cutting the patches which is not recommended to do, but when you have a young child starting on dopamine agonist can you cut the 1 mg the smallest dose?

Dr Roser Pons Between us I do it.

Lisa We do it too although it says not to, but when someone has a very young child and they want to start on a small dose.

Dr Roser Pons It is true it says you can't cut it but I do it and if I cut into a third or a fourth it makes a difference. With a fourth the patient is under treated and with a third she is hyperkinetic.

Julie How young can they start using the patches?

Dr Roser Pons Good question. I don't think we have an age limit. I must say I have only Page 12

experience with one patient. At first I started with the oral and when I saw that the oral was not enough and I wanted to give more then I went to the patch. But I was never able to stop the oral.

Julie What type of mutation or child may benefit from L-Dopa?

Dr Roser Pons That's a similar question to one we have had before. One has been published. I don’t remember which one, but the agonist you can test if L-Dopa will be able to boost the activity of AADC. Either by testing if it is done already on a reported mutation or by asking a specialist to do functional studies.

Julie Would you be so kind to tell us your opinion on this research (after the call) evidence for cyclic AMP mediated increase of Aromatic L-Amino Acid Decarboxylase activity in the striatum and mid brain. They have put a link there.

Dr Pons I don't know this study so I don’t think I can give an opinion. I would need to read it and then I would be very happy to discuss.

Julie The link is there so maybe we could forward it to you to see what you think at some point?

Dr Roser Pons I will certainly check it.

Julie When a patient responds to MAO inhibitors do you require to administer him with dopa agonist further?

Dr Roser Pons As I said usually it is given in combination. But if a patient is ok just on the MAO Page 13

inhibitor it's fine. If I have a patient on the MAO inhibitor who does not tolerate the dopamine agonist I will keep the patient on the MAO inhibitor alone, for example.

Lisa It's good for the families to know that the MAOi increases natural dopamine and the dopamine agonist is a substitute for dopamine, so they do two very different jobs with the dopamine.

Dr Roser Pons Exactly, that's very important. So the MAOi allows the normal dopamine, the little dopamine that the AADC patient has, let's say there is 10% only, the MAOi is going to allow this 10% to stay in the system longer. This dopamine that we synthesise is much much better than a dopamine agonist. A dopamine agonist is going to be something synthetic and is never going to be as good as the normal dopamine. The problem is that the dopamine that an AADCd patient has is very little so needs something else.

Julie Can AADC patients take the Covid 19 vaccine and will there be any side effects?

Dr Roser Pons In general AADC patients have a normal immune system so they should be able to tolerate the vaccination. They are severely neurologically affected, therefore considered vulnerable so they are patients that should be vaccinated.

Julie For my son, watching TV can help bring him out of the OGC.

Dr Roser Pons Any type of stress in general, with any patient with a neurological problem, will worsen the neurological problems. If you think about yourselves, if you are sick with a viral Illness, or had a vaccination it bothers you a bit and you're going to feel bad but you will still be functional. If you have a neurological problem or deficit, any type of stress, an infection, the adverse effects of a vaccination, is going to make this deficit more important. So if one of the problems are OGC, yes any type of stress could worsen it but theoretically it will pass. The adverse Page 14

effects of vaccination or infection will pass. What you can do in the meantime is treat symptomatically the symptoms of the infection or the adverse effects of the vaccination. So if you are ready to vaccinate your kids you can give some pain killers prophylactically.

Julie How does the child feel when they are having their OGC? I read they will feel pain.

Dr Roser Pons I haven't asked. I have a couple of videos of all the patients with OGC. I think they are very annoyed, I don't think they are in pain but they want to finish, they want to get over it, but I don't think it is pain. Maybe you or Lisa can tell me that.

Lisa I think we have heard from some of our more verbal patients that have had OGC that they can cause headaches, after the event, from the pulling of the eyes maybe and just from the strain. Obviously the dystonic attacks are uncomfortable as well.

Julie Can we give a child with AADC a methyl-donor for example trimethylglycine in addition to a dopamine agonist?

Dr Roser Pons Glycine is also related to neurotransmission but I don't think it makes sense with this type of neurotransmitter disorder. I don't really know but I don't think that, if I think of the patho-physiological mechanism of the disease, this would make a difference .

Julie Do you think children who have had gene therapy should be considered for treatment if they have a poor response to gene therapy?

Dr Roser Pons So if a patient with gene therapy for AADC would also be treated, yes. Some Page 15

patients with gene therapy can also receive dopaminergic medications. But often these patients have a lot of dyskinesias following gene therapy and their meds need to be decreased and discontinued. It doesn't mean they cannot take them together as long as they don't have an adverse effect.

Lisa So would you consider that poor response to gene therapy could be supported by going back to dopamine agonists and MAOis? You wouldn't exclude additional treatments after gene therapy if that's going to help?

Dr Roser Pons Yes. That's my opinion. I have not discussed this with the gene therapy teams but I think that additional therapy can be given to patients that have undergone gene therapy.

Lisa It's difficult. I think the general question of poor response to gene therapy doesn't eliminate the possibility of further treatment with traditional medications. That's ok to consider?

Dr Roser Pons I think so.

Julie Can we give clonazepam every day to help sleep?

Dr Roser Pons I think so. Sleep is very important. It helps not only with the sleep but also can help with dystonia. So absolutely, I wouldn't have any problem with giving on a daily basis benzodiazepine for a patient with AADCd.

Julie Can we give adrenal gland extract bovine to a child to support stress management if stress is a trigger for OGC?

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Dr Roser Pons I wouldn't do it and the reason for that is that the stress response, is of course when there is a stress, so if you give catecholamines in a child that is relaxed these catecholamines are not going to do anything. You need the catecholamines to be there and to be secreted when the body needs it. So to just give it as a supplement, I don't think it is going to make a difference.

Julie What are the concerns of long term usage of these medications that we should look out for?

Dr Roser Pons Some of the dopamine agonists that we used in the past could cause some heart problems, so if the patient is on an Ergot-derived dopamine agonist the heart needs to be checked. But other than that MAOIs and dopamine agonists, I don't know of any specific laboratory work up, if a patient is on chronic treatment with that. I mean I don't think there is any adverse reactions involving thyroid function or need for biochemical or cellular count. Usually the effects you see them as dyskinesias or emotional but not in the blood that you have to do a workup or a test.

Julie Is it true that we have to make food restrictions with Parnate?

Dr Roser Pons You have to do food restrictions in patients that are able to synthesise the catecholamines and the biogenic amines but for patients with AADC that are unable to synthesise biogenic amines, it is not a problem, you don't have to do that. The restrictions are for patients who don't have metabolic defects.

Julie AADC babies are unable to regulate their body temperature and my daughter always gets a fever whenever she has an OGC. I wonder if the OGC is triggered by the high temperature or the other way around?

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Dr Roser Pons That's a good question. The temperature deregulation, the OGC creates the stress. I don't know it's possible. We think in general the OGC event is related to dopamine deficiency, while we think the temperature instability is related to the autonomic dysfunction so that they both occur together, in this particular child, might not be necessarily that the one provokes the other, it's just the two symptoms of this condition occur together. I don't think that one provokes the other.

Julie We use pramipexole, how high is the dosage for an older child?

Dr Roser Pons Pramipexole, I should check that. I don't ever remember doses by heart. If you want I can check.

Lisa Can we diagnose this genetic disorder during pregnancy?

Dr Roser Pons If you know that you are at risk of having this you are going to test your foetus for that, but if you don't know it then usually you don't test it. In Greece the karyotype, is done in mothers at risk because of age. Currently instead of karyotype, array CGH is performed which provides much more detailed information. But with the micro array CGH, you can only see deletions and duplications, you cannot see point mutations. So, when you are pregnant the only way to know if your child has AADC deficiency is if you already knew that you were a carrier for the disease, and you test the gene and/or the particular mutation.

Lisa So the answer is you can be tested if you believe that you are both carriers of mutations?

Dr Roser Pons If there is a history in the family then you can test it. You could test it, but it Page 18

doesn't make any sense to do it if you don’t have, because there are thousands and thousands and millions of genes.

Lisa We are in Malaysia we have used bromocriptine and my daughters mood becomes very unstable. Could that be related to bromocriptine and should they try something else?

Dr Roser Pons It could be. I remember that parents would tell me that it just doesn't suit my child and they didn't want it. Parents know. Me as a doctor I would see dyskinesias, etc but parents see beyond that. So yes be it's possible absolutely.

Julie Are there any critical ages we have to be extra careful with certain symptoms to come up with AADC kids?

Dr Roser Pons Any growth spurt, any endocrine changes, can be a source of decompensation. In general we know that the OGC events tend to decrease over time. We also know that with puberty there are big problems with behaviour. Puberty is a storm of changes in the body of all people so it would make sense that this would decompensate a child with a neurological disorder like AADC. I know of patients that went through puberty in a more soft way but others not so it depends.

Julie Is there any food that AADC patients should avoid? Many years ago I heard they have to avoid preserved/fermented food?

Lisa I think that's to do with the MAOi.

Dr Roser Pons I don't think so. It's not a disease that restricts food, but again if a family sees that when I give this food that doesn't suit, I would avoid it but I wouldn't do strict diets. If a food causes diarrhoea I would avoid it obviously.

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Julie My daughter has a constipation issue and takes lactulose. Is there any better medication to solve that issue?

Dr Roser Pons I usually ask for help, when constipation is so severe, from a gastroenterologist, who can give us some medication that is more effective for the problem but in general I try to, before I go to meds, to increase the fibre. But this is a point I will ask for help from a specialist.

Lisa I think it is the best thing to say that each child is very different to the other and that medications have to be carefully administered with their doctors and adjusted accordingly certainly to the consensus guideline.

Roser, for doctors that would be happy to coordinate with you if they have any problems, would we be able to pass on your email address?

Dr Roser Pons Yes it would be a pleasure.

Lisa I know it's very difficult to explain because you have a very technical mind and sometimes it's hard for us to maybe get everything but if a doctor can talk to another doctor it may be more personal help that's available and more specific treatment for each child.

Great presentation thank you so much. We've learnt a lot this week and we are really grateful as always to you. Thank you everybody.

Dr Roser Pons Thank you very much to all of you, it has been a pleasure.

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AADCd Family Workshop 3 : Transcript Produced by Julie Ramsay Verified by Lisa Flint & Dr Roser Pons The AADC Research Trust would like to thank all involved.

#CureAADC #CureAADCd

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