[00:00:00] Dr. Marina Travisano: So good morning to everyone. Welcome to this webinar on NCL type 2 disease. This webinar is mostly focused on the differential diagnosis and the pathway to reach an early diagnosis in this rare disorder, and it will last one hour. During one hour, me and Dr Pasquale Striano will introduce the disease and then we will speak about the diagnostic test and treatment about this so rare disorder. Some attending notes: please do not take any screenshot of the slide and not reproduce any of the following slides and the webinar will last 60 minutes and at the end of our presentation there will be the possibility to have a discussion. So you can submit some questions at any point of the webinar via text in the chat and then, for people that cannot attend online the webinar, they can reach the webinar, they can review the webinar at the following link. So these are our disclosures and moving towards the presentation. The first topic we are going to deal with is about the importance of early diagnosis and pitfalls in reaching the diagnosis of this disorder. As you can see and as you know, NCL type 2 disease is a neurodegenerative disorder which is associated with a predictable and rapid decline of motor and cognitive function. This figure shows you the progressive nature of the disease, and this is a figure that has been done through data that has been collected in the DEM-CHILD Registry and considering the score of the motor and the language score, which together have a maximum of six, you can see that since the age of three years, usually when there is the first symptom of the disease, there is a rapid decline and the loss of the ambulation of walking and the loss of languages and unfortunately, there is an important delay in diagnosis and often the median age of diagnosis is at 4. 5 years, so about 22 months later the onset of the first symptom. So what is our goal is to put to reach the diagnosis at the first symptoms of the disease in order to get the best result from the treatment. The neurodegenerative disorder is also, the neurodegenerative nature of the disorder is also illustrated in this figure, this is the evolution of one of our patients. You can see this was the baby, the girl at the age of three years, she was able to do the tower, she has no dysmetria, no problem in coordination, but later on she lost the ambulation, she had tetraparesis, then the gastric tube, so problem in feeding, and dystonic movement disorder, so she was well-chaired and she became also blind, so that's the natural history of the disease.
And why it's important to reach an early diagnosis in this disorder? Because it's important, because it impacts on the clinical management in the choice of common anti-seizure medication, but also because if we can do a very early diagnosis, we can start the enzymatic treatment, the enzyme replacement treatment very earlier, and avoid the accumulation of storage material in neurons. MRI, a useful genetic test, and it's important to avoid journeys, long and diagnostic journey for families. It's important for participation in a clinical trial, in clinical study, and to get a targeted therapy like in this disease. And also, not less important, it's important because that's a genetic disorder with a recessive mode of inheritance, so there is a higher risk of transmission of the disease. It's about 25% of children that can have the disease and it is important for the genetic counselling, so it's important to have the diagnosis. Regarding the early symptoms, it's important to expand a few words on the language of developmental delay. You know that developmental delay is quite a specific neurological science, and it's very frequent in children, but what was highlighted in this study was that about 85% of patients with NCL type 2 disease have a language delay in their history before starting with epilepsy. So what is the first key message to bring home is that when you have children who present with an epileptic, unprovoked epileptic seizure between the age of two and four years, if there is a history of language delay, it's important to test for enzymatic activity and to think to NCL type 2 disease. So this is one of the first key messages to bring home regarding the early diagnosis. Now I leave the podium to Pasquale Striano for the following talk.
[00:09:35] Dr. Pasquale Striano: Thank you very much, Marina, and good afternoon. Thanks for this brilliant leading of the discussion and for your very nice and clear introduction to CLN2 disease. Now my task is, let me check if I can scroll. OK, I have the, OK. So I think that's, as you have very well outlined, the greatest challenge in identification of CLN2 is not only recognize the disease once it is already suspected or already full- blown phenotype, but it's rather bringing CLN2 into the differential early enough diagnosis. So a routine practice, routine clinical practice, is these children do not initially look as they have a rare neurodegenerative disorder. And that's the main challenge. They present, indeed, with very common problems, a first seizure, mild expressive language delay, clumsiness, behavioral change. But each feature can be explained by a common diagnosis when considered in isolation. That's the point. So the diagnostic opportunity in this condition arises when we connect this finding and assignment, how they evolve over time. So the topic now, my task is to highlight with, you know, to focus on the practical moments at which the standard pathway should be interrupted. And when we have to think to a rare disorder. That's the main point. Now, in this slide, you can see here, you already said, Marina, one of the main causes of delayed diagnosis is not the lack of knowledge of the disease, but the way clinical reasoning naturally works. So once the common level has been applied, like standard diagnostic heuristic, autism, developmental delay, coordination disorder, subsequent findings are typically interpreted so that they continue to feed that level. This, I would call it, this like a premature diagnostic closure. That you can see this bottleneck. So the practical solution is to think as a rare disorder.
So a teach follow up, the clinician should ask, has the child gained new skills? Has any previously acquired function been lost? Does the current diagnosis still explain major domain of the phenotype? So the final message here, the action, is that rare diseases are typically missed because the first common diagnosis is accepted too confidentially and challenged too late. And this will inexorably result in a diagnostic delay. Now, Marina, you already highlighted which is the core presentation of CLN2. This does not usually announce itself through one single pathognomic symptom. Its early presentation is a pattern across different domains. Expressive language, show it here. Expressive language delay can precede obvious, clear motor decline. Seizures are often the event, or a single epileptic seizure is the event that brings the child neurological tension. But of course, immunology is very variable and often non- specific. Then we have motor dysfunction that emerge through clumsiness, sometimes falls, and over time, progressive loss of mobility. And then visual impairment. Visual impairment is often of curulators, should not be required before the diagnosis is considered. That's very important. So please note that CLN2 is recognized longitudinally.
The path and direction of change are more informative than any isolated symptom presenting alone. So that's very important. Then, okay, now the epilepsy first pathway, what I mean with this slide. Again, it's a matter, you know, this is probably the most frequent route to diagnostic delay because a child presents with the first improbable seizure, receive an epilepsy diagnosis when there is another seizure or when there are EEG abnormality, starts an anti- seizure medication and typically enters a period of watchful waiting. This is, this corresponds to brain loss in CLN2. So the cognitive error is to treat epilepsy as the final diagnosis, rather than as one manifestation or a broader disorder. And when we recognize this bias is already late. So the crucial question here is, what was present before the first seizure? Was language development already delayed? Were there unexplained falls or clumsiness corresponding to something, a loss of coordination or rather a plateau in development? The clinician should broaden the diagnostic frame and investigate starting to consider an investigation of a genetic etiology in parallel.
So the take home message here is very clear, the main red flag for considering a neurodegenerative, even a neurodegenerative ultra rare disorder. So behavioral, and here, when behavioral levels mask disease progression, Autistic Spectrum Disorder, global developmental delay, attention difficulties, these may coexist with neurological disease, but they should never be used to explain progressive loss of function. This is very important. The danger is that regression becomes reinterpreted as reduced cooperation or emotional response and this is problematic when different professionals see only one part of the child. The longitudinal change can then disappear between specialists. This is absolutely wrong because progression is not a feature to be accommodated with old diagnosis and it should rather be the reason, the occasion to reopen the entire diagnostic process. So a behavioral diagnosis describe the phenotype, progression demands an etiological explanation. It should be the reason for which we should start as soon as possible genetic testing. Okay, these three trajectories are typically used interchangeably, but clinically they are very different. Why? Developmental delay means that skills are acquired more slowly than expected, although the process continues going on. A plateau means the acquisition stops. So the child is no longer gaining new abilities. Regression means true loss of previously acquired function or disappear, get worse and self- care disappear, declines and so on. So families may describe regression indirectly. For instance, he, she no longer does what he used to do. Or she has become less steady or the words are still there, but she use them less and less. This observation rises by the parents should be taken seriously and documented if possible with concrete examples because true regression is never part of uncomplicated developmental delay. It's a very important, it's a very relevant red flags indicated the risk of neurodegenerative disorder. So the most important diagnostic question is not only what the child can do today, but what the child could do six months ago or four months ago. That's another important take home messages.
This slide summarizes the decision point into a very simple rule. When the clinical course no longer fits with the original clinical suspect, original diagnosis, please stop following the standard pathway. The trigger may be developmental regression, a merge of myoclonus, as Marina showed, unexpected visual symptoms, worsening despite anti- seizure medication intake. At this moment, repeating the same assessments several months later is not completely neutral, let's say. The history should be reconstructed longitudinally. If available, previous videos and reports should be reviewed. In a child with a compatible phenotype, enzyme testing of TPP1 should be considered and molecular testing should be also started, if possible, in parallel. So when the trajectory contradicts or seems to be in contrast with the original label, I think that we should change our diagnostic process and we should think that something else is happening in the brain of these kids. Now, even when clinicians recognize that something's wrong, escalation might still be delayed by both cognitive and even logistical organizational barriers.
So at system level, fragmented care may create months, weeks or months of delay. So the solution to fix these problems requires a longitudinal synthesis that's also the involvement of different stakeholders, general pediatrician, the tertiary centers, pediatric neurologist. So in this condition, such rare disorders, early diagnosis depends sometimes on fighting both our own cognitive shortcuts and also the structure of healthcare system, healthcare pathway, the environment in which we work, in which we live. So the diagnostic urgency in this condition requires both better reasoning, flexibility and definitely better coordination across different stakeholders. Early CLN2 patients typically remain hidden because the symptoms migrate across different clinical domains. That is redundant to say, but it's important. The first concern may be speech delay, which is very not specific. Sometimes the speech delay is followed by first or second epileptic seizure. Sometimes in my experience, even a febrile seizure may occur as first symptoms. And so that's the reason for which each symptom may be referred to a different professional and each professional may see only a fragmented of the evolving disease. This, of course, may create a delayed diagnosis. And, you know, the problem is in most of the patient, the absence of a single longitudinal narrative. So a useful practical step is to construct, to build up a timeline with age of milestones of acquisition, first falls, first evidence of clumsiness, first lost skills, first speech delay or impairment. So CLN2 becomes visible when fragmented symptoms are reorganized into a chronological story. But this problem, this reconstruction should not be delayed in any case. Okay, so the practical value of these red flags lies in combination, again, not isolated findings. For instance, a single unprovoked decision in a young child is very common, of course, my language delay is also common, and so sometimes are occasional false. But when two or more of these domains overlap, particularly when there is a concomitant language delay, initial feeling of regression, and one or more seizures, I think that this should be seriously considered, and the clinicians in this case should not wait for the complete textbook of phenotype as Marina showed.
So the final message here is that two converging red flags are enough, are sufficient to justify disease- specific testing, and definitely the full phenotype should not be awaited. Why? Because of course, in a slowly evolving condition, a few months may have limited impact, but in such rapidly progressing neurodegenerative disorder, they may represent a major loss of function. So the therapeutic window in these diseases is not defined only by chronological age, but is typically defined by the amount of function that remains when treatment begins. That's very important. So the diagnostic urgency is a clinical intervention itself, because it preserves the possibility of acting while meaningful neurological function remains. In CLN2, time is not simply time to reach the diagnosis, it's the remaining neurological function capacity of these kids, as Marina will show in a while. Again, these two timelines, left and right, illustrate how logistics directly influence outcome. In the sequential pathway, the child moves from one appointment to another one, seizure management, developmental review, brain MRI, genetic tab rule, genetic testing. And of course, each individual step may appear appropriate, but together they create a cumulative delay. So in the parallel pathway, the same initial red flags trigger several actions at once. So neurophysiological reassessment, neuroimaging, when appropriate, target enzyme analysis, molecular testing.
The message here is that in rapidly progressive neurodegenerative disease, parallel testing is fully justified. I would say it's a clinical strategy, it's not a logistical luxury, and should be definitely considered. Marina mentioned the clinical rating scale. The CLN2 rating scale is typically often viewed as a tool for monitoring established diseases, but it can also sharpen diagnostic reasoning. What I mean, the modern language domain force, the use and adoption of modern language domain and discourse, push us to translate a clinical feeling, a bad impression, into accessible, measurable change. And so when these observations, motor dial, language dial, seizure, visual, when these observations are scored and evaluated systematically, even one point decline over a relatively short time window becomes difficult to dismiss and should be considered. So in other words, regular measurement converts subjective concern and clinical feeling into objective evidence, and this may be of paramount importance to start an immediate paradigm change of the diagnostic protocol, which is this testing protocol. If, of course, the key disease specific investigation is enzyme activity assessment, typically one enzyme activity, but definitely impromptly supported by a wide gene panel or genome or exome sequencing assessment, so broad molecular analysis. If you are used to prescribe gene panel, please make sure that TPP1 gene is included because otherwise you can skip this important and actionable disease. Of course, enzyme and genetic results are complementary because enzyme deficiency establish also the functional residual biochemical defect. But the smoking gun is molecular testing, of course. So when the suspicious is high, this should be performed. But even if the suspicion is relatively not so high, or at least two red flags are evident, I think it's definitely worthy to continue to follow up with this enzymatic diagnostic testing. So again, this is a little bit redundant, but the order in which tests are requested can be as important as the tests themselves. So brain MRI, of course, it is often typically performed, but target enzyme assay should be performed in a relatively early stage of the clinical suspect. And the time window of the diagnostic workup should be completed within a few weeks. If I send the patient, I refer the patient for a gene panel, and it takes nine months to obtain the result of genetics, this is completely wrong. So this parallel testing breaks the time cost of diagnostic silos. That's very important. I'm approaching the end of my presentation, and I want still to clarify the ownership responsibility of the diagnostic next step. So a common and under- recognized cause of delay is the diffusional responsibility. The pediatrician, for instance, assumes that the neurologist will order genetic testing. The neurologist, the pediatrician, neurologist, general psychiatrist assumes the metabolic team will request enzyme testing. This is wrong. When everyone manages one part of the phenotype, no one owns the complete trajectory. And this is a mistake.
So the clinician who recognized the red flags owns the next step until responsibility is explicitly transferred. That's a very important point, and it's a common reason for diagnostic delay. So take your responsibility to lead the diagnostic process, and then you can delegate. But this should be assessed explicitly. Final slide of my presentation is, to conclude this section, I would reduce the approach to three practical actions. So first, reframe the baseline. What I mean, document the child trajectory, not only the current examination, and make a distinction, and try to distinguish delay from plateau or through regression, if you remember the three trajectories. Second, intercept the pattern. I mean, do not anchor on the first seizure on a behavioral level. Look for the intersection of language problem, seizures, and progressive motor dysfunction. And then escalate in parallel, which means, once the picture no longer fits, initiate disease- specific biochemical and genetic testing without waiting for the standard sequential pathway. And think rare before the disease is unmistakable, because by then, the therapeutic window may already be narrowing. Thanks so much for listening.
[00:33:59] Dr. Marina Travisano: Thank you, Pasquale, for your talk and clarity of these very important concepts. And moving deeply into the earlier biomarker of NCL type 2 disease, one important biomarker, neurophysiological biomarker, is the photoparoxysmal response. This is only one of the neurophysiological biomarkers of neurosteroidal hypokinesis disorder because there are biomarkers associated with epilepsy that we can see on the electroencephalogram. So there is the slowing background activity, the appearance of frontal bilateral slow waves, there is also the disappearance of sleep spindles while the progression of the disorder while the presence of multifocal spikes and occipital focal spikes. One of the most evident biomarkers is the presence of photo- paroxysmal response which is peculiar and I will show you later some examples. But the biomarkers are also linked to the loss of visual ability so blindness and we can check the visual ability of our patient towards electroretinogram. In the earlier stages there is this peculiar pattern of this giant potential which is the biomarker that hyper excitability of the cortex and also ataxia can be related to the presence of the gian somatosensorial evocative potential. But which is the most common neurophysiological finding, mostly during the earlier stage of the disease, is the photoparoxysmal response. I want to show you this example which is very clear and can give you the opportunity to see how it is important to look for this sign. This was a 2 years and 10 months old girl with an apparently normal psychomotor development except for a slight language delay that was not considered by parents. They were neither by pediatrician, they did not focus to this symptom that, as we told before, might be very frequent in children at this age.
But when you have a seizure, this early symptom of language delay should be considered as a red flag. After her first seizure, she had a quite normal neurological examination, as you can see here, she was able to move well. EEG and slow and epileptic abnormalities were found and also intermittent photostimulation induced the appearance of occipital spikes. As I told you, the intermittent photostimulation to 1 Hz can give this photo-paroxysmal response which is very peculiar because it occurs at lower frequency of stimulation and this is a typical response. You can see this blue line. The blue line is the stimulus, you can see there is a stimulus each second and To each photostimulus there is a response which corresponds to the presence of a spike which is more evident over the bilateral occipital regions but it can difuse to all derivations. So this kind of photoparoxysmal response, which is typically to the lower frequency of stimulation, is typical of progressive myoclonic epilepsy and mostly of neuronal ceroid lipofuscinosis. Not all of them, not all types of neuronal ceroid lipofuscinosis have this typical photoparoxysmal response. But in NCL type 2 disease it's a very early biomarker, neurophysiological biomarker, but it should be looked for, otherwise it can be skipped, missed. But it's important also to consider that there are other epileptic syndromes where we can find a photoparoxysmal response at the same age, for example, also in Dravet syndrome, which is the most common genetic development in epileptic encephalopathy. We know that in this kind of epileptic syndrome there is the photoparoxysmal response, but it's not to the lower frequency of the stimulus. Also in other kind of generalized epilepsies, such as epilepsy with myoclonic atonic seizure or idiopathic generalized epilepsy- genetic generalized epilepsy- we can find the photoparoxysmal response. Also in the Angelman syndrome, in the Rendu-Osler-Weber syndrome. But we can find the photoparoxysmal response. But what is typical in this NCL type 2 disease is the presence to the lower frequency of stimulus. So that's very important to keep in mind and this is a study that we performed several years ago. It was 2017 and we collected 14 patients with NCL type 2 disease. This was a retrospective study and we tried to understand if this kind of photoparoxysmal response was present in all children and at what age. We found that this was found in most of the patients, in 13 out of 14 patients, and mostly it was to the lower frequency you can see here.
[00:42:56] Dr. Marina Travisano: But what I want to stress is that this kind of neurophysiological biomarker should be looked for because at this age often it happens that a sleep EEG is performed and because children are not collaborating in doing the EEG and so it's better to do the EEG during sleep, and sometimes it can happen that while they are doing the EEG during sleep the intermittent photosimulation is not performed. But the intermittent photosimulation is mandatory in all the EEG because it's important to look to this, because it can help toward the diagnosis. And in this study you can see that the blue line represents the first EEG that have been performed, while for many reasons the first intermittent photosimulation has been performed after, not the first EEG. So the green line and you can see that when it is performed- that is the red line- the photoparoxysmal response appears. So, the fact that the green line and the red line are quite overlapping means that if you do the intermittent photo- stimulation, if you look for the photoparoxysmal response, most of the time you can find the photoparoxysmal response. So, the key message is to do it, to look for it, because this kind of red flag is something that should be done.
Otherwise, it should be a clinical practice to perform the intermittent photostimulation. So, what about MRI? MRI can help in the early diagnosis. I would say that there are some signs, neuroradiological signs, that can be found even earlier in the brain MRI. And they are, as you can see here, the presence of white matter abnormalities, which are more frequent over posterior bilateral regions. And this is quite a specific neuroradiological finding, but this was found in about 80% of our patients, so a quite good high amount of patients during the earlier stages. And of course, also cerebellar atrophy is something that is present in all children with NCL type 2 disease, even if this is more clear during the advanced stages of the disease. And again, always regarding the MRI, here is the evolution of MRI of the brain atrophy, the cortical atrophy is evident, and also in the following images is evident the progressive cerebellar atrophy. And in conclusion, what is important in order to get a very early diagnosis is to find for, to look for clinical early markers that are language delay, regression, and unexplained unprovoked seizure. So again, the message that if a patient starts with the seizure, an unprovoked seizure between the age of two and four years, and there is a history of language delay or regression, or as Pasquale told, any kind of neurodevelopmental disorder, also behavioral problems should be right flag for diagnosis. Also, we have EEG and brain MRI biomarkers that should be looked for. And here, there are following, this is again what I told you, and in this case, it's important to ask for the enzymatic test and, or a gene panel. You know that we have these two type of tests that are available. enzymatic test is the cheapest and the more rapid test, so I suggested to do it as first test, but there are also countries in which it is very difficult to do a range enzymatic test and more easier to do a gene panel, but be aware that the NCL TPP1 gene is included in the panel. And lastly, I want to show you this flowchart which is very important. This is published, so you can find it also in PubMed. And it's to summarize which is the workflow to get the diagnosis. This can be reached in different ways according to patient presentation. If the patient presents with epilepsy and you find in the presence of photoparoxysmal response, you can suspect of NCL type 2 disease and ask for enzymatic tests and molecular testing. This should be the right way, but there are also conditions in which you have the suspect of a genetic etiology of epilepsy and you ask for a panel without clearly thinking of NCL type 2 disease. Also in this case, it's important and it's a good way to reach the diagnosis. And there are other cases in which you suspect a neural encephalitis or lipofuscinosis, but there are several types, 14 types of disease. And if you are not clear which kind of NCL disease it may be, you can ask for a panel in which NCL might be included different disorder, different type. And this is the case that I showed you. So I think that also because we have known so many times, we can skip this case I already showed you. And this was the case in where the intermittent photostimulation was very important to reach diagnosis. And so this way is right on. While there are also this second case, it's very important because this was a case of a patient who had a normal development, again with an independent gait at the age of 12 months, but he had a speech delay.
Again, this delay was not underlined by parents because the father was Danish, the mother English. So the patient went to French school, so a different language. And the language delay was considered to be due to the fact that the patient was exposed to a different language. But at the age of three years, he started with epilepsy. As there was epilepsy history on the paternal side the physician thought that it was a genetic epilepsy and they asked for a gene panel. Without thinking to NCL type 2 disease, the gene panel highlighted a compounded residuous mutation in the TPP1 gene. And this child was diagnosed in 2014 and he had the possibility, the chance to start the treatment very earlier and to be included in the trial. So this was the case when the diagnosis is made on this way, with the suspicion of a genetic basis without thinking of NCL type 2 disease, but that's always the right way to get the diagnosis. And the last case is the case where you can find the rich diagnosis when you have the suspicion of an NCL disorder and you ask for NCL gene panel. That's the case of this patient. This was a three-year-old boy, third child of four sons, with normal motor development, but again, speech delay. That's always recurrent. And he had epilepsy at the age of three years and up that was resistant to medication. He performed some investigation. You can see the brain MRI with the cerebellar atrophy, the electroretinogram with the absence of response, the visual evocative potential with increased latency. So they were all findings that suggested the diagnosis of NCL Type 2 Disease. But in this case. The enzymatic activity was normal. It was repeated twice, but it was normal. And also the skin biopsy showed the accumulation of lipofuscin in the skin. So in this case, when it's suspected for several reasons, the NCL disorder, the genetic panel for NCL disorder can be useful. And it's the third way to flowchart. And I tried to be very fast. I hope that everything was clear. And now for the following minutes, I want to leave the space for discussion if you have any question. Please, you can enter in the chat and we can discuss together with Pasquale about this.
[00:56:04] Dr. Pasquale Striano: Thank you, Marina. While waiting, we have a few minutes left for questions, but I want to thank you for this wonderful talk and also to organize for the excellent coordination and facilitation and also to all participants for joining us today and BioMarin for supporting this educational webinar. But I have a question for you, Marina, or a comment which may be helpful. In your experience, you are a national referral center for this condition. What is the most common early mistake that delays the diagnosis?
[00:56:44] Dr. Marina Travisano: The most common, is not to think this diagnosis when epilepsy start. Because in most some cases, the problem is that to think that most of people, most of physician, they think to NCL type 2 disease when It's too late, but because at this point, the neurodegeneration is still going on. While we have to think the disease at the first seizure, because this is the most important symptom that leads parents to the physician in most of cases. And at that point, that if there is a first seizure with the history of any neurodevelopmental problem, including the language, the enzymatic tests should be done. The most frequent delay is that is due to the fact that the genetic test on enzymatic activities ask the one regression start and it's too late at that time.
[00:58:15] Dr. Pasquale Striano: Yeah, I agree. One of the main challenges is that this is applicable to several rare disease. The challenge is that a rare disease is often considered only after the child has already progressed, that what you said. So the key is to think rare earlier, even when the clinical trajectory no longer fits a common diagnosis, that's the point. And I mean, I think this is the most important for non-specialists in this disorder, most final back home message. Yeah, that's it. I cannot see any further question, Marina. So maybe we can briefly conclude. And I think to me that the main message is that this condition may initially resemble common developmental and epilepsy presentation. So think rare earlier. And personally, I would like to thank you and the organizers for this web seminar and to all participants for your time and engagement today for listening. And I think it's everything for today.
[00:59:37] Dr. Marina Travisano: Thank you. Thank you all.
[00:59:39] Dr. Pasquale Striano: Thank you. Take care. Enjoy the rest of the day. Bye-bye.
[00:59:43] Dr. Marina Travisano: Bye-bye.