Ep. 186: Red flags of treatable mitochondrial disorders

00:00:00: Welcome to EA Uncast, your weekly source for education, research and updates from the European Academy of Neurology.

00:00:15: Hello everybody, my name is Piervito Lopriore.

00:00:17: I'm a neurologist and a PhD student in translational medicine in PISA.

00:00:21: In today's episodes, we will talk about the red flags of treatable mitochondrial disorders.

00:00:27: Mitochondrial disorders are the most frequent genetic metabolic disorders in humans, and pathogenic variants in all.

00:00:33: thirty-seven mitochondrial DNA genes, and in more than four hundred nuclear DNA genes have been associated with defects of the oxidative phosphorylation, which is the hallmark of these diseases.

00:00:45: What makes mitochondrial diseases particularly challenging is their extreme clinical heterogeneity, because they can present at any age and involve virtually any organ.

00:00:56: For neurologists, the key challenge is not only recognizing the wide spectrum of clinical manifestations affecting both the central and the peripheral nervous system, but also identifying the red flags that should raise the suspicion for a mitochondrial actuality and especially in cases where targeted treatments are available.

00:01:16: In this episode we will discuss how to recognize treatable mitochondrial disorders in the daily neurological practice.

00:01:23: We will explore the clinical clues that should prompt further investigations and we will also delve into the current therapeutic strategies, with a particular focus on the emerging disease-modifying approaches.

00:01:37: And we will also look ahead for the future of mitochondrial medicine, including treatment and initiatives that are currently under development.

00:01:46: I'm delighted to be joined today by two internationally recognized experts in the fields.

00:01:52: Our first guest is Professor Michelangelo Mancuso, Professor of Neurology at the University of Pisa, and Professor Chiara Lamorja.

00:01:59: leading experts in the field of mitochondrial medicine.

00:02:03: Professor Mancuso, Professor Lamorja, welcome to the EANcast and thank you very much for joining us today.

00:02:09: My first question is to Professor Mancuso.

00:02:13: Let us set optic neuropathies aside for the moment.

00:02:17: Could you give us an overview of the main treatable mitochondrial diseases?

00:02:22: Which clinical phenotypes and genetic defects should neurologists be particularly aware of?

00:02:27: And what are the key elements that help us recognize those conditions in the daily clinical practice?

00:02:36: Thank you, Birbito.

00:02:37: First of all, I'm very happy to join these episodes.

00:02:40: So, as you were introducing, we now have new developments in the field of mitochondrial medicine, and very recently, beside the edepinone

00:02:51: treatment

00:02:52: that will be covered by Chiara, but in the very recent, I would say, months.

00:02:58: but in definitely very few years.

00:03:01: We now have treatment for at least three different primary mitochondrial diseases.

00:03:08: I'm trying to cover a little bit these three disorders, who giving you few red flags to how to recognize these diseases, and that will comment briefly on the new therapeutic strategies.

00:03:21: So first of all, the first one that I want to touch is the Frederica taxia.

00:03:27: And also someone recessive neurodegenerative diseases.

00:03:30: that is caused by mutations in the frataxin gene, which is mitochondrial protein.

00:03:37: And when we have frataxin deficiency, we have mitochondrial dysfunction, oxidative stress, and the development of a clinical phenotype that usually the typical onset is in childhood or adolescence, even though we now know that we may have onset of Fredricataxia also later during the life.

00:04:03: So, how do we recognize Fredricataxia?

00:04:06: First of all, the main clinical features are, of course, neurological because... patient develop progressive gait and limb ataxia with desertia and loss of proprioception and vibration sense and reflexia.

00:04:24: But together with this neurological clinical feature, we also have musculoskeletal and orthopedic features like the pescabus scondiosis.

00:04:36: but also extra neurological involvement and mainly cardiac with the hypertrophic cardiomyopathy.

00:04:45: Diabetes may lead to.

00:04:47: most of the patient will also develop out the cut trophy and sensor in your hair and hair

00:04:54: loss.

00:04:55: So, how can we recognize this disease?

00:04:59: Usually, we have children or adolescent with progressive gait ataxia, associated with cardiomyopathy, and mainly also with pescavus, scoliosis, and during the neurological examination, we observe absent-deep tendon reflexes.

00:05:21: So, we should definitely explore this disease, because we now have the treatment, which is the Sky-Claris, it's Omebaloxalone.

00:05:32: The molecule, which was very recently approved in Europe, and the mechanism of action is the Omebaloxalone, is improving mitochondrial function, acting on the NRF signaling, but also... finding oxidative stress.

00:05:52: So it's a new therapy, which is able to, I mean, it's a symptomatic treatment.

00:05:59: It's not really disease-modifying.

00:06:02: What we observe using the OMAVL oxalone in patients with frederic attack cell, we have an improvement, the climb on the either side of our rating scale, so the severity of the disease.

00:06:16: progresses lower and in some patients we also have an improvement on the clinical scale.

00:06:23: So it's definitely a good novelty in the field.

00:06:27: The other important disease that I want to mention is the TK-II deficiency.

00:06:32: It's a neutral rare autosomal recess if again a mitochondrial disease and we have pathogenic variants in this TK-II gene which is an important enzyme playing a role to the mitochondrion, leading when we have a deficiency in this gene, we have mitochondrial DNA depletion or multiple division that mainly affect the skeletal muscle.

00:06:58: The first observation of ticket to deficiency was really in kids, in very young children, but we now know that the the the spectrum range from infantile myopathy that Mimic also SMA to slowly progressive adult disease that Mimic limb girdle muscle dystrophy or also FSHT.

00:07:27: So what we observe in this patient typically is a progressive myopathy which most of the time starting the proximal muscle and then involving the distal muscles, associated with hypotonia.

00:07:42: We have a very clear progressive respiratory muscle weakness with nocturnal hyperventilation in these patients.

00:07:52: Very rarely we have a CNS involvement, but we may have CNS involvement.

00:08:00: What makes this... group of mitochondrial disease unique is that most of the time we observe in the blood an increase not only of lactate but also of CK which is quite unique situation in mitochondrial medicine.

00:08:15: so when we have a patient with muscle weakness respiratory failure and we do document an increment of lactate and CK we should think about.

00:08:28: ticket to the fish.

00:08:29: It's also because now, very recently, EMA approved the treatment, which is called KGB, is a combination of two pyrimidine and nucleoside, and basically you can provide this drug orally, so it's quite, the impact of this drug is quite dramatic, it's amazing.

00:08:51: So we must recognize this patient.

00:08:54: The last disease, which is extremely rare that I want to discuss briefly, is the BART syndrome, is X-linked recessive mitochondrial disorder.

00:09:05: And we have a mutation in a gene, a taxed gene, which disrupted the cardioliping remobiling into the mitochondrial membranes.

00:09:14: Most of these patients are kids with the CDR.

00:09:18: cardiac involvement with severe cardiomyopathy and also ventricular arrhythmia associated with the frequently neutropenia skeletal myopathy and also typically they have methylglutaconic aciduria.

00:09:38: that can be a nice red flag to investigate.

00:09:42: So these are kids with cardiomyopathy, mainly dilated cardiomyopathy, with most of the time neutropenia and methylglutatonic acetylurea.

00:09:53: In this disease we have in the States for now this new molecule recently approved, Elamipretide, which is a short peptide that gets into the mitochondrion and is able to bind cardiolipin and the restore mitochondrial membrane structure, so it is not super efficient drug in bar syndrome, but definitely it works, it helps these children mainly for the cardiomyopathy and the fatigue associated to the disease.

00:10:25: So these are the three main diseases where we now have treatment and we should recognize.

00:10:32: Thank you, Professor Mancuso, for the wonderful overview.

00:10:37: Now, focusing on the labor erythrioptic neuropathy, or LHON, which represent one of the most pragmatic examples of the achievable mitochondrial disorders.

00:10:48: So, how can clinicians recognize LHON, especially in its early stages, and what are the current therapeutic options, Professor LaMorgia?

00:10:59: Thank you very much, Pirmvito, for your question, and I'm very happy to be part of this episode.

00:11:05: So LH-I is a hereditary optic neuropathy for which the genetic landscape is increasingly growing.

00:11:14: We knew that LH-I is due to MTDNA variants.

00:11:19: This is the classical form of LH-I.

00:11:21: But in the recent years, there are also growing evidences showing that there are also nuclear genes causing recessive forms of lawn, and clinicians should be aware also of these more rare forms of lawn.

00:11:36: So the classical one is inherited along the maternal line because it's due to MTDNA variants.

00:11:42: For the other forms, we should expect different genetic basis and transmission, of course.

00:11:49: In terms of clinical presentation, this is a very specific disease, and both of thalmologists and neurologists should be aware of the typical and specific features of this disease.

00:12:03: This is causing an acute, subacute loss of central vision.

00:12:07: Without pain at eye moments, this is a differential between long and inflammatory optic neuritis, for example, and there is no spontaneous visual recovery.

00:12:18: In terms of fundus' appearance, there are very specific features of this disease, which is the occurrence of microangiopathy, telangiectatic changes, but also pseudodema of the optic nerve fibers around the optic disc, and these are all specific features of LHON.

00:12:37: Also, it can be seen as an hyperamic feature of the optic disc.

00:12:42: A tool which is very important for supporting the diagnosis in the very early stage of the disease is OCT, which is an instrumental exam that is now available also for neurologists.

00:12:55: So it's very important to know the potential use of this instrumental exam because OCT is showing in the very early stage of the loan some specific features.

00:13:08: which is an early and transient thickening of the retina nerve fiber layer around the optic disc, which is following always the same order.

00:13:17: So you can observe a temporal inferior superior nasal thickening, and then the same order you have an atrophy of the same fibers in the same order.

00:13:29: Moreover, the segmentation of single retinal layers allows to see a very early ganglion cell layer defect, which is a very early sign of this disease, a difference, for example, with optic neuritis.

00:13:44: So there are some clinical and instrumental and fundoscopic clues that helps the clinician in making the diagnosis.

00:13:53: Visor fists typically show a centroscotoma, which is also typical for those diseases affecting the papillomacular bundle.

00:14:01: In terms of therapeutic options, there is an approved therapy for LH-I, which is ID-benone, which is the only approved therapy for this disease at the moment.

00:14:11: And this molecule allows to bypass the complex I defect, which is the biochemical feature of the disease, since MTDNA variants are all affecting complex I. Idebenol is effective in this disease in its radius forms because it's transformed to Idebenol to this enzyme which is called NQOA, which is very important to know that polymorphic variants affecting this enzyme can affect also the response to test therapy.

00:14:45: So what is emerged in the last years is that polymorphic variants affecting this enzyme can impact on idibbonon efficacy.

00:14:54: And this is very relevant especially for the three-fourth C-zero mutation, which is one of the three most common LHON mutations.

00:15:03: In terms of other therapeutic options, there are also clinical trials being conducted with gene therapy just for the eleven seven seven eight mutation, which is the most common LH-one mutation.

00:15:16: And this therapeutic strategy was not approved yet.

00:15:20: In terms of comparison between treatments, a recent meta-analysis showed that gene therapy was superior to the id-benone itself, but there are still some missing data and also association between id-benone and gene therapy in terms of better outcome is not still clear.

00:15:42: Thank you, Professor Ramogia, for this clear overview.

00:15:45: So I want to stress here the LHON and the optic neuropathy team.

00:15:51: So looking ahead, what can we expect in the near and medium term future for LHON and for the other mitochondrial optic neuropathies?

00:16:00: I'm thinking, for example, our autosomal dominant optic atrophy.

00:16:04: Are there any new therapies on the horizon?

00:16:06: Are there any ongoing or upcoming clinical trials that clinicians should be aware of?

00:16:13: Well, there is a lot of ongoing research on LHON and there are other therapeutic approach that I would define under development because they are still at the stage of preclinical studies.

00:16:27: One of these approaches, which is very promising, is gene editing for correcting MNT DNA variants.

00:16:35: especially targeting the retinal ganglion cells, of course, because this is a disease affecting the retinal ganglion cells.

00:16:42: The aim of this approach is establishing an entoroplasmic state in variants which usually are homoplasmic.

00:16:50: This is typical for electro and variants.

00:16:53: On the same line, there is a big effort also in testing the possibility of transplanting wild-type mitochondria.

00:17:01: And also, there are some developing approaches aimed at delivering genetic material or drugs targeting specifically retina gangon cells, which are the tissue which is affected by this disease.

00:17:16: However, these, as I said, are mostly preclinical studies, so not at the stage of human clinical trials.

00:17:25: Concerning OPA-I related dominant opticatrophy, this is a disease different from LH-I because this is a disease usually starting in childhood, very insidious, still characterized by selective loss of retinal ganglion cells and typically characterized by a central scotoma.

00:17:44: But the disease course is not acute, subacute as I was describing for LH-I.

00:17:50: In terms of therapeutic options, idbenone is not approved for this disease even though there is a complex one defect even for OPA-I dominant optic atrophy.

00:18:02: So there is a rationale for using idbenone even for OPA-I DOA.

00:18:07: In terms of gene therapy approaches, there are essentially three possible approaches.

00:18:12: One is the use of ASO, targeting a mainly up to sufficient variants of OPA-I, and this is an approach which is closer to the stage of a clinical trial which is expected for this year, Phase I clinical trial.

00:18:28: Another potential approach, which is actually amenable for dominant negative variants, is the use of RNA-transplicing approaches.

00:18:38: And finally, they use the classical CRISPR-Gasnine technology for gene editing.

00:18:45: This is the overall scenario, even for OPA-I DOA.

00:18:51: Thank you, Professor Lamar.

00:18:53: To conclude, the last question to Professor Mancuso.

00:18:56: Could you provide broader overview of the most relevant ongoing clinical trials in mitochondrial diseases, as well as also the key international initiatives or the collaborative efforts that are shaping the current clinical practice and also the future research in the field of mitochondrial medicine.

00:19:17: Okay, Pervito, this is a huge amount of information you want to have from me in a few minutes.

00:19:26: As I was saying at the very beginning, mitochondrial medicine is really in a special moment of its life because we are facing a new era with a lot of pharma interest in this not so rare group of disorders.

00:19:44: So definitely we already have a lot of ongoing clinical trials that are either phase one or phase two, A to B. I would say we have around fifteen clinical trials with new molecules under investigation.

00:20:00: Most of them are already in phase two.

00:20:04: So the possibilities in order to overcome the oxfoss defect are multiple because, you know, the complexity of the biochemical.

00:20:14: pathways into the mitochondrion and need to have different possible approaches.

00:20:19: We can try to improve mitochondrion genesis, for instance, with some molecules.

00:20:25: We can try to fight oxidative stress.

00:20:28: We may finally reach gene editing also in the mitochondria, where we cannot apply this technology for multiple reasons, but we now have different gene editing approaches that can be delivered into the mitochondrion.

00:20:48: We have additional molecules that are under investigation, trying to improve also mitochondrial biogenesis, but from upstream, actually on the PGC one alpha pathway, for instance.

00:21:01: So there are really a lot of ongoing clinical trials.

00:21:06: And at the same time, what is becoming more and more important now that we have the industry manifesting its interest, mitochondrial medicine, we now really need to collaborate, right?

00:21:18: The stakeholders must collaborate because we need to have multiple patients with the same phenotype.

00:21:27: At some time, these diseases are extremely rare.

00:21:31: Think about it, you can do deficiency of bar syndrome.

00:21:34: This is the reason why, in the past twenty years, a lot of international cooperation is ongoing.

00:21:41: We now have a European registry, for instance, for mitochondrial diseases, which is called genomic.

00:21:49: And we have a very strong involvement, also the European reference network collaborating with scientists and also with the European Academy of Neurology, not only to... increase the awareness of these very important disorders, but also, you know, putting money to help the experts to build consensus statement or guidelines, documents that can be delivered to the patients, to the clinicians.

00:22:21: You know, I try to give good advice on how to recognize, how to diagnose, how to manage.

00:22:28: all these different mitochondrial diseases.

00:22:31: so it's a very nice moment for medical medicine and we are very confident that within five ten years more molecules will be available in the market and hopefully soon also gene therapy for our patients.

00:22:48: Thank you.

00:22:49: so as we wrap up today's episodes let's briefly summarize some key points.

00:22:55: so my two condo diseases are complex.

00:22:57: as Professor Mancuso was saying these disorders are mostly system disorders and increasing number of mitochondrial diseases are now treatable or at least modifiable when recognized early.

00:23:10: So early diagnosis relies on spotting the key red flags which are for example the multi organ involvement, the clear family history, some typical neuromastro patterns or also characteristic lab or imaging findings.

00:23:26: LHON, as Professor Lamogia was saying, is a clear example, because prompt recognitions and Idebenone, together with emerging also gene therapies, show how targeted treatment can change the trajectory of the disease.

00:23:39: And behind LHON there are other... disorders such as Fridaecotaxia, Barth syndrome and TK to the deficiency and also new trials and new therapies, including, for example, empty day maintenance disorders, which are rapidly expanding options for mitochondrial patients.

00:23:59: Above all, the progress in this field is a team effort, as Professor Mancuso was saying.

00:24:05: So we need multidisciplinary care, we leave a referral to expert centres, participants in registries, international consensus initiatives, a partnership with industry, which are essential to improve the diagnosis, the management, and ultimately the lives of people with mitochondrial disorders.

00:24:24: I would like to sincerely thank my guests for sharing their expertise.

00:24:28: and insights with us today.

00:24:31: And to our listeners, thank you for joining us on EANcast Weekly Neurology.

00:24:36: We hope this episode inspires curiosity in this exciting field.

00:24:40: Until next time, goodbye, and thank you for listening.

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