Mitochondrial disease from A to Z. د. جهاد السعيد

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[00:00:00]Registration.

[00:00:03]Peace be upon you. Good evening. Happy New Year to you all. Today, we will discuss a branch, or rather a subspecialty, that is emerging but very important in pediatrics: mitochondrial diseases. Until recently, until the beginning of the century, there was virtually nothing concrete in this field.

[00:00:32]Everything we will cover in today's lecture is truly new and extremely important. We must be familiar with it, and it forms an introduction to this science or specialty. In today's lecture, we will discuss what a pediatrician should know about mitochondrial diseases so that they have the necessary understanding to deal with a child who has this disease or one of the syndromes that result from a mitochondrial disorder.

[00:01:12]We will begin with an introduction to mitochondrial function in general, then we will learn about the difference between mitochondrial DNA inertia and nucleic acid inertia.

[00:01:34]Then we will learn about diseases related to mitochondrial DNA, and then mitochondrial diseases related to nucleic acid DNA.

[00:01:47]After that, we will move on to the very important part of... The lecture will discuss when to suspect mitochondrial disease (MTD), including the diagnosis. We will review diagnostic methods and approaches, and then explore available treatments for this group of diseases. Until recently, less than 20 years ago, there was no treatment, and a diagnosis of mitochondrial disease was considered a very bad prognosis.

[00:02:38]Mitochondria, or the cell's powerhouses, are the cell's energy generators. This process involves two crucial mechanisms. The first is the Krebs cycle, or tricarboxylation, which takes place within the mitochondrial matrix, specifically in the mitochondrial cavity. The second mechanism is oxidative phosphorylation.

[00:03:32]Phospholysis occurs via the electron transport chain, a series of proteins that transport electrons and are located in the inner mitochondrial membrane.

[00:03:47]If we go back a bit to our biology, we'll remember that mitochondria are organelles that float in the cytoplasm of all eukaryotic cells. As you may recall, they resemble cigars and have a double membrane. The inner membrane has creases or folds, meaning it folds inwards into the mitochondrial cavity, as if it were a barrier at the expense of the inner membrane. The outer membrane consists of periphery capsules that surround and enclose the mitochondria.

[00:04:32]In fact, let's say 90 % of energy is produced by mitochondria.

[00:04:46]Therefore, a cell that has a problem with its mitochondria is essentially a cell doomed to die sooner or later. Now, a little bit of simple biochemistry: we know that the main The source of energy is sugar. Sugar first undergoes glycolysis to produce pyruvate. Pyruvate is then converted into lactate. This first step, known as glycolysis, takes place in the cell's cytoplasm.

[00:05:25]This is the only part of the process that doesn't require oxygen or mitochondria.

[00:05:32]This glycolysis produces a very small amount of energy, insufficient to meet the cell's needs, not exceeding 10% of its total energy. Of course, this process doesn't require oxygen. As we mentioned, 90% of the energy will be generated later after the pyruvate enters the mitochondria and is then recycled into acetyl coenzyme. This acetyl coenzyme enters the Krebs cycle to produce a charged electron.

[00:06:24]This charged electron is then used in the crucial process of oxyphosphorylation, which occurs within the Krebs cycle. The Krebs cycle doesn't just burn pyruvate; it also needs to take acetyl-CoA, which comes from beta-oxidation. This process takes place in the mitochondria, specifically in the mitochondrial membrane, and involves fatty acids. This means that the energy from the fatty acids, as we can see, is coming to the outer mitochondrial membrane. The fatty acids are then transported into the mitochondria using carnitine. We need to remember that carnitine's sole function is to transport fatty acids from the cell's cytoplasm into the mitochondria. That's what it's called: carnitine transporter.

[00:07:39]Then, this fatty acid undergoes beta-oxidation inside the mitochondria, resulting in acetyl-CoA, which in turn enters the Krebs cycle, as we can see. I hope you're following along with me in this way.

[00:07:55]In fact, even the Krebs cycle itself produces only a small amount, not exceeding 15%. Of the energy produced by the cell, where does the rest of the energy come from? Where is the real energy being produced?

[00:08:12]Notice that even in the Krebs cycle, which is still just a Krebs cycle, a large amount of energy hasn't been produced. Rather, charged electrons have been produced. These charged electrons will be transferred from complex I to complex C in the inner mitochondrial membrane, as you can see here in this series of peptides. When the electron is transferred from complex I to complex C, it creates a high concentration of protons in the space between the two mitochondrial membranes. In this location, the high concentration of protons is from H +, which are hydrogen ions with the electron removed. This high concentration of H+ will later activate ATP, or what is known as the ATP pump, which will then work to return the proton from the space between the two membranes to the inside of the mitochondrial matrix and produce ATP. So, the process of electron transfer The charged electron in the electron transport chain of the inner mitochondrial membrane undergoes a process known as oxidative phosphorylation.

[00:09:50]This process ultimately produces ATP via the ATP pump, which is the ATP synthase located in the inner mitochondrial membrane. The electron is then received by oxygen. Note that this is the first time oxygen has been used; it has never been used before in any of the above processes. Now, oxygen is used as the final acceptor of the charged electron, which then combines with hydrogen to produce water. A small amount of CO2 is released from the Krebs cycle, and another small amount is released from glycolysis.

[00:10:45]Lactate is then converted into a non-toxic compound, and a small amount of CO2 is produced.

[00:10:53]In short, I want to remember two important points from mitochondrial biochemistry: the mitochondrial is the powerhouse of energy production through two processes. The first step in the biochemistry process is the Krebs cycle, which involves fatty acids, pyruvate (sugar), and acetyl-CoA (also derived from protein). We know that in spherocytosis, even amino acids themselves can be used as an energy source after fats and other sources, or unused muscle tissue, are depleted. This protein itself can also be used as energy by converting it to acetyl-CoA, a different process carried out by liver cells (which we won't delve into now). So, everything that needs energy in the body must first be cycled through the Krebs cycle within the mitochondria to produce a charged electron.

[00:12:00]Then, the charged electron undergoes oxidative phosphorylation to produce ATP.

[00:12:08]That covers the topic of mitochondria. This explanation is very important for understanding how the problem occurs. There's something very important we need to know about mitochondrial DNA: The genetic material, the DNA, found in mitochondria is a simple circular chromosome. There are usually three to seven copies of this circular chromosome, no more, located in the matrix inside the mitochondria.

[00:12:51]These copies are usually identical, meaning there are three to seven copies of the same chromosome if it's identical. This is called homoplasmic mitochondrial DNA, meaning there's a state of homology, similarity, or match—whatever you want to call it—within the DNA of the mitochondria, inside a single mitochondria and from one mitochondria to another. So, mitochondrial DNA is not like nucleic acid DNA.

[00:13:35]They differ in that mitochondrial DNA is simpler and doesn't have two chromosomes—there's no chromosome coming from the father and a chromosome coming from the mother. It's just a single chromosome. So, the mitochondrial chromosome is just a single chromosome, simple and small. And that's not all. The second point is that mitochondrial DNA can vary from one mitochondrial to another because it lacks the complex protection and histone proteins found in nucleolar DNA. These proteins protect and stabilize nucleic acids. Every chromosome, as you know, has telomeres and many other protective properties in nucleolar DNA that ensure its stability and integrity, protecting it from mitogens, radiation, oxidative stress, and other factors.

[00:14:44]Unfortunately, this protection is absent in mitochondrial DNA. Therefore, we say that mitochondrial DNA is variable. It can be exposed to many environmental factors, and a cell with, say, 1000 mitochondria might contain many different forms of mitochondrial DNA because they are frequently exposed to mitotic agents.

[00:15:12]Mutation factors are the factors that induce mutations and affect the integrity of mitochondrial DNA. Since the structure of mitochondrial DNA is not fixed and undergoes changes due to genetic, and sometimes acquired, factors, this can lead to variations in consistency. For example, if we have three or four cobbases on the mitochondrial chromosome, we might see that two or three of them have mutations, while one remains unchanged. This results in different mitochondria.

[00:16:02]We call this heteroplasmic variation, or variation, or difference, or separation, or abnormality—whatever you want to call it—in mitochondrial DNA. This is also important because the higher the degree of heteroplasmic variation, the greater the likelihood that a mutation can express itself. A pathogenic mutation is more likely to express itself. This is not the case with nucleolar DNA. Nucleolar DNA is usually either heterozygous or As for homozygosity, I don't have the principle of homoplasmic and heteroplasmic DNA.

[00:16:49]This is unimportant in nuclear DNA; it's only important in mitochondrial DNA. So, are all the proteins and enzymes that function in the Krebs cycle, in oxidative phosphorylation, and in the structure of the mitochondria—as we said, the mitochondria is an organelle, in fact, the largest organelle in the cell after the nucleus in eukaryotic cells—the largest of which is the mitochondria? The mitochondria have an amazing characteristic: they synthesize their own proteins. They contain ribosomes and synthesize their own proteins; they don't depend on the cell for ribosome production.

[00:17:46]Is all the genetic material necessary for the synthesis and structure of the mitochondria found in mitochondrial DNA? No, actually, no.

[00:17:59]Mitochondria contain genes that oversee oxidative phosphorylation, mainly those that are While the rest of the structural genes and the genes related to Krebs cycle enzymes and others are actually supervised and produced by the nucleolar DNA, we can say that the vast majority of enzymes and proteins related to mitochondria are actually produced and supervised by the nucleolar DNA, while the percentage, i.e., around 13 genes and 13 proteins, excuse me, all of them work in oxidative phosphorylation. These are the ones found in the mitochondrial genetic material, mitochondrial DNA.

[00:19:03]Now, before we get into mitochondrial diseases, does anyone want to ask any questions regarding the biochemistry introduction we talked about?

[00:19:22]Okay, let's continue with mitochondrial diseases.

[00:19:32]Of course, the cause could be a defect in mitochondrial DNA or a defect in nucleonuclear DNA, provided it involves the function of a protein related to, or with a structural or enzymatic role in, the mitochondria. For example, let's say it's caused by a disease, such as the well-known Blake's disease.

[00:20:10]Blake's disease is a mitochondrial disease, but some of the genes involved are located in nucleonuclear DNA.

[00:20:18]This mutation leads to a defect in one of the mitochondrial enzymes. So, we understand what's happening: I might have a mitochondrial disease, but the gene responsible for it is located within the mitochondria, and I might have another mitochondrial disease, but the gene and the mutation responsible for it are located in the nucleonuclear DNA. That's why I have both.

[00:21:12]Mitochondrial diseases can indeed affect any systemic disease, meaning they can affect any The organs in the body, but the organs that suffer the most and the ones that most clinically show signs of damage, are those that consume the most energy.

[00:21:31]So, which organs consume the most energy in our bodies? The most, without a doubt, are the central nervous system, especially the brain and the eyes, followed by the heart muscle and skeletal muscles. Therefore, we need to see that, unfortunately, mitochondrial diseases damage the most precious and valuable parts of the human body: the nervous system, heart, and eyes. So, if a typical presentation would be about neurology, ophthalmology, and cardiomyopathy, then what would it be?

[00:22:23]As we said, mitochondrial diseases are a relatively new field of study.

[00:22:28]Until 1988, the available information was rudimentary. In 1988, the first mutation related to mitochondrial DNA was discovered, and the first treatment approved for mitochondrial DNA was only approved 10 years ago, in 2015. The first mitochondrial replacement surgery was also performed that year. It was performed in 2017, and the first FDA-approved drug for mitochondrial DNA was in 2023.

[00:23:06]Our lecture contains the latest information up to 2025-2026.

[00:23:17]So, if I have mitochondrial DNA, as we said, 11% of it is related to mitochondrial DNA, and 89% is related to mutations carried on nucleotide DNA. Of course, in mitochondrial DNA disorders related to mitochondrial DNA, as we said, the more heteroplasmic and the greater the degree of segregation and heterogeneity in the genetic content of the mitochondrial DNA, the more severe the disease. The fundamental difference between them is that mitochondrial DNA mutations, which govern their ability to manifest, are homozygous or heterozygous, while in mitochondrial DNA mutations, which govern their ability to manifest The concept is based on the idea of ​​whether it's homoplasmic, whether there's homogeneity in the mitochondrial DNA, or whether there's a high level of heteroplasmic DNA or a low level of plasmid DNA. Homozygos and heterozygos are related to mitochondrial DNA, while homozygos and heterozygos are related to nucleic acid DNA. This concept is clear, colleagues, before we continue. Okay, so if we start with the first group of mitochondrial diseases, which are mitochondrial DNA-related diseases, we'll see, as you can see in this slide, that they are all syndromes and codes such as HON, MELAS, MID, and others. I don't care if you memorize these names and codes, which seem like gibberish. What I care about is that you remember something very important: these abbreviations and codes are shorthand for the symptoms and clinical manifestations of each of these syndromes. In fact, they are no longer called syndromes because their causes are now known. It's better to call them disorders, not mitochondrial diseases. Let's start with the most common of all, which is LHR, or Liberal Hypooptic Neuropathy, the most common form of mitochondrial disease. In this lecture, I don't aim to present detailed information about each mitochondrial disease, but rather to address what's important to me as a pediatrician. The main goal is to develop a clinical understanding in pediatricians so they can diagnose and differentiate mitochondrial disorders in children and then guide the child toward appropriate treatment. Liberal Hypooptic Neuropathy is the most common mitochondrial disease. It manifests as central vision loss and bilateral color vision loss, usually first. The first organs to be affected are the ganglion cells in the retina, known as RJ cells. These cells actually form the optic nerve. Their axons are... The optic nerves that develop and form are the ones that become damaged, and the first manifestations are central vision loss followed by color vision loss.

[00:27:47]The mutations responsible for this disease have been isolated. The genetic basis of this disease is three mutations, as you can see in the slide. These mutations are present in 95% of cases of libido-retinopathy of optic neuropathy and are found in mitochondrial DNA. The more heteroplasmic the mutation, the greater the extent of the blindness and the earlier it appears.

[00:28:17]Fortunately, with early diagnosis, there is now a specific treatment. I wanted to mention this in this slide before discussing treatments to remind you that if this disease is diagnosed early, the child's sight can be saved. The treatment is known as adipine, and there are several mechanisms and methods for administering it. It has been approved by the European Medicines Agency and the FDA. The second disease in this group is melax-lactamase (MLA), as we mentioned. As the name suggests, it refers to mitochondrial involvement.

[00:28:56]Myopathy, encephalopathy, lactic acidosis, and streptococcal disease mean that this disease manifests as episodes of fluctuations. We observe that the clinical condition of this patient is unstable, and most patients are seen around six or seven years old. The child is usually fine, then suddenly experiences severe episodic attacks or symptoms resembling a stroke, such as fainting, loss of consciousness, and always severe attacks of the migraine. If we ask the child's family, they might say, "He was complaining of a headache, and we took him to several doctors who diagnosed him with migraine, valvular heart disease, and migraine." This could be one of the symptoms of myeloablative disorder. As we mentioned, recurrent status epilepticus can be a manifestation of myeloablative disorder, especially since in such cases, I remember to investigate lactic acidosis. When it occurs according to these criteria, I must consider and rule out myeloablative disorder from other accompanying manifestations. I might see hearing loss, ataxia, and endocrine disorders such as diabetes may appear later.

[00:30:16]80% of cases are caused by these factors. A mitochondrial DNA mutation, a specific and well- studied mutation known as the MTT Y gene, is the cause of the stroke that occurs between myelosarcoma and myelosarcoma. This stroke is actually caused by severe inflammatory and destructive damage to the endothelial cells due to apoptosis, inflammation, and ROS ( reactive oxygen species). These oxygen compounds, containing highly oxidative oxygen, are formed as a result of mitochondrial dysfunction.

[00:31:04]This leads to endothelial erosion and, consequently, to the mechanisms of actual stroke. There are currently no specific treatments for myelosarcoma, but a combination of several agents, such as antioxidants, cofactors (which we will discuss later), lactate, laurylamine agonists, and anti-epileptic drugs, can all control the condition, ease symptoms, and significantly improve the prognosis. The third mitochondrial DNA-related disease is mitochondrial dysplasia (MDM).

[00:31:46]Maternal Inherited Diabetes and Dementia (MIDD) manifests as diabetes, as its name suggests, with symptoms like juvenile diabetes and hearing loss. It is inherited from the mother. Other manifestations may include myopathy, neuropathy, and nephropathy, resulting in amino acid imbalances. The interesting thing is that the gene responsible for MID is the same gene responsible for melax, but there are differences in the heteroplasmic ratio. In other words, MID can be considered a form of mutation in the MTT gene within mitochondrial DNA, but at a lower heteroplasmic level. Therefore, we can say that both are clinical spectrums of the same gene, a mutation in the same gene, but within a different heteroplasmic spectrum. When the heteroplasmic level is less than 45%, it results in MID. When the mutation is greater than 85% of the heteroplasmic level, it results in melax. We're saying that now, when we want to look, we need to look at this thing that we'll discuss later in genetic diagnosis.

[00:33:31]When I request gene studies for a disease, I know it's a mitochondrial disease resulting from mitochondrial DNA mutation. It's not enough for me to request a mutation identification test or to do Next Generation Score (NGS) to reveal the mutation.

[00:33:50]If I have a mitochondrial DNA mutation, it's not enough. I have to tell them, "I want to see... I'd appreciate it if you could give me an idea about the heteroplasmy level." The lab, the one that knows its job, should be able to provide this information when you request Next Generation Score (NGS) on mitochondrial DNA. We see this now in reports; they tell me, "This patient has, for example, a mutation in MTG1, but the heteroplasmy is less than 10%." So I know that this mutation is... For the doctor, it's possible they won't interpret the clinical manifestations, or they'll tell me, "He has a very high level of heteroplasmy from this mitochondrial DNA gene mutation." So, they know that, yes, no, that means the clinical symptoms I have perfectly match this diagnosis, and this is considered a diagnosis.

[00:35:00]The idea of ​​diagnosing MID is important because we can't give oral metformin to them since they already have lactic acid deficiency. Before we give metformin to a diabetic patient, because this might be diagnosed at a later age, and they might say, "I started having type 2 diabetes in my youth, so I diagnosed it. I might have type 2 diabetes and start metformin before measuring lactate," this is unacceptable. In young adults and younger, when I diagnose diabetes, before we rush to prescribe metformin for any reason—and I'm speaking generally—before we rush to prescribe metformin for any reason, we must first make sure that... His lactate level isn't high because it's one of the most important side effects of using metformin. As we know, it causes lactic acidosis. The fourth type of MTDN MTDS is mirabilis or myelomeningocele and red fibroids. This is characterized by the occurrence of progressive myelomeningocele and red fibroids.

[00:36:26]We see them as rigid or refractory on the cellular biopsy.

[00:36:32]Notice that now we want to see that I'm going to go through it. I'm studying mitochondrial diseases, and every now and then I go through a disease that I know and have studied, but I didn't know that it's related to the mitochondria. This is the first one of them, mirabilis syndrome. I used to study it when I studied syndromes, but no one told me that it's related to the mitochondria.

[00:36:57]I'm going to see red ataxia in a little while, and we'll see fatty acid oxidation in a little while. All of these are In fact, mitochondrial disease manifests as ataxia, cardiomyopathy, lipomatosis, and dysplasia. There is damage, meaning neurological, cardiac, and skeletal muscle involvement. There are treatments that improve the condition. One treatment available now is administering coenzyme Q10, which improves mitochondrial function, especially in patients with MRTS. Therefore, we are very helpful if we diagnose it, and diagnosis is easy because the genetic basis of mitochondrial DNA is now known, and the causative gene is responsible for 80% of cases. So it's very easy.

[00:37:54]Currently, we are working on new treatments, which are still under research; we will discuss them shortly. The most beneficial treatment for MRTS is coenzyme Q10, which is already present in MRTS.

[00:38:11]As its name suggests, NERV syndrome is neurogenic, with ataxia, retinopathy, and pigmentation.

[00:38:25]Our patient's reference is the same. The vital systems are very affected, including vision loss, retinal pigmentation, and inflammation. I have retinitis pigmentosa and vision deterioration, in addition to ataxia and seizures. There is also involvement of the brain and eye, and then muscle involvement, muscle weakness, and we might also see developmental delays and dementia. This is the sixth disease, or type six, out of seven. The sixth of these is known as PPI (Progressive External Amblyopia). I want you to know it very well because it's a childhood disease with three forms. The first form is Pure PPI, meaning I only have progressive bilateral palsy of the eye muscles. It manifests as progressive ptosis. A child who was fine suddenly develops weakness in the eye muscles, either resulting in drooping eyelid or ptosis.

[00:39:58]Thank you, Dr. Rahaf. I have three types of PPI. The first type is the Pure form, but Pure PPI The second form, which I call Bio Plus, involves eye muscle involvement, such as ptosis (drooping eyelid) or progressive strabismus (crossed eyes). There's also involvement outside the eye, usually in the muscles. The most severe form is Kearns-Sayr syndrome. However, they are all caused by a single genetic defect, but to varying degrees. This defect is known as single-large scale mitochondrial DNA deletion. It involves a long, widespread deletion mutation, as if a large portion of the mitochondrial DNA is being silenced. This results in these three forms, all of which involve eye involvement. This eye involvement may be isolated, or it may be accompanied by external muscle involvement. The most severe form is Kearns-Sayr syndrome.

[00:41:30]The interesting thing about these cases is that, despite all of them being mitochondrial DNA defects, and despite the fact that when they are affected, they follow a pattern of... Mitochondrial DNA inheritance means we see that Henle syndrome is inherited maternally through affected mothers.

[00:41:50]However, in reality, most patients are sporadic. There's no logical explanation yet as to why these are the only ones affected. The majority of patients have congenital DNA inheritance-related cases, but I think the process of sexual maturation might be affected. As we said, for example, in Down syndrome, I know that the process of sexual maturation is affected, even though it's not related to mitochondria. I wanted to give an example of how a systemic disease can be hereditary but we only see it as sporadic.

[00:42:27]This is because the genetic disease itself might reduce the likelihood of future mating, so most of the cases we see are actually neonatal degenerative sporadic. But this is just my own interpretation, and I haven't found any evidence for it in the references I'm looking for in the lecture. However, it's important for me to know that PE syndromes, which are the pure and plus PE syndromes, are not the only ones. O Plus and Kernsair are three syndromes. Most cases are sporadic.

[00:42:55]This is important because when we do genetic counseling and advise parents, the picture might seem a little rosy. We don't tell them that we're applying the principle that the mother will pass on the myotonic disorder to the children she gives birth to. We can't say that. Usually, in these three syndromes, the worst form is Kernsair. It usually manifests as eye involvement. The worst part is that it manifests at school age. The child usually has nothing wrong with them. Usually, as soon as they start, they begin to show strabismus or drooping of the eye.

[00:43:44]Who can help me and mention two diseases, or one disease, that can also manifest as drooping? There's a very common disease.

[00:43:55]Who can help me? What is the very common disease that can manifest as drooping?

[00:44:04]Myotonic dystrophy can manifest as drooping. The second disease that can manifest at a slightly older age is myasthenia gravis. Yes, as the doctor mentioned. Yes, but let's add to them now.

[00:44:19]In our memory, one of the most important and prominent manifestations of mitochondrial disease is ophthalmoplegia, especially when it affects the muscles responsible for eye function. This means that when I perform ophthalmoscopy, I see retinopathy of pigmentation. When I perform an ECG, I see a heart block. So, Kernisner disease is the disease that affects vision and insight.

[00:44:49]We should always remember that whenever I see a concurrent heart and eye involvement, I might see ataxia, deafness, dementia, or diabetes, but I see these less frequently and they manifest at a later stage. I might include them in my prognosis, meaning that something like this is likely to happen to me. A distinctive sign of this disease is that there is a slight increase in protein levels if I perform a CSF study.

[00:45:21]As we said, it is phenotype 1 of the large scale diagnosis.

[00:45:35]Treatments vary depending on the severity of the condition.

[00:45:40]While the milder form, which is pure PI, or treatment is only medication. Surgical procedures on the eye muscles, like those performed by ophthalmologists, are not always performed.

[00:45:47]We give a warning that this patient might develop kyphosis (K2) in the future, so we can follow up. This is important to discuss with our ophthalmology colleagues: the disease isn't limited to the eye, even if the problem is only with the eye muscles. Of course, if there are injuries outside the eye muscles, we can discuss other treatment options later. There are many treatments given for kyphosis. We can use a heart implanter, and if possible, we can perform a heart transplant. We can also perform therapeutic procedures on the eye for kyphosis pigmentosa. There's a gene therapy currently being developed that relies on mitochondrial augmentation therapy, and this is the best treatment, although it's still under development. But if we remember, all mitochondrial science before 1988 was practically nonexistent. The current generation of practicing doctors probably didn't hear about any of this. So, if we have a promising treatment under development... Currently, this means that in two or three years, it could become widely available with mitochondrial augmentation therapy.

[00:47:17]The idea is that they simply take the CD34 white blood cells and treat them, replacing the diseased mitochondria within them, and then reintroduce these white blood cells (these are mitochondrial white blood cells) back into the same patient, and the patient recovers.

[00:47:45]As we said, clinical studies are still in their advanced stages and have yielded very good results for KS and Pearson, which is the worst form.

[00:47:58]Pearson is form number seven and is the last form of mitochondrial disease related to the mitochondrial DNA. It is a fatal multisystem form.

[00:48:13]Most of these cases occur when there is a very high level of heteroplasmy, meaning it has early, distinctive, and characteristic manifestations. In addition to the aforementioned neurological and ocular manifestations, there will be sedroplastics. Sideroplastic anemia, in addition to the fact that I have exocrine pancreatic insufficiency and lactic acidosis, I think of Pearson syndrome when I have lactic anemia with exocrine pancreas regurgitation, meaning I have chronic diarrhea or a loss of fat-soluble enzymes, along with sideroplastic anemia and lactic acidosis.

[00:49:00]Faced with this triad, if there is a neurological problem, I have to consider Pearson syndrome.

[00:49:16]Thank you to Dr. Rahaf for following up with me regularly. Yes, this is what I'm referring to: the presence of sideroplastic anemia and exocrine pancreatic insufficiency. Of course, it all remains, as we said, within the context of a neurological disease.

[00:49:41]Now we will move on to defining only mitochondrial disorders that result from nuclear DNA. The most common is Albers-Hatten syndrome.

[00:50:06]Even I have difficulty reading them; it's a German name. Hatten-Lüscher syndrome ( HLS) is the most common mitochondrial disorder resulting from nuclear DNA deficiency.

[00:50:20]Of course, as we can see now... Here we're talking about autosomal receptive because the dominant idea regarding the ability of the mutation to express itself here is whether it's homozygous or heterozygous. Also, here we have the autosomal receptive or autosomal dominant pattern, and we might see some cases that are X-linked. There's no problem when the mutation is carried on the nuclear DNA.

[00:50:52]IHS is characterized by the occurrence of intractable seizures, deterioration in psychomotor development and consciousness, and deterioration in liver function.

[00:51:10]Of course, the liver is also one of the organs that consumes a lot of energy, so it suffers from hepatic damage, along with neurological damage, which is characteristic of IHS.

[00:51:29]This point in particular is important to keep in mind so that we don't deprive the patient or misinterpret the cause of the patient's elevated liver enzymes as valproate use. So, when a patient comes to me... Interruptible seizures, severe convulsions, could be due to elevated enzymes. I treated it with valproate, and I noticed that my liver enzymes became elevated. So, I shouldn't conclude that this is caused by a toxic dose or toxicity from the valproate. It could be due to the underlying disease itself, such as mitochondrial disease. I also have three syndromes caused by a single gene, known as the polygenic mitochondrial disease. These syndromes present with three different clinical manifestations, but they share the same genetic origin and are all autosomal recessive. They are Sandu, Miras, and Iosca.

[00:52:40]Of course, as we said, I don't want you to memorize these abbreviations, but they aren't really abbreviations; they give me an idea of ​​how the disease manifests. Sandu stands for Sensory Ataxia Neuropathy Dysarthritis and Oval Mobility. It's like taking the first letter of each word and putting them in one sentence for simplicity.

[00:53:03]Recalling and inheriting are key aspects of mitochondrial receptive ataxia syndrome, and the term "infantile spondylolisthesis" refers to innate spondylolisthesis.

[00:53:15]Notice that if I don't want to strain my head and memorize these jargons, I can simply remember that I'm referring back to the first law I mentioned. This condition involves a deterioration in the functions of the nervous system, particularly the eyes, muscles, and heart. Of course, ataxia is a very important sign. We need to see that it's one of the characteristic neurological lesions and anatomical changes of mitochondrial disease. It's not just lesions of the pseudobulbars, but also lesions of the cerebellum. One of the most important causes of cerebellar atrophy is mitochondrial disease.

[00:54:03]Therefore, we need to see that in many cases of ataxia, ataxia occurs.

[00:54:09]Most cases of mitochondrial disease are accompanied by ataxia. Now, there's the third type, which is edoacidosis.

[00:54:37]edoacidosis is also an abbreviation for autosomal dominant atrophy.

[00:54:44]Its typical manifestation is... Progressive vegetative-vascular dystonia means the absence of light; the person can no longer distinguish between darkness and light, or color and black. We remember when it occurred, it usually happened to high school students, meaning a child or young person around 15 or 16 years old who had no problems before.

[00:55:13]As we said, it's autosomal dominant, so it can be seen in girls or boys.

[00:55:21]Diagnosis is important because it's for treatment and for progesterone.

[00:55:27]Suddenly, I started losing my color vision, and then I lost my vision in both sides. Of course, the mechanism is genetic.

[00:55:38]Degeneration demyelination occurs in the retinal ganglion cells, and the gene responsible for it is now known and specific as the OPA1 gene.

[00:55:54]This gene is responsible for the production of dynamin-related GTP bases, which are responsible for the integrity of the inner mitochondrial membrane.

[00:56:13]This dynamin is a structural protein, and as we mentioned, the inner membrane is where oxidative phosphorylation actually occurs. All of this happens in my inner mitochondrial membrane, so this protein is very important. The fourth type is Barth syndrome, and this is an extracellular mitochondrial disease characterized by cardiomyopathy and skeletal myopathy, in addition to neutropenia.

[00:56:43]Note that simple blood tests in a child with a neurological injury can be key to diagnosis if you see unexplained manifestations such as hydroplastic anemia, neutropenia, or resistant acidosis. I must keep in mind that this could be a sign of Barth syndrome. The neurological condition he has is caused by mitochondrial disease, specifically Barth syndrome. There's a new treatment for this known as mitochondrial cardiolipin lipid replacement.

[00:57:24]This is essentially a repair process for the cardiolipin that's part of the mitochondrial structure. The fifth type of mitochondrial disease, whose genes are located in the nucleotide DNA, is Frederick ataxia. This is a common question in exams; we see it frequently. It's like, wherever there's a Frederick ataxia patient, they bring it up.

[00:58:02]Frederick ataxia is actually the most common type of mitochondrial disease. The FXN gene is responsible for frataxin production.

[00:58:16]As we said, it's inherited in the nucleotide DNA, so it's autosomal reactive.

[00:58:24]Frataxin is a protein that's very important in the process of iron homocysticercosis within the mitochondria.

[00:58:33]Frataxin is also very important for neuronal health and stability.

[00:58:43]This protein is synthesized in cytoplasmic ribosomes and then transported to the mitochondria. The problem arises when, note that it is mitochondrial deficiencies, but its gene is located in the nucleotide DNA, and the ribosome that translates and synthesizes frataxin is located in the cytoplasm, not the mitochondria.

[00:59:09]However, the resulting frataxin will perform its function in the process of iron fixation and activation. Iron, as we know, is an essential element in oxidative phosphorylation and electron transport within the mitochondria. Therefore, the problem is significant. If I don't have active frataxin, the mitochondria's function becomes impaired.

[00:59:44]Frataxin, as we said, is very important for neuronal stability.

[00:59:51]When my frataxin level decreases, I will have a dual deficiency. It's not just the mitochondria that will experience dysfunction and weakness in the function and coordination of sphincters. The typical presentation of Friedreich's ataxia is that it manifests in school-aged children as frequent falls. I develop progressive ataxia, usually starting in the lower extremities and then the trunk. This is accompanied by speech problems, the first of which is dysarthria or slurred speech. It means I have a speech impediment or stammering, like a stammering man who speaks with difficulty. The most distinctive feature in examinations is what I see when I examine a patient with Friedreich's ataxia.

[01:00:43]In addition to the ataxia, as we mentioned, and the gait disturbance and slurred speech, there's something that points to a possible cerebellar problem. However, when I examine them, I see that the tendon fibrillation is absent, weak, or even nonexistent.

[01:01:11]This contradicts the neuromuscular ligand because the problem is actually more in the proprioceptive system.

[01:01:22]I have a positive Pap smear.

[01:01:24]The positive Pap smear might lead me to upper motor neuron ligand, while the upper tendon relaxation might lead me to lower motor neuron ligand. And on top of all that, I have a loss of deep sensation. This divergence is necessary in a patient with ataxia and gait disturbance, and who is of school age or older. I must be referred immediately to Frederick Ataxi. He might ask what else I would like to examine, and I would tell him I would like to examine the eyes and the heart because this could be related to hypertrophic cardiomyopathy.

[01:02:12]The diagnosis is made through genetic testing, which is the primary clinical diagnosis and cannot be confirmed by anything else. An echocardiogram or an MRI might reveal atrophy or some degeneration in the cerebral palsy or spinal cord. They all perform the necessary examinations and give me progress in the diagnostic process, but the diagnosis must be confirmed by genetic testing. Diagnostic testing in 95% of cases involves a qualitative investigation of the FXN gene, which is located on chromosome 9. We need to be specific, not make general promises; we need to define the required FXN gene panel.

[01:03:18]Type 6 mitochondrial disease, which results from a nucleolar DNA defect, is fatty acid oxidation defect. Why is fatty acid oxidation included in mitochondrial disease? Let's go back to the first lecture. We said that all fatty acids need to be transported by carnitine into the mitochondria to undergo beta-oxidation and produce acetylcholine. So, acetylcholine goes into the Krebs cycle. Therefore, fatty acid oxidation defect is a mitochondrial disease, even though its nucleolar DNA is located in the nucleolar DNA, and even though its oxidation is located in the nucleolar DNA. The DNA is not the same, but as a result, I'm experiencing a defect in beta-oxidation within the mitochondria. This defect could be in the form of acetylcarnitine translucency itself, or in carnitine mitogenesis, or it could be in the medium-chain dehydrogenase ( MCD) or MCAD/MKM/MKD... Acidosis and hypoglycemia with absence of ketones.

[01:05:28]So, when I don't want to see non-ketotic hypoglycemia, I have to keep in mind that I have fatty acid oxidation. If I see high CPK, this also points me more towards rhabdomyolysis (muscle breakdown).

[01:05:46]Then I might move to the second stage of diagnosis, where I order more investigations. I might order the acylcarnitine profile (this test is available), or I might order free carnitine and total carnitine levels, or I might order fatty acid, lozenge, and medium- chain levels. All of these are available. Now, if I order this second step of study and any of these are positive, I have to move to the final stage and confirm the diagnosis by ordering the genotype sequence of the genes responsible for mitochondria, or any genes I know by name. Fatty acid oxidation defect (FAD) is a condition that requires further investigation, such as carnitine chain analysis or a specific gene panel test for FAD enzyme 1B1.

[01:06:44]If a specific abnormality is found, for example, in the long or medium chain, then clinical suspicion is followed by early laboratory tests, specifically targeted tests like hypoglycemia, acidosis, ketones, and elevated CPK. Further investigation might focus on carnitine chain abnormalities, acylcarnitine profile, and elevated FAD levels. Then, I need to confirm the diagnosis with the appropriate diagnostic test.

[01:07:27]Type VII mitochondrial disease, which results from nucleodendrone defects, is the most common mitochondrial disease. The primary cause is an electron transport disorder, meaning I have an impaired oxidative molecule.

[01:07:58]Oxofospheric phosphorylation in the inner mitochondrial membrane, as we mentioned, involves complexes 1, 2, and 4.

[01:08:05]These all transfer electrons, and each time they transfer an electron, they perform a proton uptake within the space between the two membranes.

[01:08:18]This is called chemosmosis.

[01:08:22]Chemosmosis is what will later activate the ITP pump. So, what's happening here in this chain of events is that this entire sequence is disrupted.

[01:08:40]Most genes, as we'll see, are actually related. Most mutations are related to mitochondrial DNA, but in some cases, one of the genes in complex 4 might be present in nuclear DNA. That's why we're linking this chain of events to nuclear DNA. We need to be careful with prognostics and advice when giving it, keeping in mind that not all Disiosis means it originates from mitochondrial DNA, but it can come from both. Flake disease is one of the few mitochondrial diseases, although it is the most common, which is Castol.

[01:09:37]However, it is classified as a disease resulting from nuclear defects, but in reality, it affects both the nucleus and the mitochondrial DNA. So, we must be aware of this.

[01:09:54]I'm telling you that there is a slight clinical difference: usually, the patterns resulting from nuclear defects appear later, meaning their clinical manifestation is delayed. The clinical manifestation of lesions is slightly later than the patterns resulting from a defect in mitochondrial DNA. What happens in Flake disease is subcutaneous spongiform necrosis, necrotizing encephalopathy, meaning I develop spongiform necrosis in the brain. The typical age of manifestation is before four years of age. I start to develop regurgitation, hypotonia, epilepsy, respiratory distress, and osteoporosis.

[01:10:44]In addition to the eye changes, as we mentioned, there's also vision impairment and ophthalmoplegia, which are frightening and terrifying signs. I'm a million times more alarmed than I am when I see them. I have a child who was fine, then suddenly develops progressive strabismus or weakness in the eye muscles. Or I have an infant with torticollis, especially if it's not fixed, meaning they have what's called torticollis. They also have torticollis, meaning their body assumes a certain posture, their head tilts, just to stabilize themselves and achieve alignment because they have ophthalmoplegia.

[01:11:26]Diplobia is the functional term resulting from ophthalmoplegia.

[01:11:30]In every case like this, before referring your patient to an ophthalmologist to find the cause, look for 100 possible causes yourself. Check if they have a central nervous system lesion; it could be an episis, a stem cell, or, as we mentioned, they might have six cranial nerves. There are three pairs of cells responsible only for eye movement, so you need to make sure that the brainstem and oxybetes are normal, and that you don't have any nerves. Then you need to make sure you don't have any metabolic disorders, especially our beloved LJD or PJD. We need to keep this in mind when I see an eye injury; our responsibility is more important than the ophthalmologist's.

[01:12:16]Where were we?

[01:12:18]Excuse the digression, but we were saying that the typical age of onset for LJD is before four years old, with eye manifestations and developmental delays. And of course, I have lactic acidosis. The diagnosis is very easy now. I have mitochondrial biomarkers, which we will discuss in a bit. And I have MRI, and I have the genetic test, which is of course from the important mitochondrial biomarkers.

[01:12:54]As for lactic acidosis, pyruvate accumulation, and mitochondrial effervescence, of course, the mitochondrial effervescence is elevated. I also have mitochondrial extras.

[01:13:09]Fiscar formation means that vesicles form from the cell, similar to what they call exocytosis, if you recall from biology.

[01:13:27]The cell can release vesicles, and these vesicles may contain fragments, or even complete mitochondria, or fragments of damaged mitochondria. By studying these, we can discover diseases related to mitochondria. That's why this is now one of the important biomarkers in diagnosing lesions, called the Mitovis Panel MRI.

[01:13:57]We also see that in radiology, there are qualitative changes that occur in the form of hypo-intensity or hyper- intensity depending on the time used in the MRI.

[01:14:12]Of course, in certain areas, such as the basal ganglia, as you can see, and putamin engorgement. Putamin lesions are specific to the basal ganglia, but I saw lesions in the MRI in this area. The first thing I have to think about is lesions, especially if biomarkers haven't been used.

[01:14:30]I need to perform a biopsy myself. Markers, of course, the final diagnosis depends on the mitochondrial gene sequence.

[01:14:42]And, as we saw a moment ago, for one of the mitochondrial diseases, it's not enough to study mitochondrial DNA alone; we must study mitochondrial DNA and nodal DNA. So, the physician's approach is very, very important in improving performance and the outcome of genetic studies because if I start wrong, the result will be disappointing. It's preferable that we conduct the tests on a specific sample, not just any blood sample. Of course, there are many treatments for ligation: adipine, coenzyme Q10, oleuropein, thiamine, riboflavin, cysteine, and sodium citrate. In addition, there's the type 8 gene, which is MNG1. Of course, colleagues, I know I'm going a bit fast. If we were to give a lecture on each of the mitochondrial diseases, it wouldn't be enough because it's become a vast field, and it's a specialty, or rather, a subspecialty. Specialty means that now there are people with metabolic disorders.

[01:16:04]After metabolic disorders, I'll tell you, I only work with mitochondria, and this happens. So, we can't give one or two lectures to talk about every mitochondrial disorder. As a pediatrician, I'm not concerned with all this talk; I'm concerned with all the complexities. I mean, I need to know what we're going to say in this lecture and more. May God grant you well-being.

[01:16:28]Okay, of course, MG1A ( Mentochondrial Neurogastroenteritis) is a mitochondrial neurogastroenteritis, an encephalopathy. It means it affects the whole body, not just the brain and muscles. There's also damage to the gastroenterological system.

[01:16:51]This leads to digestive and swallowing disorders, and often dyspepsia. Their main suffering is actually digestive. In some cases of mitochondrial diseases, we see a child with failure to thrive, who doesn't eat or like food, and has difficulty swallowing. Difficulty chewing, disorders resembling irritable bowel syndrome, and constipation. The parents always come in with a digestive problem.

[01:17:15]You ask about development, and it turns out the child is very weak and cannot tolerate exercise. You do investigations, and finally, you get mitochondrial disease. This is one of the manifestations that can cause MNG.

[01:17:31]Of course, there are specific treatments for it, which we will discuss later, including enzyme-linked medication.

[01:17:40]I have type nine, which is MLE, or HJ, from myopathy: lactic acidosis, sideroplastic anemia. Notice this is the second type of mitochondrial disease that causes sideroplastic anemia. We just came across sideroplastic anemia in two forms, one of which is Pearson's disease, right?

[01:18:07]You can see it in your mind when you review the lecture.

[01:18:12]Well done, Dr. Diab, thank you. So, MLE also causes sideroplastic anemia and autosomal resuscitation, and its mutation is in the biosig gene, which is responsible for manufacturing Psidiouridine M is an enzyme related to uridine and pyrimidine nucleotides.

[01:18:46]Its primary manifestation is affecting the body and muscles, resulting in myopathy, lactic acidosis, and sideroplastic anemia. Diagnosis is made through muscle biopsy, in addition to the biomarkers we mentioned, especially sideroplastic anemia with lactic acidosis. These markers must be indicated, along with neurological involvement of the smooth muscle.

[01:19:14]The diagnosis is confirmed with next-generation succinate. The last one is Singer syndrome. Singer syndrome is, of course, one of the severe forms. It presents with cardiomyopathy and myopathy, and cataracts are a distinctive feature. The eye involvement here is cataracts, not retinal pigmentation, not external tarsalgia as seen in the previous types. So note that I have several types. For eye injuries, the most common is extraocular myelitis, meaning I develop retinal degeneration. The second most common is optic nerve atrophy, which is seen in the first type, rheumatoid arthritis (RA). Then I develop retinitis pigmentosa, which can be seen in several forms. Finally, I might develop keratoconus.

[01:20:16]Notice how many types of eye diseases can be linked to mitochondrial disease.

[01:20:24]Diagnosis is easy for Singer using mitochondrial biomarkers and next-generation retinopathy.

[01:20:31]We ask for the TIM 22 complex panel, which is the gene responsible. The last point I'll conclude today's lecture with is that we know the aging process itself is a mitochondrial disease because all current research indicates that the aging process is mitochondrial senescence. This means that the mitochondrial machinery, which operates throughout life, experiences a slight decline in oxidative phosphorylation and phosphorylation.

[01:21:08]ATP becomes less efficient, and the accumulation of reactive oxygen species increases. This leads to brain fog and muscle atrophy. All of this is due to a protein called humanin.

[01:21:26]This protein, a structural protein within the mitochondria and chondria, decreases with age. A significant decrease in humanin concentration was observed in patients with age-related diseases such as Alzheimer's, Parkinson's, and others. So, they started producing it and administering it to these patients. We don't claim it's a cure for aging, but it has become the number one treatment for all age-related diseases.

[01:21:56]This is where I'll conclude today's lecture, as the next part is crucial.

[01:22:04]Today's lecture has been largely a prelude to the very important topic we'll cover tomorrow. May God bless you, Dr. Ahmed. Yes, you're right.

[01:22:17]Aging is the aging of the soul, not the aging of the body, but it's all interconnected. Even if... Spirits and morale were high. If the mold is damaged, meaning the heart is no longer functioning, then God willing, we will discuss the most important part of the lecture: how we diagnose mitochondrial diseases and what the biomarkers of mitochondrial diseases are. We will also discuss the approach of 111=3 in diagnosis and treatment. This approach has been developed, and God willing, you will like it. We will also talk about available, promising, and currently implemented mitochondrial treatments, as well as those that are approved. All of this will be covered in the next lecture, God willing. Happy New Year to you all. Thank you for attending, and I wish you a blessed Eid.