Known autosomal recessive form mtDNA multiple deletion syndrome- the so-called mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The disease manifests itself at a younger age and manifests itself with the same set of neurological symptoms typical for mitochondrial diseases in combination with severe dysfunction of the gastrointestinal tract (intestinal nseudo-obstruction syndrome with bouts of repeated vomiting, diarrhea, weight loss).

In sick MNGIE revealed a pronounced decrease in the activity of the enzyme thymidine phosphorylase, caused by mutations of the corresponding gene on chromosome 22ql3.32-qter. Thus, the disease is based on a genetically determined pathology of thymidine metabolism, leading to impaired replication and / or maintenance of the mtDNA molecule.

MtDNA depletion syndrome is a condition in which patients have not a qualitative, but a quantitative defect in mtDNA - i.e. a sharp decrease in the number of copies of mtDNA molecules (Fig. 68 B). It is characteristic that the depletion of mtDNA is observed only in strictly defined tissues (for example, only in muscles, only in the liver, in muscles and kidneys, etc.).

Clinical picture depends on the involvement of specific tissues and usually includes in various combinations myopathy (including congenital), convulsive syndrome, hepatic and renal failure, cardiomyopathy. Characterized by lactic acidosis, the phenomenon of "torn red fibers", there is a combined insufficiency of the respiratory chain complexes containing mtDNA-encoded subunits (I, III-V).

Disease is congenital or manifests in the 1st-2nd year of life and usually has a fatal course. In most of the described cases of mtDNA depletion syndrome, an autosomal recessive mode of inheritance is registered. The genetic defect has not been identified. It is assumed that the disease is caused by damage to a nuclear gene that controls mtDNA replication. A relatively benign secondary form of this syndrome is also known, in which the depletion of mtDNA in cells is caused by the use of the anti-HIV drug zidovudine.

Types of mitochondrial DNA pathology. The site responsible for the development of myoclonus epilepsy with torn red fibers MERRF is presented

Due to the peculiarities genetics mitochondrial encephalomyopathies DYK-diagnostics of these diseases has a number of fundamental differences from traditional approaches applicable to mendelian diseases. Generalization of many years of experience in the examination of patients with mitochondrial pathology in the leading research centers of the world made it possible to develop a clear and consistent diagnostic algorithm that provides the greatest efficiency of diagnostic search [Krasnopolskaya KD, Zakharova ELO., 1998; Shoffner J., Wallace D. 1992; DiMauro S., 1993; Chinnery P. et al., 1999 (a)]. This algorithm includes several main stages.

At the first stage, detailed clinical and genealogical and laboratory-instrumental analysis, the purpose of which is to accumulate evidence in favor of an educated guess about the mitochondrial nature of the disease under study. The most obvious evidence of mitochondrial disease can be evidenced by:

a) maternal type of inheritance (taking into account all polymorphic and even subclinical manifestations in siblings - children of a sick mother);
b) the peculiar nature of the syndrome (the presence of multisystem and multiorgan pathology with the involvement of organs that are different in embryonic origin and functions);
c) a progressive course, the presence of metabolic crises (the latter is especially important for mitochondrial syndromes of early childhood);
d) an increase in the level of lactate in the blood and cerebrospinal fluid (including against the background of food and physical activity);
e) amino aciduria and organic aciduria.

Search for multi-organ pathology should be carried out purposefully, using the necessary paraclinical methods, in order to identify overt or latent cardiomyopathy, renal tubulopathy, hepatocellular dysfunction, diabetes, growth hormone deficiency, intestinal villous atrophy, changes in blood smear and bone marrow punctate, myopathy, peripheral, cochlear and visual neuropathy, retinal pathology, petrification and focal changes in the brain matter.

post updated on 02/28/2019

Introduction(features of human mitochondria)... A feature of the functioning of mitochondria is the presence of their own mitochondrial genome - circular mitochondrial DNA (mtDNA), which contains 37 genes, the products of which are involved in the process of energy production in the respiratory chain of mitochondria. mtDNA is located in the inner membrane of mitochondria and consists of five conjugated enzyme complexes, which in total number 86 subunits. They are mainly encoded by nuclear genes (nDNA), but seven subunits of the first enzyme complex (ND1, 2, 3, 4, 4L, 5, 6), one subunit of the third (cytochrome b), three subunits of the fourth (COI, COII, COIII) and two to five (ATPases 6 and 8) are encoded by structural mtDNA genes. Thus, enzymatic complexes (i.e. proteins) encoded by both nuclear (nDNA) and mitochondrial genes (mtDNA) are involved in ensuring the diverse biochemical functions of mitochondria.

note! The main biochemical processes that are related to energy metabolism and occur in the mitochondria are: the tricarboxylic acid cycle (Krebs cycle), beta-oxidation of fatty acids, the carnitine cycle, electron transport in the respiratory chain, and oxidative phosphorylation. Any of these processes can be disrupted and cause mitochondrial failure.

Cause of mitochondrial disease (hereinafter MB). The main properties of the mitochondrial genome are the cytoplasmic inheritance of genes, the absence of recombinations (i.e., the reorganization of genetic material through the exchange of individual segments, regions, DNA double helices) and a high mutation rate. The mitochondrial genome is characterized by pronounced instability and a high rate of nucleotide substitutions, on average 10 - 17 times higher than the rate of mutation of nuclear genes, and during the life of an individual, somatic mutations often occur in it. The immediate cause of the onset and development of mitochondrial dysfunction lies in defects in the oxidative phosphorylation system, imperfect repair mechanisms, the absence of histones and the presence of free oxygen radicals - byproducts of aerobic respiration.

For mutations of the mitochondrial genome, the phenomenon [ !!! ] heteroplasmy, in which (due to the specificity of mitochondrial inheritance), as a result of cell division, the distribution (varying over a wide range - from 1 to 99%) of mutant mtDNA between daughter cells occurs randomly and unevenly, as a result of which copies of mtDNA carrying normal and / or a mutant allele. In this case, different tissues of the body or adjacent areas of the same tissue may differ in the degree of heteroplasmy, i.e. according to the degree of presence and ratio of mitochondria in the cells of the body with both mutant and normal mtDNA (in subsequent generations, part of the cells may have only normal mtDNA, another part only mutant, and the third part with both types of mtDNA). The content of mitochondria with mutant mtDNA increases gradually. Due to this "lag period" (from the English "lag" - delay), future patients often reach puberty (and give birth to offspring, almost always carrying the same mutations in mtDNA). When the number of mutant copies of mtDNA reaches a certain concentration threshold in the cell, the energy metabolism in the cells is significantly impaired and manifests itself in the form of a disease (note: a feature of hereditary MBs is often the complete absence of any pathological signs at the beginning of a patient's life).

note! Heteroplasmy is characterized by the simultaneous existence of mutant and normal mtDNA in one cell, tissue, organ, which determines the severity, nature and age of MB manifestation. The amount of altered mtDNA can also increase with age under the influence of various factors and gradually reach a level that can cause clinical manifestations of the disease.

In accordance with the aforementioned features of the double mitochondrial genome, the type of MB inheritance can be different. Since mtDNA in the body is almost exclusively of maternal origin, when a mitochondrial mutation is transmitted to offspring in the pedigree, the maternal type of inheritance takes place - all children of a sick mother are sick. If a mutation occurs in a nuclear gene (nDNA) that codes for mitochondrial protein synthesis, the disease is transmitted according to the classical Mendelian laws. Sometimes an mtDNA mutation (usually a deletion) occurs de novo at an early stage of ontogenesis, and then the disease manifests itself as a sporadic case.

note! Currently, more than 100 point mutations and several hundred structural rearrangements of mtDNA are known, associated with characteristic neuromuscular and other mitochondrial syndromes - from lethal in the neonatal period of life to diseases with late onset.

Definition... MBs can be characterized as diseases caused by genetic and structural-biochemical defects of mitochondria and accompanied by impaired tissue respiration and, as a consequence, a systemic defect in energy metabolism, as a result of which the most energy-dependent tissues and target organs are affected in various combinations: the brain, skeletal muscles and myocardium. (mitochondrial encephalomyopathies), pancreas, organ of vision, kidneys, liver. Clinically, disorders in these organs can be realized at any age. At the same time, the heterogeneity of symptoms complicates the clinical diagnosis of these diseases. The need to exclude MB arises in the presence of multisystem manifestations that do not fit into the usual pathological process. The frequency of dysfunction of the respiratory chain is estimated from 1 in 5-10 thousand to 4-5 per 100 thousand newborns.

Semiotics... Neuromuscular pathology in MB is usually represented by dementia, seizures, ataxia, optic neuropathy, retinopathy, sensorineural deafness, peripheral neuropathy, myopathy. However, about 1/3 of patients with MB have normal intelligence, and they have no neuromuscular manifestations. MB include, in particular, Kearns-Sayre encephalocardiomyopathy (retinitis pigmentosa, external ophthalmoplegia, complete heart block); MERRF syndrome (myoclonus-epilepsy, "torn" red fibers); (mitochondrial encephalo-myopathy, lactic acidosis, stroke-like episodes); Pearson syndrome (encephalomyopathy, ataxia, dementia, progressive external ophthalmoplegia); NAPR syndrome (neuropathy, ataxia, retinitis pigmentosa); and some forms of ophthalmopathic myopathy. All these forms are united by myopathic syndrome, expressed to one degree or another.

note! The two main clinical signs of MB are the increase over time in the number of organs and tissues involved in the pathological process, as well as the almost inevitable damage to the central nervous system. Polymorphism of clinical manifestations, including damage to organs that at first glance are physiologically and morphologically unrelated, in combination with different periods of manifestation and steady progression of disease symptoms with age, allows one to suspect a [genetic] mtDNA mutation.

note! In clinical practice, the ability to differentiate the clinical picture of MB from the more common somatic, autoimmune, endocrine and other pathological conditions, most of which are treatable, is of great importance. It is necessary to conduct a thorough assessment of family history, data from routine clinical and laboratory-instrumental examination methods, before prescribing specific genetic and biochemical tests aimed at finding mitochondrial pathology in a patient.

Diagnostics ... The diagnostic algorithm for any MB should include the following steps: [ 1 ] identification of a typical clinical picture of mitochondrial syndrome or "unexplained" multisystem lesion and a hereditary history confirming the maternal type of inheritance; [ 2 ] further diagnostic search should be aimed at detecting common markers of mitochondrial dysfunction: an increase in the level of lactate / pyruvate in serum and cerebrospinal fluid, impaired carbohydrate, protein, amino acid metabolism, as well as the clinical picture with the involvement of at least three of these systems in the pathological process: Central nervous system, cardiovascular system, muscular, endocrine, renal, organs of vision and hearing; [ 3 ] in case of clinical and confirmed laboratory and instrumental signs of mitochondrial pathology, PCR analysis of blood lymphocytes is carried out for a targeted search for mtDNA point mutations; a study that is considered the gold standard for the diagnosis of MB [cytopathies] - a biopsy of skeletal muscles with histochemical, electron microscopic, immunological and molecular genetic analyzes, characteristic changes in which will be in any MB (see below); [ 5 ] the most sensitive tests for the diagnosis of MB are methods for assessing the level of heteroplasmy of pathological mtDNA in various organs and tissues: fluorescence PCR, cloning, denaturing high-resolution liquid chromatography, sequencing, Southern blot hybridization, etc.

Histochemical study of muscle biopsies of patients, including staining with trichrome according to the Gomori method, demonstrates changes characteristic of MB - torn red fibers of myofibrils, which contain a large number of proliferating and damaged mitochondria that form agglomerates along the periphery of the muscle fiber. In this case, the amount of torn red fibers in the biopsy should be ≥ 2%. Enzyme-histochemical analysis shows a deficiency of cytochrome-C-oxidase in 2 and 5% of myofibrils (for patients under 50 and over 50 years old) of their total number in biopsies. Histochemical analysis of succinate dehydrogenase (SDH) activity demonstrates SDH-positive staining of myofibrils - ragged blue fibers, which, in combination with SDH-positive staining of the walls of the arteries supplying the muscles, indicates a high degree of damage to the mitochondria of myocytes. When carrying out electron microscopy of muscle biopsies, pathological inclusions, structural rearrangements of mitochondria, changes in their shape, size and number are determined.

note! Despite the significant progress achieved since the discovery of genetic mutations in mtDNA, most of the diagnostic methods used in clinical practice have a low degree of specificity for individual MBs. Therefore, the diagnostic criteria for a particular MB, first of all, consist of a combination of specific clinical and morphological pictures.

Treatment principles ... MB therapy (cytopathies) is exclusively symptomatic in nature and is aimed at reducing the rate of progression of the disease, as well as improving the quality of life of patients. For this purpose, patients are prescribed a standard combination of drugs, including coenzyme Q10, idebenone - a synthetic analogue of CoQ10, creatine, folic acid, vitamins B2, B6, B12 and other drugs that improve redox reactions in cells (drugs that carry electrons in the respiratory chain and cofactors of enzymatic reactions of energy metabolism). These compounds stimulate the synthesis of ATP molecules and reduce the activity of free radical processes in mitochondria. Meanwhile, according to a systematic review, most of the drugs with antioxidant and metabolic effects and used in MB have not been evaluated in large-scale randomized placebo-controlled trials. Therefore, it is difficult to assess the severity of their therapeutic effect and the presence of significant side effects.

More about MB in the following sources:

article "Neuromuscular pathology in mitochondrial diseases" L.А. Saykova, V.G. Pustozerov; St. Petersburg Medical Academy of Postgraduate Education of Roszdrav (journal "Bulletin of the St. Petersburg Medical Academy of Postgraduate Education" 2009) [read];

article "Chronic diseases of non-inflammatory genesis and mutations of the human mitochondrial genome" K.Yu. Mitrofanov, A.V. Zhelankin, M.A. Sazonova, I.A. Sobenin, A. Yu. Postnov; Skolkovo Innovation Center. Research Institute of Atherosclerosis, Moscow; GBOU Scientific Research Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow; Institute of Clinical Cardiology named after AL Myasnikova FGBU RKNPK Ministry of Health and Social Development of the Russian Federation (magazine "Cardiological Bulletin" No. 1, 2012) [read];

article "Mitochondrial DNA and hereditary human pathology" by NS Prokhorova, L.A. Demidenko; Department of Medical Biology, State Institution "Crimean State Medical University named after S.I. Georgievsky ", Simferopol (journal" Tavrichesky medical and biological bulletin "No. 4, 2010) [read];

article "Mitochondrial genome and mitochondrial diseases in humans" I.O. Mazunin, N.V. Volodko, E.B. Starikovskaya, R.I. Sukernik; Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk (journal "Molecular Biology" No. 5, 2010) [read];

article "Perspectives of mitochondrial medicine" by D. B. Zorov, N.K. Isaev, E.Yu. Plotnikov, D.N. Silachev, L. D. Zorova, I.B. Pevzner, M.A. Morosanova, S.S. Yankauskas, S.D. Zorov, V.A. Babenko; Moscow State University M.V. Lomonosov, Institute of Physical and Chemical Biology named after A.N. Belozersky, Research Institute of Mitoengineering, Laser Scientific Center, Faculty of Bioengineering and Bioinformatics; Russian National Research Medical University. N.I. Pirogov (journal "Biochemistry" No. 9, 2013) [read];

article "Strokes in mitochondrial diseases" N.V. Pizova; Department of Nervous Diseases with courses in neurosurgery and medical genetics, Yaroslavl State Medical Academy (journal "Neurology, Neuropsychiatry, Psychosomatics" No. 2, 2012) [read];

article "Diagnostics and prevention of nuclear-encoded mitochondrial diseases in children" E.A. Nikolaev; Research Clinical Institute of Pediatrics, Moscow (journal "Russian Bulletin of Perinatology and Pediatrics" No. 2, 2014) [read];

article "Epilepsy in children with mitochondrial diseases: features of diagnosis and treatment" Zavadenko NN, Kholin AA; GBOU VPO Russian National Research Medical University. N.I. Pirogov, Ministry of Health and Social Development of Russia, Moscow (journal "Epilepsy and paroxysmal states" No. 2, 2012) [read];

article "Mitochondrial pathology and problems of the pathogenesis of mental disorders" V.S. Sukhorukov; Moscow Research Institute of Pediatrics and Pediatric Surgery of Rosmedtechnologies (Journal of Neurology and Psychiatry, No. 6, 2008) [read];

article "Algorithm for the diagnosis of mitochondrial encephalomyopathies" S.N. Illarioshkin (journal "Nervous Diseases" No. 3, 2007) [read];

article "Topical issues of treatment of mitochondrial disorders" V.S. Sukhorukov; FSBI "Moscow Research Institute of Pediatrics and Pediatric Surgery" of the Ministry of Health of Russia (journal "Effective Pharmacotherapy. Pediatrics" No. 4, 2012 [read];

article "Leukoencephalopathy with a predominant lesion of the brain stem, spinal cord and increased lactate in MR spectroscopy (clinical observation)" V.I. Guzeva, E. A. Efet, O. M. Nikolaeva; St. Petersburg Pediatric Medical University, St. Petersburg, Russia (journal "Pediatric Neurosurgery and Neurology" No. 1, 2013) [read];

teaching aid for third-year students of the medical and diagnostic faculty of medical universities "Hereditary mitochondrial diseases" Ugolnik, I. V. Manaenkova; Educational institution "Gomel State Medical University", Department of Pathological Physiology, 2012 [read];

fast: Mitochondrial disease(neurodegeneration) - to the site with 17 links to sources (articles, presentations, etc.).

© Laesus De Liro

Mitochondrial diseases are a diverse group of diseases caused by damage to certain structures in human cells that are essential in converting food into energy. Mitochondrial diseases cause decreased energy production and associated symptoms.

Cells are the building blocks of the human body, microscopic structures that are associated with a membrane and contain numerous components - organelles that are responsible for functions such as cell reproduction, transport of materials and protein synthesis. Cellular respiration, the process by which food molecules are converted into high-energy molecules for energy, takes place in structures called mitochondria. Mitochondrial energy is essential for all cellular functions.

Until the mid-twentieth century, not much was known about mitochondrial disease. The first diagnosis of mitochondrial disorder was made in 1959, and the mtDNA genetic material was discovered in 1963. In the 70s and 80s of the last century, much more became known about mitochondria, and the group of mitochondrial disorders is expanding to this day. Research in the 90s of the last century led to the classification of mitochondrial diseases.

Common mitochondrial disorders

As of today, there are over forty different mitochondrial disorders. Some of the more common disorders include:

Kearns-Sayre Syndrome (KSS). KSS usually occurs before the age of 20. Symptoms include gradual difficulty in eye movement, drooping eyelids, muscle weakness, short stature, hearing loss, loss of coordination, heart problems, cognitive delays, and diabetes.

Myoclonus epilepsy with torn red fibers (MERRF). MERFF is a mitochondrial syndrome in which a mitochondrial defect as well as a tissue abnormality called "ruptured red fibers" is detected microscopically. Symptoms include seizures, loss of coordination, short stature, build-up of lactic acid in the blood, difficulty in pronunciation, dementia, and muscle weakness.

Mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS). MELAS is a progressive disease, mitochondrial syndrome affects several organ systems, including the central nervous system, heart muscle, skeletal muscle, and the gastrointestinal tract. Symptoms include muscle weakness, stroke, eye muscle paralysis, and cognitive impairment.

Leber hereditary optic neuropathy(LHON). LHON causes progressive vision loss that results in varying degrees of blindness and primarily affects men over the age of 20. Cardiac abnormalities can also occur.

Lee syndrome. This degenerative brain disease is usually diagnosed at a young age. Worsening is often accompanied by symptoms such as seizures, dementia, difficulty feeding and speaking, respiratory dysfunction, heart problems, and muscle weakness. The prognosis is generally poor and death occurs over several years.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The main signs include symptoms that mimic gastrointestinal obstruction and nervous system abnormalities. Other symptoms may include eye muscle paralysis, muscle weakness, loss of coordination, and brain abnormalities.

Pearson's Syndrome. Symptoms usually appear first in childhood, and the characteristics of this rare syndrome are highlighted by pancreatic dysfunction and anemia. Complications - obesity, diarrhea, enlarged liver and other signs.

Neuropathy, ataxia, and retinitis pigmentosa (NARP). Symptoms of this disorder include nervous system disorders, loss of coordination, and progressive loss of vision. It can also lead to developmental delays, dementia, and muscle weakness. Usually occurs during childhood.

Causes of mitochondrial disorders

Although mitochondrial diseases can be caused by damage to mitochondrial genetic material, and thus affect any of the hundreds of chemical reactions required to convert oxygen and nutrients into energy, they all have one thing in common: the ability of mitochondria to generate energy is impaired. Waste from multiple reactions can begin to accumulate in cells and interfere with other chemical reactions, and over time cause further mitochondrial damage.

Inheritance of mitochondrial diseases

In many cases, a mitochondrial disorder is transmitted genetically from parent to child. This can often be useful for determining the type of inheritance. Genetic defects can be passed through nDNA, the genetic material that determines most inherited characteristics, or through mtDNA. Some types of inherited mitochondrial disorders include:

Autosomal recessive inheritance. Every person has two sets of genes, each inherited from one of the parents. In the case of some genetic diseases, a person needs to have two copies of the defective gene in order to show symptoms of the disease; and if only one of the two genes is defective, then the person is considered a carrier. In autosomal recessive inheritance, an individual receives a defective gene from each parent.

Maternal inheritance. MtDNA is only passed from mother to child because the mitochondria of the sperm are in the tail of the sperm, which is not involved in conception. Some mitochondrial disorders, therefore, can only be passed from mother to child.

X-chromosomal recessive inheritance. A baby's gender is determined by inheriting strands of DNA called chromosomes. A female child inherits two X chromosomes, while a male child inherits an X chromosome from one parent and a Y chromosome from the other. If a defective gene encoding a disease is found on the X chromosome, then a male child cannot have a healthy copy of the gene (since he only has one X chromosome); thus, he will have frustration. Girls are less at risk because they must have two copies of the defective gene (one on each X chromosome) for the disease to develop.

Autosomal dominant inheritance. Unlike inheritance in an autosomal recessive manner, only one defective copy of a gene must be inherited for the disorder to develop, so the child has a 50 percent chance of developing the disorder.

In some cases, people without a genetic factor suffer from mitochondrial syndrome. These cases are called accidental or sporadic, and they can be caused by a variety of reasons, including certain medications (such as those used to treat HIV), anorexia, exposure to certain toxins, prolonged periods of oxygen deprivation, or the age of the parents.

Mitochondrial Syndrome Symptoms

Since more than 90 percent of the energy required by the human body is generated by the mitochondria, the effects of mitochondrial disturbances can be far-reaching. Research shows that the brain, nerves, skeletal muscle, liver, heart, kidneys, hearing aid, eyes, and pancreas are particularly affected by high energy requirements. Some of the more common symptoms of mitochondrial disease in organ systems include the following:

Other symptoms include developmental disorders in young children, stunted growth, short stature, fatigue, breathing problems, swallowing problems, and an increased risk of infections.

Diagnosis of mitochondrial diseases

The array of symptoms that appear in children suffering from mitochondrial disorders are common to many other diseases. Often the hallmark of mitochondrial disorder, which distinguishes it from other diseases with similar symptoms, is additional symptoms that usually do not appear in the case of non-mitochondrial disease.

Because of the complex nature of mitochondrial disorders, doctors take multifaceted approaches to diagnosing these conditions. The process usually begins with a comprehensive physical examination, an assessment of the patient's medical and family history. Often, a neurologic examination is done to determine if there are any brain abnormalities. More extensive tests may be performed to diagnose mitochondrial syndrome and rule out other diseases. Some of these testing methods are as follows:

Initial assessment. The first line of testing usually involves the least invasive methods, such as taking a blood sample for evaluation. In some cases, a diagnosis can be made based on blood tests; in others, blood tests may indicate that further testing is needed.

Secondary assessment. These tests can be more intense, more aggressive, and / or more risky. Examples include lumbar puncture, urinalysis, magnetic resonance imaging (MRI), additional blood tests, electrocardiogram (ECG).

Tertiary assessment... Complex and / or invasive procedures such as skin analysis or muscle biopsy. In some cases, tertiary tests are needed to make a definitive diagnosis.

In certain situations, a doctor may not be able to diagnose a patient with a particular mitochondrial disorder, even after careful evaluation. Therefore, it should be borne in mind that, despite the complexity of testing mitochondrial disorders, their diagnosis is not always possible.

Treatment of mitochondrial diseases

There are no specific drugs for treating mitochondrial disorders. The treatment plan focuses primarily on delaying the progression of the disease or reducing the patient's symptoms. Treatment methods depend on many factors, including the type of disease, the person's age, the organs affected, and the state of health. Not all patients benefit from treatment.

Therapy, meanwhile, can consist of courses of vitamins, nutritional supplements, physical or occupational therapy, traditional medicines, for example:

• vitamins such as B vitamins (thiamine, riboflavin, niacin, folic acid, biotin and pantothenic acid), vitamin E, vitamin C,
• coenzyme Q10 (CoQ10), which is involved in cellular respiration in normal mitochondria,
• levocarnitine taken orally or given intravenously
• antioxidant therapy,
• physical or occupational therapy for myopathies.

For some patients, minimizing physiological factors such as extreme cold, high temperatures, poor nutrition, fasting, and lack of sleep can improve their condition. Alcohol, cigarette smoke, and MSG can also worsen mitochondrial disorders.

In some cases, a properly formulated diet is necessary to avoid worsening symptoms. Parents of a child with mitochondrial syndrome should consult a dietitian for an individualized diet. An individualized diet plan may include frequent small meals, increasing or decreasing the amount of fat consumed, and avoiding or supplementing certain vitamins or minerals.

New research

Scientists are looking for drugs to treat mitochondrial diseases. The problem is complicated by the fact that these diseases are very rare: for example, the total number of patients with MELAS does not exceed 60 thousand people worldwide, which makes it unprofitable to develop drugs for such diseases. Despite this, drugs have appeared that are quite effective in combating the manifestations of mitochondrial pathology.

So, for the treatment of Friedreich's ataxia, the drug EPI-743 is used, which has been shown to be effective in several studies. This agent optimizes mitochondrial energy production and reduces redox imbalances.

In the treatment of encephalomyelopathy (MELAS), L-arginine showed a certain positive effect, intravenous and oral administration of which made it possible to reduce the severity of the main symptoms of this disease: headache, nausea with vomiting, visual impairment and consciousness. This was shown in a 9-year study by Japanese scientists.

Prognosis of mitochondrial disorders

The prognosis of an individual mitochondrial disease depends on many factors, including the particular disorder, mode of inheritance, patient's age, and organs affected. For example, two children suffering from the same mitochondrial disease may have two completely different courses of therapy. In some cases, patients may be able to control their symptoms to a large extent by different procedures, or if the progression of the disease is slow. In other cases, the disease progresses rapidly and leads to certain death.

In the case of a child at risk of mitochondrial disorders, parents may be interested in genetic counseling. Genetic testing, however, cannot accurately determine how and when a child may develop mitochondrial disease or how severe it is.

Denial of responsibility: The information provided in this article on mitochondrial diseases is intended to inform the reader only. It cannot be a substitute for the advice of a healthcare professional.

Mitochondrial diseases are a group of hereditary pathologies resulting from disturbances in cellular energy, characterized by polymorphism of clinical manifestations, expressed in the predominant damage to the central nervous system and muscular system, as well as other organs and systems of the body.

An alternative definition of mitochondrial pathology states that this is a wide group of pathological conditions caused by genetic, structural and biochemical defects of mitochondria, impaired tissue respiration and, as a consequence, insufficient energy metabolism.

As A. Munnich points out, "mitochondrial diseases can cause any symptom, in any tissue, at any age, with any type of inheritance."

The mitochondrial respiratory chain is the main endpoint of aerobic metabolism. Therefore, mitochondrial pathology is often called “diseases of the mitochondrial respiratory chain” (MCD); this is a relatively new class of diseases.

Historical aspects of mitochondrial pathology

R. Luft et al. (1962) found a relationship between muscle weakness and impaired oxidative phosphorylation in muscle tissue. S. Nass and M. Nass (1963) discovered the existence of their own genetic apparatus of mitochondria (several copies of the ring chromosome were found). In 1960-1970. the concept of mitochondrial diseases appeared, that is, pathology etiologically mediated by mitochondrial dysfunction. In the 1980s. accurate molecular genetic evidence was obtained for the mitochondrial nature of a number of diseases (Leber's disease, Pearson's syndrome).

Etiopathogenetic aspects of mitochondrial pathology

Depending on the presence of the main metabolic defect, it is customary to consider four main groups of mitochondrial diseases: 1) disorders of pyruvate metabolism; 2) defects in fatty acid metabolism; 3) violations of the Krebs cycle; 4) defects in electron transport and oxidative phosphorylation (OXPHOS).

The causes of mitochondrial pathology are mutations in genes encoding proteins involved in the processes of energy exchange in cells (including subunits of the pyruvate dehydrogenase complex, enzymes of the Krebs cycle, components of the electron transport chain, structural proteins of the electron transport chain (ETC), mitochondrial transporters of the inner membrane, regulators of mitochondrial nucleotid pool, as well as factors that interact with mitochondrial DNA (mtDNA).

Mitochondrial disorders are associated with a large number of diseases other than primary mitochondrial cytopathies. Nevertheless, in these diseases, mitochondrial dysfunctions make a significant contribution to the pathogenesis and clinical manifestations of diseases. The diseases described can be metabolic, degenerative, inflammatory, congenital / acquired malformations, and neoplasms.

The mitochondrion is an organelle that is present in virtually every cell with the exception of mature red blood cells. That is why mitochondrial diseases can affect any system and organ of the human body. In this regard, it is more correct to call these conditions "mitochondrial cytopathies".

The main features of mitochondrial cytopathies include pronounced polymorphism of clinical symptoms, multisystem nature of the lesion, variability of the course, progression and inadequate response to the applied therapy.

The respiratory chain is localized on the inner mitochondrial membrane and includes five multienzyme complexes, each of which, in turn, consists of several dozen subunits. Mitochondrial DNA encodes only 13 of the respiratory chain protein subunits, 2 mtRNA protein subunits, and 22 mitochondrial transport RNA (tRNA). The nuclear genome encodes over 90% of mitochondrial proteins.

The end result of oxidative phosphorylation that occurs in the 1-γ complexes is energy production (ATP). Adenosine triphosphate is the main source of energy for cells.

Mitochondrial DNA interacts closely with nuclear DNA (nDNA). In each of the 5 respiratory complexes, most of the subunits are encoded by nDNA, not mtDNA. Complex I consists of 41 subunits, of which 7 are encoded by mtDNA, and the rest are encoded by nDNA. Complex II has only 4 subunits; most of them are encoded by nDNA. Complex III is represented by ten subunits; mtDNA coding - 1, nDNA - 9. Complex IV has 13 subunits, of which 3 are encoded by mtDNA, and 10 - nDNA. Complex V includes 12 subunits, mtDNA coding - 2, nDNA - 10.

Cellular energy disturbances lead to polysystemic diseases. First of all, organs and tissues that are most energy-dependent are affected: the nervous system (encephalopathy, polyneuropathy), the muscular system (myopathy), the heart (cardiomyopathy), kidneys, liver, endocrine system and other organs and systems. Until recently, all these diseases were defined under numerous masks of other nosological forms of pathology. To date, more than 200 diseases have been identified, the cause of which is mitochondrial DNA mutations.

Mitochondrial diseases can be caused by abnormalities in both the mitochondrial and nuclear genomes. As P. F. Chinnery et al. (2004) and S. DiMauro (2004), mtDNA mutations were detected in 1 case per 8000 population, and the prevalence of mitochondrial diseases is about 11.5 cases per 100 thousand population.

Each cell contains from several hundred to several thousand organelles - mitochondria, containing from 2 to 10 circular mitochondrial DNA molecules capable of replication, transcription and translation, regardless of nuclear DNA.

Genetic aspects of mitochondrial pathology

Mitochondrial genetics differs from classical Mendelian genetics in three important aspects: 1) maternal inheritance (the entire cytoplasm, together with the organelles in it, are received by the descendants together with the egg); 2) heteroplasmy - the simultaneous existence in the cell of normal (wild) and mutant types of DNA; 3) mitotic segregation (both types of mtDNA during cell division can be distributed randomly between daughter cells).

Mitochondrial DNA accumulates mutations more than 10 times faster than the nuclear genome, since it lacks protective histones and its environment is extremely rich in reactive oxygen species, which are a byproduct of metabolic processes in mitochondria. The proportion of mutant mtDNA must exceed a critical threshold level before cells begin to exhibit biochemical abnormalities in mitochondrial respiratory chains (threshold effect). The percentage of mutant mtDNA can vary in individuals within families, as well as in organs and tissues. This is one of the explanations for the variability of the clinical picture in patients with mitochondrial dysfunctions. The same mutations can cause various clinical syndromes (for example, A3243G mutation - encephalopathy with stroke-like paroxysms - MELAS syndrome, as well as chronic progressive external ophthalmoplegia, diabetes mellitus). Mutations in different genes can cause the same syndrome. The classic example of this situation is MELAS syndrome.

Varieties of mitochondrial pathology

If we list the main mitochondrial diseases, then among them will be the following: mitochondrial neurogastrointestinal encephalopathy (MNGIE), syndrome of multiple deletions of mitochondrial DNA, lipid myopathy with normal carnitine levels, carnitine palmitoyltransferase deficiency, mitochondrial Alperoxide mellitus Syndrome , Leber's disease (LHON), Wolfram syndrome, MEMSA syndrome, Pearson syndrome, SANDO syndrome, MIRAS syndrome, MELAS syndrome, MERRF syndrome, SCAE syndrome, NARP syndrome, Barth syndrome, CPEO syndrome, Lee syndrome, etc.

The following clinical syndromes of mitochondrial pathology are most common in childhood: MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like paroxysms), MERRF syndrome (myoclonus epilepsy with lacerated red fibers), Kearns-Sayr syndrome, pigmented retinitis , ataxia, impaired cardiac conduction), NARP syndrome (neuropathy, ataxia, retinitis pigmentosa), Lee syndrome (subacute necrotizing encephalomyelopathy), Leber's disease (hereditary optic neuropathy).

There is a large pool of diseases that are caused not by mutations in mitochondrial DNA, but by mutations in nuclear DNA that encodes the work of mitochondria. These include the following types of pathology: Barth's disease (myopathy, cardiomyopathy, transient neutro- and thrombocytopenia), mitochondrial gastrointestinal encephalopathy (autosomal recessive multisystem disease): ptosis, ophthalmoplegia, peripheral neuropathy, gastrointestinal causation, adductal leukemia The age of the onset of the latter disease is highly variable - from the neonatal period to 43 years.

Diagnosis of mitochondrial pathology

Clinical criteria for the diagnosis of mitochondrial diseases are relatively numerous: 1) myopathic symptom complex (exercise intolerance, muscle weakness, decreased muscle tone); 2) seizures (myoclonic or multifocal); 3) cerebellar syndrome (ataxia, intentional tremor); 4) damage to the eye-motor nerves (ptosis, external ophthalmoplegia); 5) polyneuropathy; 6) stroke-like paroxysms; 7) migraine-like headaches; 8) craniofacial dysmorphia; 9) dysmetabolic manifestations (vomiting, episodes of lethargy, coma); 10) respiratory disorders (apnea, hyperventilation, tachypnea); 11) damage to the heart, liver, kidneys; 12) the progressive course of the disease.

In the diagnosis of mitochondrial diseases, the following clinical criteria are used: 1) signs of connective tissue damage (hypermobility syndrome, skin hyperelasticity, posture disorders, etc.); 2) neurodegenerative manifestations, leukopathies during magnetic resonance imaging (MRI) of the brain; 3) repeated episodes of impaired consciousness or unexplained episodes of vomiting in newborns; 4) unexplained ataxia; 5) mental retardation without specific reasons; 6) burdened family history; 7) sudden deterioration of the child's condition (convulsions, vomiting, respiratory distress, lethargy, weakness, muscle tone disorders - more often muscle hypotension, coma, lethargy; liver and kidney damage that does not respond to conventional therapy).

Laboratory (biochemical) studies are aimed primarily at detecting lactic acidosis and / or pyruvate acidosis in patients. It should be remembered that normal lactic acid levels do not exclude the presence of mitochondrial disease. Other biochemical indicators investigated for suspected mitochondrial pathology include ketone bodies in blood and urine, plasma acylcarnitines, and organic acids and amino acids in blood and urine.

M. V. Miles et al. (2008) proposed to evaluate the content of muscle coenzyme Q10 in children with a defect in the enzymes of the mitochondrial respiratory chain.

Cytomorphodensitometric studies allow assessing the activity of the mitochondria of lymphocytes (decrease in the number, increase in volume, decrease in activity).

From instrumental studies (in addition to neuroimaging methods), skeletal muscle biopsy with specific histochemical reactions is used to detect the phenomenon of "ragged red fibers" (RRF) in the obtained biopsy. Torn red fiber syndromes are: MELAS, MERRF, KSS, PEO (progressive external ophthalmoplegia), and Pearson's syndrome. Syndromes without RRF: Leigh disease, NARP, LHON (Leber hereditary optic neuropathy).

Genetic research methods are reduced to determining the most frequent mutations and sequencing of mitochondrial DNA.

Treatment of mitochondrial pathology

Unfortunately, therapies for mitochondrial diseases have not been developed. From the standpoint of evidence-based medicine, it is believed that there is no effective treatment for this representative group of diseases. Nevertheless, in various countries of the world, pharmacological agents and biologically active substances are used, aimed at normalizing metabolism and providing adequate energy for mitochondria.

In the case of MELAS syndrome, treatment should be aimed at treating seizures, endocrine disorders, and eliminating the consequences of a stroke.

P. Kaufmann et al. (2006) indicate that since lactate levels often correlate with the severity of neurological manifestations, it is advisable to use dichloroacetate to reduce lactate levels. In our country, dimet(Dimephosphon) is used for a similar purpose.

In the studies of Japanese authors Y. Koga et al. (2002, 2005, 2006, 2007) intravenous administration of L-arginine (a precursor of NO) was used with good effect to stimulate vasodilation in the acute period of stroke, as well as its oral administration to reduce the severity of subsequent episodes.

Among the drugs used in the treatment of mitochondrial pathology, the following appear: vitamin B 1 (thiamine) - 400 mg / day, vitamin B 2 (riboflavin) - 100 mg / day, vitamin C (ascorbic acid) - up to 1 g / day, vitamin E (tocopherol) - 400 IU / day, nicotinamide (niacin) - up to 500 mg / day, coenzyme Q 10 - from 90 to 200 mg / day, L-carnitine - from 10 mg to 1-2 g / day, succinic acid - from 25 mg to 1.5 g / day, Dimephosphone 15% - 1.0 ml per 5 kg of body weight. Cytochrome C (intravenous), Reamberin (intravenous) and Cytoflavin (intravenous and oral) are also used.

Other drugs of pharmacotherapy are corticosteroids, mineralocorticoids (with the development of adrenal insufficiency), anticonvulsants - for seizures / epilepsy (excluding valproic acid and its derivatives, limiting the use of barbiturates). In our observations, the most effective anticonvulsant therapy was the use of drugs levetiracetam (Keppra), topiramate (Topamax), or their combinations.

Neurodietology for mitochondrial pathology

The main principle of the diet in mitochondrial pathology is the restriction of nutrients that have a negative effect on metabolic mechanisms - until the formation of a metabolic block (the diet is simultaneously enriched with other components at a normal or increased level). This therapeutic strategy is called going around the block. An important exception in this regard is the group of mitochondrial disorders associated with pyruvate metabolism (deficiency of the pyruvate dehydrogenase complex with concomitant carbohydrate / glycogen / amino acid disorders). That being said, a ketogenic diet and other types of high-fat diets are recommended.

Substances that are food cofactors are widely used (coenzyme Q 10, L-carnitine, acetyl-L-carnitine, vitamin B2, ascorbic acid, vitamin E, vitamin B 1, nicotinamide, vitamin B 6, vitamin B 12, biotin, folic acid , vitamin K, α-lipoic acid, succinic acid, Se). It is recommended to avoid individual nutritional factors that induce exacerbation of mitochondrial disease (fasting, consumption of fats, proteins, sucrose, starch, alcohol, caffeine, monosodium glutamate; quantitative eating disorders and inadequate intake of food energy). If necessary, clinical nutrition is carried out (enteral, parenteral, gastrostomy).

Timely diagnosis of mitochondrial diseases, the search for clinical and paraclinical criteria for these diseases at the preliminary, pregenetic stage are extremely important. This is necessary for the selection of adequate metabolic therapy and prevention of deterioration or disability in patients with these rare diseases.

C. S. Chi (2015) emphasizes that confirmation or exclusion of mitochondrial pathology remains fundamental in pediatric practice, especially when the clinical signs of the disease are not specific, as a result of which a follow-up approach to assessing symptoms and biochemical parameters is required.

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V. M. Studenikin *, 1,Doctor of Medical Sciences, Professor, Academician of RAE
O. V. Globa **,Candidate of Medical Sciences

* GOU VPO RNIMU them. N.I. Pirogova, Ministry of Health of the Russian Federation, Moscow
** GOU VPO PMGMU them. I.M.Sechenov, Ministry of Health of the Russian Federation, Moscow

Mitochondrial pathology and problems of the pathogenesis of mental disorders

V.S. Sukhorukov

The mitochondrial pathology and problems of pathophysiology of mental disorders

V.S. Sukhorukov
Moscow Research Institute of Pediatrics and Pediatric Surgery of Rosmedtechnologies

Over the past decades, a new direction has been actively developing in medicine, associated with the study of the role of cellular energy metabolism disorders - processes affecting universal cellular organelles - mitochondria. In this regard, the concept of "mitochondrial diseases" appeared.

Mitochondria perform many functions, but their main task is the formation of ATP molecules in the biochemical cycles of cellular respiration. The main processes occurring in mitochondria are the tricarboxylic acid cycle, fatty acid oxidation, carnitine cycle, transport of electrons in the respiratory chain (using I-IV enzyme complexes) and oxidative phosphorylation (V enzyme complex). Mitochondrial dysfunctions are among the most important (often early) stages of cell damage. These disorders lead to insufficient energy supply to cells, disruption of many other important metabolic processes, further development of cellular damage up to cell death. For the clinician, the assessment of the degree of mitochondrial dysfunction is essential both for the formation of ideas about the nature and extent of the processes occurring at the tissue level, and for the development of a plan for therapeutic correction of the pathological condition.

The concept of "mitochondrial diseases" was formed in medicine at the end of the twentieth century due to the recently discovered hereditary diseases, the main etiopathogenetic factors of which are mutations of genes responsible for the synthesis of mitochondrial proteins. First of all, diseases associated with mutations of mitochondrial DNA discovered in the early 60s were studied. This DNA, which has a relatively simple structure and resembles the ring chromosome of bacteria, has been studied in detail. The complete primary structure of human mitochondrial DNA (mitDNA) was published in 1981), and already in the late 1980s, the leading role of its mutations in the development of a number of hereditary diseases was proved. The latter include hereditary atrophy of Leber optic nerves, NARP syndrome (neuropathy, ataxia, retinitis pigmentosa), MERRF syndrome (myoclonus epilepsy with "torn" red fibers in skeletal muscles), MELAS syndrome (mitochondrial encephalomyopathy, lodactate-adenopathy) Kearns-Sayre syndrome (retinitis pigmentosa, external ophthalmoplegia, heart block, ptosis, cerebellar syndrome), Pearson's syndrome (bone marrow damage, pancreatic and hepatic dysfunction), etc. The number of descriptions of such diseases is increasing every year. According to the latest data, the cumulative incidence of hereditary diseases associated with mitDNA mutations reaches 1: 5000 people in the general population.

To a lesser extent, hereditary mitochondrial defects associated with damage to the nuclear genome have been studied. To date, relatively few of them are known (various forms of infant myopathies, diseases of Alpers, Leigh, Barth, Menkes, carnitine deficiency syndromes, some enzymes of the Krebs cycle and the mitochondrial respiratory chain). It can be assumed that their number should be much larger, since the genes encoding information in 98% of mitochondrial proteins are located in the nucleus.

In general, we can say that the study of diseases caused by hereditary disorders of mitochondrial functions has made a kind of revolution in modern concepts of the medical aspects of human energy metabolism. In addition to the contribution to theoretical pathology and medical systematics, one of the main achievements of medical "mitochondriology" was the creation of effective diagnostic tools (clinical, biochemical, morphological and molecular genetic criteria for polysystemic mitochondrial insufficiency), which made it possible to assess polysystemic disorders of cellular energy exchange.

As for psychiatry, already in the 30s of the twentieth century, data were obtained that patients with schizophrenia after physical exertion sharply increase the level of lactic acid. Later, in the form of a formalized scientific hypothesis, the postulate appeared that some mechanisms regulating energy exchange are responsible for the absence of "psychic energy" in this disease. However, for quite a long time such assumptions were perceived as, to put it mildly, "unpromising from a scientific point of view." In 1965 S. Kety wrote: "It is difficult to imagine that a generalized defect in energy metabolism - a process that is fundamental for every cell in the body - could be responsible for highly specialized features of schizophrenia." Nevertheless, the situation changed over the next 40 years. The successes of "mitochondrial medicine" were so convincing that they began to attract the attention of a wider circle of doctors, including psychiatrists. The result of a consistent increase in the number of relevant studies was summed up in the work of A. Gardner and R. Boles "Does" Mitochondrial Psychiatry "Have a Future?" ... The interrogative form of the postulate in the title carried a tinge of exaggerated modesty. The amount of information given in the article was so great, and the authors' logic was so flawless that there was no need to doubt the promising nature of "mitochondrial psychiatry".

To date, there are several groups of evidence for the participation of disturbances in energy processes in the pathogenesis of mental illness. Each of the groups of evidence is discussed below.

Mental Disorders in Mitochondrial Diseases

Differences in the threshold tissue sensitivity to the deficiency of ATP production leaves a significant imprint on the clinical picture of mitochondrial diseases. In this respect, the nervous tissue is primarily of interest as the most energy-dependent. From 40 to 60% of the ATP energy in neurons is spent on maintaining the ion gradient on their outer shell and transferring the nerve impulse. Therefore, dysfunctions of the central nervous system in classic "mitochondrial diseases" are of paramount importance and give reason to call the main symptom complex "mitochondrial encephalomyopathies". Clinically, the focus was on such brain disorders as mental retardation, seizures, and stroke-like episodes. The severity of these forms of pathology in combination with severe somatic disorders can be so great that other, milder disorders associated, in particular, with personal or emotional changes, remain in the shadows.

The accumulation of information about mental disorders in mitochondrial diseases began to occur in comparison with the above disorders much later. Nevertheless, there is now sufficient evidence of their existence. Depressive and bipolar affective disorders, hallucinations, and personality changes have been described in Kearns-Sayre syndrome, MELAS syndrome, chronic progressive external ophthalmoplegia, and Leber's hereditary optic neuropathy.

Quite often, the development of classic signs of mitochondrial disease is preceded by moderate mental disorders. Therefore, patients can initially be seen by psychiatrists. In these cases, other symptoms of mitochondrial disease (photophobia, vertigo, fatigue, muscle weakness, etc.) are sometimes regarded as psychosomatic disorders. The renowned researcher of mitochondrial pathology P. Chinnery in an article written jointly with D. Turnbull points out: “Psychiatric complications are constantly associated with mitochondrial disease. They usually take the form of reactive depression ... We have repeatedly observed cases of severe depression and suicidal attempts even before (italics of the authors of the article), as the diagnosis was made. "

Difficulties in establishing the true role of mental disorders in the diseases under consideration are also associated with the fact that psychiatric symptoms and syndromes can be regarded in some cases as a reaction to a difficult situation, in others - as a consequence of organic brain damage (in the latter case, the term "psychiatry" in general not used).

Based on the materials of a number of reviews, we present a list of mental disorders described in patients with proven forms of mitochondrial diseases 1. These violations can be divided into three groups. I. Psychotic disorders - hallucinations (auditory and visual), symptoms of schizophrenia and schizophrenic states, delirium. In some cases, these disorders follow progressive cognitive impairment. II. Affective and anxiety disorders - bipolar and unipolar depressive states (they are described most often), panic states, phobias. III. Cognitive impairment in the form of attention deficit hyperactivity disorder. This syndrome has been described not only in patients diagnosed with mitochondrial disease, but also in their relatives. In particular, a case is described when a disease, which was based on the deletion of one nucleotide pair of mitDNA in the region of the transport RNA gene, first manifested itself in a boy in school years in the form of attention deficit hyperactivity disorder. The progression of mitochondrial encephalomyopathy led to the death of this patient at the age of 23 years. IV. Personality disorders. Such disorders have been described in a number of cases with a diagnosis confirmed by molecular genetic studies. Typically, personality disorders develop after cognitive impairment. A case of autism in a patient with a point mutation of mitDNA in the region of the transport RNA gene is described.

Common signs of mitochondrial and mental illness

We are talking about a certain clinical similarity of some mental diseases and mitochondrial syndromes, as well as the general types of their inheritance.

First of all, attention is drawn to the data on the prevalence of cases of maternal inheritance of certain mental diseases, in particular bipolar disorders. Such inheritance cannot be explained from the standpoint of autosomal mechanisms, and the equal number of men and women among patients with bipolar disorders makes it unlikely that X-linked inheritance is possible in this case. The most adequate explanation for this may be the concept of transmission of hereditary information through mitDNA. There is also a tendency towards maternal inheritance in schizophrenic patients. True, in this respect there is an alternative explanation used in our context: it is assumed that this tendency may be due to unequal conditions of patients of different sexes in search of a partner.

An indirect confirmation of the connection between mitochondrial and some mental diseases is also the tendency to the cyclical nature of their clinical manifestations. This is common knowledge for diseases such as bipolar disorder. However, at present, data on ultra-, circadian and seasonal rhythms of clinical manifestations of dysenergetic states are beginning to accumulate in mitochondriology. This feature even determined the name of one of their nosological mitochondrial cytopathies - "cyclic vomiting syndrome".

Finally, the considered similarity of the two groups of diseases appears in their accompanying somatic signs. Psychosomatic symptoms well known to psychiatrists, such as hearing impairment, muscle pain, fatigue, migraines, irritable bowel syndrome, are constantly described in the symptom complex of mitochondrial diseases. As A. Gardner and R. Boles write, “if mitochondrial dysfunction is one of the risk factors for the development of certain psychiatric diseases, these comorbid somatic symptoms may rather be a consequence of mitochondrial dysfunction, rather than a manifestation of“ communicative distress ”,“ hypochondrial pattern ”or“ secondary gain ”. Sometimes such terms are used to refer to the phenomenon of somatization of mental disorders.

In conclusion, we point out one more similarity: an increase in white matter density determined by magnetic resonance imaging is noted not only in bipolar affective disorders and major depression with a late onset, but also in cases of ischemic changes in mitochondrial encephalopathies.

Signs of mitochondrial dysfunction in mental illness

Schizophrenia

As mentioned above, mentions of signs of lactic acidosis and some other biochemical changes, indicating a violation of energy metabolism in schizophrenia, began to appear in the 30s of the twentieth century. But only starting from the 90s, the number of relevant works began to grow especially noticeably, and the methodological level of laboratory research also increased, which was reflected in a number of review publications.

On the basis of the published works D. Ben-Shachar and D. Laifenfeld divided all the signs of mitochondrial disorders in schizophrenia into three groups: 1) morphological disorders of mitochondria; 2) signs of a violation of the oxidative phosphorylation system; 3) violation of the expression of genes responsible for mitochondrial proteins. This division can be supported by examples from other works.

Autopsy of the brain tissue of patients with schizophrenia L. Kung and R. Roberts revealed a decrease in the number of mitochondria in the frontal cortex, caudate nucleus and shell. At the same time, it was noted that it was less pronounced in patients receiving antipsychotics, in connection with which the authors considered it possible to talk about the normalization of mitochondrial processes in the brain under the influence of neuroleptic therapy. This gives grounds to mention the article by N.S. Kolomeets and N.A. Uranium on mitochondrial hyperplasia in the presynaptic terminals of axons in the substantia nigra in schizophrenia.

L. Cavelier et al. Examining autopsy material from the brain of patients with schizophrenia revealed a decrease in the activity of the IV complex of the respiratory chain in the caudate nucleus.

The results presented made it possible to suggest a primary or secondary role of mitochondrial dysfunction in the pathogenesis of schizophrenia. However, the autopsy material examined belonged to patients treated with antipsychotics, and, naturally, mitochondrial disorders were associated with drug exposure. Note that such assumptions, often not unfounded, accompany the entire history of the detection of mitochondrial changes in various organs and systems in mental and other diseases. As for the possible influence of the neuroleptics themselves, it should be recalled that the tendency to lactic acidosis in patients with schizophrenia was discovered as early as 1932, almost 20 years before their appearance.

A decrease in the activity of various components of the respiratory chain was found in the frontal and temporal cortex, as well as in the basal ganglia of the brain and other tissue elements - platelets and lymphocytes of schizophrenic patients. This made it possible to speak about the polysystemic nature of mitochondrial insufficiency. S. Whatley et al. , in particular, they showed that in the frontal cortex the activity of the IV complex decreases, in the temporal cortex - the I, III and IV complexes; in the basal ganglia - I and III complexes, no changes were found in the cerebellum. It should be noted that in all areas studied, the activity of the intramitochondrial enzyme, citrate synthase, corresponded to the control values, which gave grounds to speak of the specificity of the results obtained for schizophrenia.

In addition to the studies considered, one can cite the carried out in 1999-2000. J. Prince et al. who studied the activity of respiratory complexes in different parts of the brain of schizophrenic patients. These authors did not find signs of changes in the activity of complex I, however, the activity of complex IV was reduced in the caudate nucleus. The latter, as well as the activity of complex II, was increased in the shell and in the nucleus accumbens. Moreover, the increase in the activity of complex IV in the shell significantly correlated with the severity of emotional and cognitive dysfunction, but not with the degree of motor disorders.

It should be noted that the authors of most of the above works explained the signs of energy metabolism disorders by the effect of neuroleptics. In 2002, very interesting data in this regard were published by A. Gardner et al. on mitochondrial enzymes and ATP production in muscle biopsies from schizophrenic patients treated with antipsychotics and not treated with them. They found that a decrease in the activity of mitochondrial enzymes and ATP production was found in 6 out of 8 patients who did not receive antipsychotics, and an increase in ATP production was found in patients on antipsychotic therapy. These data to a certain extent confirmed the conclusions made earlier in the work of L. Kung and R. Roberts.

In 2002, the results of another notable work were published. It studied the activity of complex I of the respiratory chain in platelets of 113 schizophrenic patients in comparison with 37 healthy ones. The patients were divided into three groups: 1st - with an acute psychotic episode, 2nd - with a chronic active form, and 3rd - with residual schizophrenia. The results showed that the activity of complex I was significantly increased in comparison with the control in patients of groups 1 and 2 and decreased in patients in group 3. Moreover, a significant correlation was found between the obtained biochemical parameters and the severity of clinical symptoms of the disease. Similar changes were obtained when studying the RNA and protein of the flavoprotein subunits of complex I in the same material. The results of this study thus not only confirmed the high likelihood of polysystemic mitochondrial failure in schizophrenia, but also allowed the authors to recommend appropriate laboratory methods for monitoring the disease.

After 2 years in 2004, D. Ben-Shachar et al. published interesting data on the effect of dopamine on the respiratory chain of mitochondria, which is assigned a significant role in the pathogenesis of schizophrenia. It was found that dopamine can inhibit the activity of complex I and ATP production. In this case, the activity of complexes IV and V does not change. It turned out that, unlike dopamine, norepinephrine and serotonin do not affect ATP production.

Remarkable is the emphasis made in the above studies on the dysfunction of complex I of the mitochondrial respiratory chain. This kind of change may reflect relatively moderate disturbances in mitochondrial activity, which are more significant from the point of view of functional regulation of energy exchange than gross (close to lethal for the cell) drops in cytochrome oxidase activity.

Let us now briefly dwell on the genetic aspect of mitochondrial pathology in schizophrenia.

In 1995-1997 L. Cavelier et al. it was found that the level of "normal deletion" of mitDNA (the most common deletion of 4977 base pairs, affecting the genes of subunits I, IV and V of the complexes and underlying several severe mitochondrial diseases, such as Kearns-Sayre syndrome, etc.) is not changed in autopsy material of the brain of patients with schizophrenia, does not accumulate with age and does not correlate with altered cytochrome oxidase activity. By sequencing the mitochondrial genome in schizophrenic patients, the researchers of this group showed the presence of different from the control polymorphism of the cytochrome b gene.

In these years, a series of works by R. Marchbanks et al. Was also published. who studied the expression of both nuclear and mitochondrial RNA in the frontal cortex in cases of schizophrenia. They found that all quantitatively increased sequences compared to control were related to mitochondrial genes. In particular, the expression of the mitochondrial gene of the 2nd subunit of cytochrome oxidase was significantly increased. Four other genes were associated with mitochondrial ribosomal RNA.

Japanese researchers, examining 300 cases of schizophrenia, found no signs of the 3243AG mutation (causing a disorder in complex I in MELAS syndrome). No increased mutational frequency was found in the mitochondrial genes of the 2nd subunit of complex I, cytochrome b and mitochondrial ribosomes in schizophrenia in the work of K. Gentry and V. Nimgaonkar.

R. Marchbanks et al. discovered a mutation in 12027 of the mitDNA nucleotide pair (gene of the 4th subunit of complex I), which was present in men with schizophrenia and which was not in women.

The characteristics of the three nuclear genes of complex I were studied in the prefrontal and visual cortex of schizophrenic patients by R. Karry et al. ... They found that transcription and translation of some subunits was decreased in the prefrontal cortex and increased in the visual (the authors interpreted these data in accordance with the concept of "hypofrontality" in schizophrenia). The study of genes (including genes for mitochondrial proteins) in the hippocampal tissue in patients treated with antipsychotics with schizophrenia did not reveal any changes.

Japanese researchers K. Iwamoto et al. Studying changes in the genes responsible for hereditary information for mitochondrial proteins in the prefrontal cortex in schizophrenia in connection with treatment with antipsychotics, obtained evidence in favor of a drug effect on cellular energy metabolism.

The above results can be supplemented by data from intravital studies, which were reviewed by W. Katon et al. : when studying the distribution of the phosphorus isotope 31P using magnetic resonance spectroscopy, a decrease in the level of ATP synthesis in the basal ganglia and temporal lobe of the brain of patients with schizophrenia was revealed.

Depression and bipolar disorder

Japanese researchers T. Kato et al. Magnetic resonance spectroscopy showed a decrease in intracellular pH and in the level of phosphocreatine in the frontal lobe of the brain in patients with bipolar disorders, including those who did not receive treatment. By the same authors, a decrease in the level of phosphocreatine in the temporal lobe was found in patients resistant to lithium therapy. Other authors have found a decrease in ATP levels in the frontal lobe and basal ganglia of patients with major depression. Note that similar symptoms were observed in patients with some mitochondrial diseases.

As for the molecular genetic data, it should be noted right away that the results of a number of studies indicate that there is no evidence of the involvement of mitDNA deletions in the development of mood disorders.

A number of studies of mitDNA polymorphism, in addition to the very fact of difference in its haplotypes in patients with bipolar disorders and subjects from the control group, revealed some mutations characteristic of the former, in particular, in positions 5178 and 10398 - both positions are located in the zone of genes of complex I.

There are reports of the presence of mutations in the genes of complex I, and not only in mitochondrial, but also in nuclear. Thus, in cultures of lymphoblastoid cells obtained from patients with bipolar disorders, a mutation was found in the NDUFV2 gene, localized on chromosome 18 (18p11), and encoding one of the subunits of complex I. Sequencing of mitDNA in patients with bipolar disorders revealed a characteristic mutation in position 3644 of the ND1 subunit gene, also belonging to complex I. An increase in the level of translation (but not transcription) was found for some subunits of complex I in the visual cortex of patients with bipolar disorders. Among other studies, we cite two works in which the genes of the respiratory chain were investigated and their molecular genetic disorders were found in the prefrontal cortex and hippocampus of patients with bipolar disorders. In one of the works of A. Gardner et al. in patients with major depression, a number of mitochondrial enzyme disorders and a decrease in the level of ATP production in musculoskeletal tissue were revealed, while a significant correlation was found between the degree of decrease in ATP production and clinical manifestations of mental disorder.

Other mental disorders

There is little research into mitochondrial dysfunction in other mental disorders. Some of them were mentioned in the previous sections of the review. Here we specially mention the work of P. Filipek et al. , in which 2 children with autism and a mutation on chromosome 15, in the 15q11-q13 region, were described. Both children showed moderate motor developmental delay, lethargy, severe hypotension, lactic acidosis, decreased activity of complex III, and mitochondrial hyperproliferation in muscle fibers. This work is notable for the fact that it was the first to describe mitochondrial disorders in the symptom complex of a disease etiologically associated with a specific region of the genome.

Genealogical data on the possible role of mitochondrial disorders in the pathogenesis of mental illness

Above, we have already mentioned such a feature of a number of mental illnesses as an increased frequency of cases of maternal inheritance, which may indirectly indicate the participation of mitochondrial pathology in their pathogenesis. However, there is also more convincing evidence of the latter in the literature.

In 2000, the data obtained by F. McMahon et al. Were published. who sequenced the entire mitochondrial genome in 9 unrelated probands, each of whom came from a large family with maternal transmission of bipolar disorders. There were no obvious differences in haplotypes compared to control families. However, for some positions of mitDNA (709, 1888, 10398, and 10463), a disproportion between sick and healthy was found. At the same time, we can note the coincidence of the data on position 10398 with the already mentioned data of the Japanese authors, who suggested that the 10398A polymorphism of mitDNA is a risk factor for the development of bipolar disorders.

The most significant genealogical evidence of the role of mitochondrial dysfunctions in the development of mental disorders is the fact that patients with classical mitochondrial diseases have relatives (more often on the maternal side) with moderate mental disorders. Anxiety and depression are frequently mentioned among these disorders. So, in the work of J. Shoffner et al. it was found that the severity of depression in mothers of "mitochondrial" patients is 3 times higher than in the control group.

Noteworthy is the work of B. Burnet et al. , who for 12 months conducted anonymous survey of patients with mitochondrial diseases, as well as their family members. Among the questions were those related to the health status of the parents and close relatives of patients (on the paternal and maternal side). Thus, 55 families (group 1) with a putative maternal and 111 families (group 2) with a putative non-maternal mode of mitochondrial disease inheritance were studied. As a result, relatives of patients on the maternal side, in comparison with the paternal side, were found to have a higher frequency of several pathological conditions. Among them, along with migraines and irritable bowel syndrome, there was depression. In group 1, intestinal dysfunction, migraine and depression were observed in a greater percentage of mothers from the surveyed families - 60, 54 and 51%, respectively; in group 2 - in 16, 26 and 12%, respectively (p<0,0001 для всех трех симптомов). У отцов из обеих групп это число составляло примерно 9-16%. Достоверное преобладание указанных признаков имело место и у других родственников по материнской линии. Этот факт является существенным подтверждением гипотезы о возможной связи депрессии с неменделевским наследованием, в частности с дисфункцией митохондрий.

Pharmacological aspects of mitochondrial pathology in mental illness

The effect of drugs used in psychiatry on mitochondrial function

In the previous sections of the review, we have already briefly touched upon the issues of therapy. In particular, the question of the possible effect of antipsychotics on mitochondrial functions was discussed. It was found that chlorpromazine and other phenothiazine derivatives, as well as tricyclic antidepressants, can affect energy metabolism in the brain tissue: they can reduce the level of oxidative phosphorylation in certain parts of the brain, are able to uncouple oxidation and phosphorylation, reduce the activity of complex I and ATPase, and reduce the level of utilization ATP. However, the interpretation of the facts in this area requires great care. Thus, the uncoupling of oxidation and phosphorylation under the influence of neuroleptics was noted by no means in all areas of the brain (it is not determined in the cortex, thalamus and caudate nucleus). In addition, there are experimental data on the stimulation of mitochondrial respiration by antipsychotics. In the previous sections of the review, we also cite works showing the positive effect of antipsychotics on mitochondrial function.

Carbamazepine and valproate are known for their ability to suppress mitochondrial function. Carbamazepine leads to an increase in the level of lactate in the brain, and valproate is able to inhibit the processes of oxidative phosphorylation. The same kind of effects (albeit only in high doses) were revealed in an experimental study of serotonin reuptake inhibitors.

Lithium, which is widely used in the treatment of bipolar disorders, also appears to have a positive effect on cellular energy metabolism. It competes with sodium ions by participating in the regulation of calcium pumps in mitochondria. A. Gardner and R. Boles in their review cite the words of T. Gunter, a well-known specialist in the metabolism of calcium in mitochondria, who believes that lithium "can affect the rate at which this system adapts to different conditions and different needs for ATP." In addition, lithium is believed to decrease the activation of the apoptotic cascade.

A. Gardner and R. Boles cite in the mentioned review a lot of indirect clinical evidence of a positive effect of psychotropic drugs on symptoms, presumably dependent on dysenergetic processes. Thus, intravenous administration of chlorpromazine and other antipsychotics reduces migraine headaches. The efficacy of tricyclic antidepressants in the treatment of migraine, cyclic vomiting syndrome and irritable bowel syndrome is well known. Carbamazepine and valproate are used in the treatment of neuralgias and other pain syndromes, including migraines. Lithium and serotonin reuptake inhibitors are also effective in treating migraines.

Analyzing the above rather contradictory information, we can conclude that psychotropic drugs are undoubtedly capable of influencing the processes of energy exchange in the brain and mitochondrial activity. Moreover, this influence is not unambiguously stimulating or inhibiting, but rather “regulating”. At the same time, it can be different in the neurons of different parts of the brain.

The foregoing suggests that the lack of energy in the brain, perhaps, concerns primarily the areas especially affected by the pathological process.

The effectiveness of energotropic drugs for mental disorders

In the aspect of the problem under consideration, it is important to obtain evidence of a decrease or disappearance of the psychopathological components of mitochondrial syndromes.

In this aspect, the report of T. Suzuki et al. about a patient with schizophrenia-like disorders on the background of MELAS syndrome. After the application of coenzyme Q10 and nicotinic acid, the patient's mutism disappeared for several days. There is also a study that provides evidence of the successful use of dichloroacetate (often used in "mitochondrial medicine" to lower lactate levels) in a 19-year-old man with MELAS for its effects on delirium with auditory and visual hallucinations.

The literature also contains a description of the history of a patient with MELAS syndrome with identified point mutation 3243 in mitDNA. This patient developed psychosis with auditory hallucinations and persecutory delusions, which was controlled within a week with low doses of haloperidol. Later, however, he developed mutism and affective dullness, which did not respond to treatment with haloperidol, but disappeared after treatment for a month with idebenone (a synthetic analogue of coenzyme Q10) at a dose of 160 mg / day. In another patient with MELAS syndrome, coenzyme Q10 at a dose of 70 mg / day helped to cope with persecution mania and aggressive behavior. The success of the use of coenzyme Q10 in the treatment of MELAS syndrome has also been established at work: we are talking about a patient in whom not only stroke-like episodes were prevented, but also relieved of headaches, tinnitus and psychotic episodes.

There are also reports on the effectiveness of energotropic therapy in patients with mental illness. Thus, a 23-year-old patient with a therapeutically resistant depression was described, the severity of which significantly decreased after 2-month use of coenzyme Q10 at a dose of 90 mg per day. A similar case is described in the work. The use of carnitine in combination with energy metabolism cofactors has been shown to be effective in the treatment of autism.

Thus, in the modern literature there is some evidence of a significant role of mitochondrial disorders in the pathogenesis of mental disorders. Note that in this review we did not dwell on neurodegenerative diseases of the elderly, for most of which the importance of mitochondrial disorders has already been proven, and their consideration requires a separate publication.

Based on the data presented, it can be argued that there is a need to unite the efforts of psychiatrists and specialists dealing with mitochondrial diseases, aimed both at studying the dysenergetic foundations of disorders of higher nervous activity, and analyzing the psychopathological manifestations of diseases associated with disorders of cellular energy exchange. In this aspect, both new diagnostic (clinical and laboratory) approaches and the development of new methods of treatment require attention.

1 It should be noted that among the relevant descriptions, cases with the identified mitDNA mutation 3243AG, a generally recognized cause of the development of MELAS syndrome, occupy a large place.

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