Genetic analysis to confirm the diagnosis of mitochondrial disease. Mitochondrial syndrome in a child. The role of mitochondrial dysfunction in the genesis of cardiomyopathies in children
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, Rosmedtekhnologii
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 that affect universal cell 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, electron transport in the respiratory chain (using enzyme complexes I-IV) and oxidative phosphorylation (enzyme complex V). 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 the therapeutic correction of the pathological condition.
The concept of "mitochondrial diseases" was formed in medicine at the end of the 20th century due to hereditary diseases discovered shortly before, the main etiopathogenetic factors of which are mutations in the genes responsible for the synthesis of mitochondrial proteins. First of all, diseases associated with mutations in mitochondrial DNA discovered in the early 1960s were studied. This DNA, which has a relatively simple structure and resembles the circular 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 80s, the leading role of its mutations in the development of a number of hereditary diseases was proved. The latter include Leber's hereditary optic atrophy, NARP syndrome (neuropathy, ataxia, retinitis pigmentosa), MERRF syndrome (myoclonus epilepsy with "torn" red fibers in skeletal muscles), MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes), 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 frequency 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 infantile myopathies, Alpers's, Ley's, Barth's, Menkes' diseases, syndromes of carnitine deficiency, some enzymes of the Krebs cycle and the respiratory chain of mitochondria). It can be assumed that their number should be much larger, since the genes encoding the information of 98% of mitochondrial proteins are located in the nucleus.
In general, it can be said that the study of diseases caused by hereditary disorders of mitochondrial functions has made a kind of revolution in modern ideas about medical aspects. energy metabolism person. In addition to the contribution to theoretical pathology and medical systematics, one of the main achievements of medical "mitochondriology" was the creation of an effective diagnostic toolkit (clinical, biochemical, morphological and molecular genetic criteria for polysystemic mitochondrial insufficiency), which made it possible to assess polysystemic disorders of cellular energy metabolism.
As for psychiatry, already in the 30s of the twentieth century, data were obtained that in patients with schizophrenia after physical activity the level of lactic acid rises sharply. Later, in the form of a formalized scientific assumption, the postulate appeared that some regulatory mechanisms of energy exchange are responsible for the lack of "mental energy" in this disease. However, for quite a long time such assumptions were perceived as, to put it mildly, “unpromising with scientific point vision." In 1965, S. Kety wrote: "It is difficult to imagine that a generalized defect in energy metabolism - a process that is fundamental to every cell in the body - could be responsible for the highly specialized features of schizophrenia". However, the situation changed in 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 the consistent growth 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 included in the title carried a shade of exaggerated modesty. The amount of information provided in the article was so large, and the logic of the authors was so flawless that there was no longer any doubt about the prospects of "mitochondrial psychiatry".
To date, there are several groups of evidence for the involvement 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 sensitivity of tissues to insufficient ATP production leaves a significant imprint on clinical picture mitochondrial diseases. In this regard, the nervous tissue is primarily of interest as the most energy-dependent. From 40 to 60% of the energy of ATP in neurons is spent on maintaining the ion gradient on their outer shell and the transmission of the nerve impulse. Therefore, dysfunction of the central nervous system in classical "mitochondrial diseases" are of paramount importance and give reason to call the main symptom complex "mitochondrial encephalomyopathies". Clinically, such brain disorders as mental retardation, convulsions and stroke-like episodes came to the fore. 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 personality or emotional changes, remain in the shadows.
The accumulation of information about mental disorders in mitochondrial diseases began to occur much later in comparison with the above disorders. Nevertheless, there is now a sufficient amount of evidence for 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 hereditary optic neuropathy.
Quite often, the development of classic signs of mitochondrial disease is preceded by moderately severe mental disorders. Therefore, patients may initially be observed by psychiatrists. In these cases, other symptoms of mitochondrial disease (photophobia, vertigo, fatigue, muscle weakness, etc.) are sometimes regarded as psychosomatic disorders. The well-known researcher of mitochondrial pathology P. Chinnery, in an article written jointly with D. Turnbull, points out: “Psychiatric complications constantly accompany mitochondrial disease. They usually take the form of reactive depression ... We have repeatedly observed cases of severe depression and suicidal attempts even before (emphasis added by the authors of the article) the diagnosis was established.
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 damage to the brain (in the latter case, the term "psychiatry" in general not used).
Based on the materials of a number of reviews, here is 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 schizophrenia-like 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 a "mitochondrial" disease, but also in their relatives. In particular, a case is described when a disease based on a deletion of one nucleotide pair of mitDNA in the region of the transfer RNA gene first manifested itself in the school years in a boy 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 confirmed diagnoses by molecular genetic studies. As a rule, personality disorders develop after cognitive impairment. A case of autism in a patient with a mitDNA point mutation in the region of the transfer RNA gene is described.
Common features characteristic of mitochondrial and psychiatric diseases
We are talking about a certain clinical similarity of some mental illnesses and mitochondrial syndromes, as well as common types of their inheritance.
First of all, attention is drawn to the data on the prevalence of cases of maternal inheritance of certain mental illnesses, in particular bipolar disorders. Such inheritance cannot be explained in terms 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 for maternal inheritance in patients with schizophrenia. True, in this respect there is an alternative explanation used in our context: it is assumed that this trend may be due to unequal conditions for patients of different sexes in the search for a partner.
Indirect confirmation of the connection between mitochondrial and some mental diseases is also a tendency to the cyclicity of their clinical manifestations. With diseases such as bipolar disorder, this is common knowledge. However, data on ultra-, circadian, and seasonal rhythms of clinical manifestations of dysenergetic states are now beginning to accumulate in mitochondriology as well. 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 be the result of mitochondrial dysfunction rather than a manifestation of “communicative distress”, “hypochondrial pattern” or “ secondary acquisition” (“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, the mention of signs of lactic acidosis and some other biochemical changes, indicating a violation of energy metabolism in schizophrenia, began to appear from the 30s of the twentieth century. But only starting from the 1990s, 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 published works, D. Ben-Shachar and D. Laifenfeld divided all 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) disturbances in 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 putamen. At the same time, it was noted that it was less pronounced in patients treated with antipsychotics, and therefore the authors considered it possible to talk about the normalization of mitochondrial processes in the brain under the influence of antipsychotic therapy. This gives reason to mention the article by N.S. Kolomeets and N.A. Uranova about mitochondrial hyperplasia in presynaptic axon terminals in the area of substantia nigra in schizophrenia.
L. Cavelier et al. , examining the autopsy material of the brain of patients with schizophrenia, revealed a decrease in the activity of the IV complex of the respiratory chain in the caudate nucleus.
These results allowed us to suggest a primary or secondary role of mitochondrial dysfunction in the pathogenesis of schizophrenia. However, the autopsy material studied was related 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 discovery of mitochondrial changes in various bodies and systems in mental and other diseases. With regard to the possible influence of 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 in patients with schizophrenia. This made it possible to speak about the polysystemic nature of mitochondrial insufficiency. S. Whatley et al. , in particular, showed that in the frontal cortex the activity of complex IV decreases, in the temporal cortex - 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 the activity of the intramitochondrial enzyme, citrate synthase, corresponded to the control values in all the studied areas, which gave grounds to speak about the specificity of the obtained results for schizophrenia.
In addition to the studies considered, one can cite the work carried out in 1999-2000. the work of J. Prince et al. who studied the activity of respiratory complexes in different parts of the brain of patients with schizophrenia. These authors found no signs of changes in the activity of complex I, but the activity of complex IV was reduced in the caudate nucleus. At the same time, the latter, as well as the activity of complex II, was increased in the shell and in the nucleus accumbens. Moreover, an 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 works cited above attributed the signs of energy metabolism disorders to the effects of neuroleptics. In 2002, very interesting data in this respect were published by A. Gardner et al. on mitochondrial enzymes and ATP production in muscle biopsy specimens from patients with schizophrenia 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 in patients on antipsychotic therapy, an increase in ATP production was found. These data to a certain extent confirmed the earlier conclusions made by L. Kung and R. Roberts.
In 2002, the results of another remarkable work were published. It studied the activity of complex I of the respiratory chain in the platelets of 113 patients with schizophrenia in comparison with 37 healthy ones. The patients were divided into three groups: group 1 - with an acute psychotic episode, group 2 - with a chronic active form, and group 3 - with residual schizophrenia. The results showed that the activity of complex I was significantly increased compared to the control in patients of groups 1 and 2 and decreased in patients of 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 in the study of flavoprotein subunits of complex I in the same RNA and protein material. The results of this study thus not only confirmed the high likelihood of multisystem mitochondrial failure in schizophrenia, but also allowed the authors to recommend appropriate laboratory methods for disease monitoring.
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 plays a significant role in the pathogenesis of schizophrenia. It has been found that dopamine can inhibit complex I activity and ATP production. At the same time, the activity of IV and V complexes does not change. It turned out that, unlike dopamine, norepinephrine and serotonin do not affect ATP production.
Noteworthy is the emphasis made in the above works 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 the functional regulation of energy metabolism 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 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 patients with schizophrenia, the researchers of this group showed the presence of a cytochrome b gene polymorphism different from the control.
In these years, a series of works by the group 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 of the sequences upscaled from control were related to mitochondrial genes. Was significantly increased, in particular, the expression of the mitochondrial gene of the 2nd subunit of cytochrome oxidase. Four other genes were related to mitochondrial ribosomal RNA.
Japanese researchers, examining 300 cases of schizophrenia, did not find signs of the 3243AG mutation (which causes a violation in complex I in MELAS syndrome). No increased mutation 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. found a mutation in the 12027 nucleotide pair of mitDNA (the gene of the 4th subunit of complex I), which was present in male patients with schizophrenia and which was not in women.
Characterization of three nuclear genes of complex I was studied in the prefrontal and visual cortex of patients with schizophrenia by R. Karry et al. . They found that the transcription and translation of some subunits was reduced in the prefrontal cortex and increased in the visual cortex (the authors interpreted these data in accordance with the concept of "hypofrontality" in schizophrenia). In the study of genes (including genes of mitochondrial proteins) in the hippocampal tissue of patients treated with antipsychotics with schizophrenia, no changes were found.
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 neuroleptic treatment, obtained evidence in favor of drug effects 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 the temporal lobe of the brain of patients with schizophrenia was revealed.
Depression and Bipolar Affective Disorders
Japanese researchers T. Kato et al. magnetic resonance spectroscopy revealed a decrease in intracellular pH and the level of phosphocreatine in the frontal lobe of the brain in patients with bipolar disorders, including those who did not receive treatment. The same authors revealed a decrease in the level of phosphocreatine in the temporal lobe 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 signs were observed in patients with some mitochondrial diseases.
With regard to molecular genetic data, it should immediately be noted that the results of a number of studies indicate the absence of evidence for 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 the difference in its haplotypes in patients with bipolar disorders and examined from control group, revealed some mutations characteristic of the former, in particular, in positions 5178 and 10398 - both positions are in the zone of complex I genes.
There are reports of the presence of mutations in the genes of complex I, not only in mitochondrial, but also in nuclear ones. So, in cultures of lymphoblastoid cells obtained from patients with bipolar disorders, a mutation was found in the NDUFV2 gene, localized on the 18th chromosome (18p11), and encoding one of the subunits of complex I. MitDNA sequencing of patients with bipolar disorders revealed a characteristic mutation at position 3644 of the ND1 subunit gene, which also belongs to complex I. An increase in the level of translation (but not transcription) has been found for some subunits of complex I in the visual cortex of patients with bipolar disorder. Among other studies, we will cite two studies 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 detected, and a significant correlation was found between the degree of ATP production decrease and clinical manifestations of a mental disorder.
Other mental disorders
There is little research on mitochondrial dysfunction in other psychiatric disorders. Some of them were mentioned in the previous sections of the review. Here, we specifically mention the work of P. Filipek et al. , which described 2 children with autism and a mutation in the 15th chromosome, in the region 15q11-q13. Both children were found to have moderate motor developmental delay, lethargy, severe hypotension, lactic acidosis, reduced 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 regarding 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 involvement of mitochondrial pathology in their pathogenesis. However, there is more convincing evidence for 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 from an extended family with maternal transmission of bipolar disorder. 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 people was found. At the same time, it can be noted that the data on position 10398 coincide with the already mentioned data of Japanese authors, who suggested that the 10398A mitDNA polymorphism is a risk factor for the development of bipolar disorders.
The most significant genealogical proof of the role of mitochondrial dysfunctions in the development of mental disorders is the fact that patients with classic mitochondrial diseases have relatives (more often on the maternal side) with moderate mental disorders. Anxiety and depression are often mentioned among such 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 conducted an anonymous survey of patients with mitochondrial diseases, as well as their family members, for 12 months. Among the questions were related to the state of health of the parents and close relatives of patients (on the paternal and maternal lines). Were thus investigated 55 families (group 1) with a suspected maternal and 111 families (group 2) with a suspected non-maternal mode of inheritance of mitochondrial disease. As a result, relatives of patients on the maternal side, compared with the paternal side, showed a higher incidence of several pathological conditions. Among them, along with migraines and irritable bowel syndrome, was depression. In group 1, intestinal dysfunctions, migraine and depression were observed in a larger percentage of mothers from the surveyed families - 60, 54 and 51%, respectively; in the 2nd group - 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
Effect of drugs used in psychiatry on mitochondrial function
In the previous sections of the review, we have already touched briefly on therapy issues. 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 areas of the brain, can uncouple oxidation and phosphorylation, reduce the activity of complex I and ATPase, lower the level of utilization ATP. However, the interpretation of 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 neuroleptics. In the previous sections of the review, we also present works that testify to 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 (though only at high doses) were revealed in an experimental study of serotonin reuptake inhibitors.
Lithium, widely used in the treatment of bipolar disorders, also, apparently, can have a positive effect on the processes of cellular energy metabolism. It competes with sodium ions, participating in the regulation of calcium pumps in mitochondria. A. Gardner and R. Boles in their review cite T. Gunter, a well-known specialist in mitochondrial calcium metabolism, 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 hypothesized to reduce the activation of the apoptotic cascade.
A. Gardner and R. Boles cite in the above review a lot of indirect clinical evidence of the positive effect of psychotropic drugs on symptoms, presumably dependent on dysenergy processes. Thus, intravenous administration of chlorpromazine and other antipsychotics reduces migraine headache. The effectiveness 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 neuralgia and other pain syndromes, including migraine. Lithium and serotonin reuptake inhibitors are also effective in the treatment of migraine.
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 uniquely stimulating or inhibitory, but rather “regulating”. At the same time, it can be different in neurons of different parts of the brain.
The foregoing suggests that the lack of energy in the brain, perhaps, primarily concerns areas especially affected by the pathological process.
The effectiveness of energotropic drugs in 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 message of T. Suzuki et al. deserves attention in the first place. about a patient with schizophrenia-like disorders on the background of the MELAS syndrome. After the application of coenzyme Q10 and nicotinic acid, the patient's mutism disappeared for several days. There is also a paper that reports the success of dichloroacetate (often used in "mitochondrial medicine" to lower lactate levels) in a 19-year-old man with MELAS syndrome, in relation to the effect on the picture of delirium with auditory and visual hallucinations.
The literature also contains a description of the history of a patient with the MELAS syndrome with a detected point mutation 3243 mitDNA. This patient developed psychosis with auditory hallucinations and delusions of persecution, which was managed within a week with low doses of haloperidol. However, he later 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 was also stated in the work: we are talking about a patient who not only prevented stroke-like episodes, but also stopped headaches, tinnitus and psychotic episodes.
There are also reports on the effectiveness of energy-tropic therapy in patients with mental illness. Thus, a 23-year-old patient with treatment-resistant depression was described, the severity of which significantly decreased after a 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 proved 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 importance mitochondrial disorders have already been proven, and their consideration requires a separate publication.
On the basis of the above data, it can be argued that the need has come to combine the efforts of psychiatrists and specialists dealing with mitochondrial diseases, aimed both at studying the dysenergy bases of disorders of higher nervous activity, and at analyzing the psychopathological manifestations of diseases associated with disorders of cellular energy metabolism. 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 corresponding descriptions, a large place is occupied by cases with a detected mitDNA 3243AG mutation, a generally recognized cause of the development of the MELAS syndrome.
Literature
Mitochondrial diseases (MH)- a group of hereditary diseases associated with defects in the functioning of mitochondria, leading to impaired energy functions in cells.
History reference:
The concept of "mitochondrial diseases" was formed in medicine at the end of the twentieth century. First of all, diseases associated with mutations in mitochondrial DNA, discovered in the early 60s, were studied. The complete primary structure of human mitochondrial DNA was published in 1981, and already at the end of the 80s the leading role of its mutations in the development of a number of hereditary diseases was proved. The latter include: Leber's hereditary optic nerve atrophy, NARP syndrome (neuropathy, ataxia, retinitis pigmentosa), MERRF syndrome (myoclonus epilepsy with "torn" red fibers in skeletal muscles), MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes), Kearns-Sayre syndrome (retinitis pigmentosa, external ophthalmoplegia, heart block, ptosis, cerebellar syndrome), Pearson's syndrome (bone marrow damage, pancreatic and hepatic dysfunction) and many others.
To a lesser extent, hereditary mitochondrial defects associated with damage to the nuclear genome have been studied.
Pathogenesis.
Mitochondria are responsible for generating most of the energy needed for cell function. In fact, they are such an important source of energy that there are hundreds of them in every cell. With MZ, both part of the mitochondria and all of them can “turn off”, which leads to the cessation of the production of the necessary energy.
Since nerve and muscle cells are the most energy-intensive cells, muscle and neurological problems, such as muscle weakness, exercise intolerance, hearing loss, balance and coordination disorders, epileptic seizures, are the most common in MH.
Mitochondrial diseases that cause severe muscle problems are called mitochondrial myopathies (myo means "muscle" and pathos means "disease"), and those that cause both muscle and neurological problems are called mitochondrial encephalomyopathies (encephalo - "brain")
When a cell is filled with defective mitochondria, it not only lacks ATP, but unused fuel molecules and oxygen can accumulate in it, with catastrophic consequences. In this case, excess fuel molecules are used inefficiently for ATP synthesis, resulting in the formation of potentially dangerous products, such as lactic acid (This also occurs when cells are deprived of oxygen, for example, muscle cells during increased physical exertion). The accumulation of lactic acid in the blood - lactic acidosis - is associated with muscle fatigue, and can cause damage to nerve and muscle tissue.
At the same time, oxygen not used in the cell can be transformed into destructive compounds called reactive oxygen species, including the so-called. free radicals (They are the target for the so-called antioxidant drugs and vitamins).
ATP synthesized in mitochondria is the main source of energy for muscle contraction and excitation of nerve cells (because the cells of these tissues are the most metabolically active, energy dependent). Thus, nerve and muscle cells are particularly sensitive to mitochondrial defects. The combined effect of energy loss and accumulation of toxins in these cells is thought to be responsible for the development of symptoms of mitochondrial myopathies and encephalomyopathies.
Clinic
In cases where a person with a mutation in the mitochondrial gene carries a mixture of normal and mutant DNA, the mutations may initially have no external manifestations at all. Normal mitochondria for the time being provide cells with energy, compensating for the lack of function of mitochondria with defects. In practice, this is manifested by a more or less long asymptomatic period in many mitochondrial diseases. However, sooner or later there comes a time when defective forms accumulate in an amount sufficient for the manifestation of pathological signs. The age of onset of the disease varies in different patients. Early onset of the disease leads to a more severe course and a poor prognosis.
Characteristic signs of mitochondrial cytopathies:
Skeletal muscles: low exercise tolerance, hypotension, proximal myopathy including facial and pharyngeal muscles, ophthalmoparesis, ptosis
Heart: cardiac arrhythmias, hypertrophic myocardiopathy
Central nervous system: optic nerve atrophy, retinopathy pigmentosa, myoclonus, dementia, stroke-like episodes, mental disorders
Peripheral nervous system: axonal neuropathy, disorders of the motor function of the gastrointestinal tract
Endocrine system: diabetes, hypoparathyroidism, pancreatic exocrine dysfunction, short stature
Thus, the involvement of different organs and the simultaneous manifestation of outwardly unrelated anomalies are typical for mitochondrial diseases. Examples are:
1. Migraines with muscle weakness
2. External ophthalmoplegia with impaired conduction of the heart muscle and cerebellar ataxia
3. Nausea, vomiting with optic atrophy and cardiomyopathy
4. Short stature with myopathy and stroke-like episodes
5. Exocrine pancreatic dysfunction with sideroblastic anemia
6. Encephalomyopathy with diabetes
7. Diabetes with deafness
8. Deafness with external ophthalmoplegia, ptosis and retinopathy
9. Developmental delay or loss of skills and ophthalmoplegia, ophthalmoparesis
The nature and severity of clinical manifestations of mitochondrial diseases is determined by:
The severity of the mtDNA mutation;
The percentage of mutant mtDNA in specific organs and tissues;
Energy demand and functional reserve of organs and tissues containing mtDNA (their “sensitivity threshold” to defects in oxidative phosphorylation).
Myopathy
The main symptoms of mitochondrial myopathy are muscle wasting and weakness, and exercise intolerance.
In some individuals, weakness is most pronounced in the muscles that control eye and eyelid movements. The two most common consequences of this weakness are gradual eye movement paralysis (progressive external ophthalmoplegia, PNO), and drooping of the upper eyelids (ptosis). Often, people automatically compensate for TNR with head movements in order to look in different directions, and may not even be aware of any problems. Ptosis is potentially more troublesome as it can impair vision and also give the face a lethargic expression, but it can be corrected surgically or by using special glasses with an eyelid lifter.
Mitochondrial myopathies can also cause weakness of other muscles in the face and neck, leading to slurred speech and difficulty swallowing. In these cases, speech therapy (classes with a speech therapist) or the inclusion in the diet of foods that are easier to swallow can help.
Exercise intolerance, also referred to as exercise fatigue, is an unusual feeling of fatigue in response to physical activity. The degree of this intolerance varies greatly from person to person. Some may only experience problems with physical activity, such as jogging, while others may have difficulty doing daily activities, such as going to the mailbox or picking up a carton of milk.
encephalomyopathy
Mitochondrial encephalomyopathy typically includes some of the aforementioned myopathy symptoms, in addition to one or more neurological symptoms. As with myopathy, there is considerable variability in both types of symptoms and severity in different individuals.
Among the most common symptoms of mitochondrial encephalomyopathy are hearing loss, migraine-like headaches, and epileptic seizures. In at least one syndrome, headaches and seizures are often accompanied by stroke-like episodes
In addition to damage to the eye muscles, mitochondrial encephalomyopathy can affect both the eyes themselves and areas of the brain responsible for vision. For example, loss of vision due to optic atrophy (degeneration of the optic nerve) or retinopathy (degeneration of some of the cells lining the fundus of the eye) are common symptoms of mitochondrial encephalomyopathy. Compared to muscle problems, these effects are more likely to lead to severe visual impairment.
Quite often, mitochondrial encephalomyopathy causes ataxia, or difficulty with balance and coordination.
Diagnostics.
None of the hallmark symptoms of mitochondrial disease—muscle weakness, exercise intolerance, hearing loss, ataxia, seizures, learning disabilities, cataracts, diabetes, and short stature—is unique to the disease. However, a combination of three or more of these symptoms in the same individual is indicative of a mitochondrial disease, especially if the symptoms affect more than one body system.
The physical examination usually includes tests of strength and endurance, such as repetitive clenching and unclenching of the fist, or walking up and down small stairs. A neurological examination may include testing of reflexes, vision, speech, and basic cognitive abilities.
There are a number of routine clinical methods studies that can be used in suspected mitochondrial cytopathy:
Lactate acidosis is an almost constant companion of mitochondrial diseases (only this sign is insufficient for making a diagnosis, since it can also be detected in other pathological conditions; in this regard, it may be useful to measure the level of lactate in the venous blood after moderate exercise, for example, on a bicycle ergometer)
EMG study - in itself, this study also cannot be a marker of mitochondrial cytopathy; however, normal or near-normal EMG in patients with severe muscle weakness may be suspicious of mitochondrial pathology.
EEG - EEG data is not specific enough
Skeletal muscle biopsy is the most informative method for diagnosing mitochondrial cytopathy - in addition to detecting RRF with Gomory's tricolor stain, other histochemical and immunological studies are useful: staining for cytochromes oxidase and succinate dehydrogenase, immunohistochemical studies using antibodies to individual subunits of the respiratory complex; muscle tissue is convenient for biochemical research of the respiratory chain, as well as a material for genetic research.
It is advisable to divide muscle biopsy specimens into three parts - one for microscopic examination (histology, histochemistry and electron microscopy), the second for enzymological and immunological analysis (study of the characteristics of the components of the respiratory chain) and the third - directly for molecular genetic analysis. The search for known mutations in muscle material allows, in most cases, successful DNA diagnosis of the disease. In the absence of known mtDNA mutations in muscle tissue, the next step is a detailed molecular genetic analysis - sequencing of the entire mtDNA chain (or nuclear DNA candidate genes) in order to identify a new mutation variant.
Electron microscopic examination of skeletal muscles - gives excellent results, so this method should be used if possible
Treatment.
As for the therapy of mitochondrial cytopathies, we can only talk about symptomatic so far.
Treatment of mitochondrial diseases is usually carried out in two main areas:
Increasing the efficiency of energy metabolism in tissues (thiamine, riboflavin, nicotinamide, coenzyme Q10 (kudesan), L-carnitine (elcar), calcium and magnesium preparations, vitamin C, cytochrome C)
Prevention of damage to mitochondrial membranes by free radicals with the help of antioxidants (vitamin E, a-lipoic acid) and membrane protectors.
The practice includes more and more new drugs of combined action, such as, for example, idebenone (Noben) - an improved structural analogue of coenzyme Q10, which favorably affects the activity of the respiratory tract and has a pronounced antioxidant, anti-apoptotic and neurotrophic effect.
Obviously, the expansion of the therapeutic arsenal for mitochondrial diseases dictates the urgent need for practitioners of various specialties (neurologists, psychiatrists, pediatricians, geneticists, hematologists, etc.) to be well acquainted with the algorithm for diagnosing these diseases.
Mitochondrial diseases are a heterogeneous 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, they are microscopic structures that are associated with a membrane and contain numerous components - organelles, 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 used as an energy source, takes place in structures called mitochondria. Mitochondrial energy is essential for all cellular functions.
Until the mid-twentieth century, little was known about mitochondrial diseases. The first diagnosis of a mitochondrial disorder was made in 1959, and 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 1990s led to the classification of mitochondrial diseases.
Common mitochondrial disorders
As of today, there are more than 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 broken red fibers (MERRF). MERFF is a mitochondrial syndrome in which a mitochondrial defect as well as a tissue abnormality called "torn red fibers" is detected microscopically. Symptoms include seizures, loss of coordination, short stature, buildup of lactic acid in the blood, difficulty speaking, dementia, and muscle weakness.
Mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS). MELAS is a progressive disease, mitochondrial syndrome affects multiple organ systems, including the central nervous system, cardiac muscle, skeletal muscle, and gastrointestinal tract. Symptoms include muscle weakness, stroke, eye muscle paralysis, and cognitive impairment.
Leber's hereditary optic neuropathy(LHON). LHON causes progressive loss of vision leading to varying degrees of blindness and primarily affects men over the age of 20. Cardiac anomalies may also occur.
Lee Syndrome. This degenerative brain disease is usually diagnosed at a young age. The deterioration is often accompanied by symptoms such as seizures, dementia, feeding and speech difficulties, respiratory dysfunction, heart problems, and muscle weakness. The prognosis is generally poor and death occurs within a few years.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The main signs include symptoms that mimic gastrointestinal obstruction and abnormalities of the nervous system. Other symptoms may include eye muscle paralysis, muscle weakness, loss of coordination, and brain abnormalities.
Pearson syndrome. Symptoms usually appear first in childhood, the characteristics of this rare syndrome being highlighted by pancreatic dysfunction and anemia. Complications - obesity, diarrhea, liver enlargement and other signs.
Neuropathy, ataxia and retinitis pigmentosa (NARP). Symptoms of this disorder include nervous system disturbances, loss of coordination, and progressive loss of vision. May also lead to developmental delays, dementia, muscle weakness. Usually occurs in 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 needed to convert oxygen and nutrients into energy, they all have one thing in common: the ability of mitochondria to produce energy is impaired. Waste products from numerous reactions can begin to accumulate in cells and interfere with other chemical reactions, and over time cause further damage to the mitochondria.
Inheritance of mitochondrial diseases
In many cases, a mitochondrial disorder is passed down 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 hereditary characteristics, or through mtDNA. Some types of hereditary mitochondrial disorders include:
Autosomal recessive inheritance. Every person has two sets of genes, each inherited from one parent. In the case of some genetic diseases, a person needs to have two copies of the defective gene in order to have 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 the defective gene from each parent.
maternal inheritance. MtDNA is only passed from mother to child because the mitochondria of the spermatozoon are in the tail of the spermatozoon, which is not involved in conception. Some mitochondrial disorders, therefore, can only be passed from mother to child.
X-chromosome recessive inheritance. The sex of a child is determined by the inheritance of 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 the defective gene encoding the disease is found on the X chromosome, then the male child cannot have a healthy copy of the gene (because he only has one X chromosome); thus, he will have disorders. Girls are less at risk because they must have two copies of the defective gene (one on each X chromosome) to develop the disease.
Autosomal dominant inheritance. Unlike autosomal recessive inheritance, only one defective copy of the 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 occasional or sporadic and can be caused by a variety of causes, including certain medications (such as those used to treat HIV), anorexia, exposure to certain toxins, prolonged periods of oxygen deprivation, or age of the parents.
Symptoms of the mitochondrial syndrome
Since more than 90 percent of the energy needed by the human body is generated by mitochondria, the effects of mitochondrial disorders can be far-reaching. Research shows that the brain, nerves, skeletal muscles, liver, heart, kidneys, hearing aid, eyes, and pancreas are particularly affected due to high energy demands. Some of the most common symptoms of mitochondrial disease in organ systems include the following:
Other symptoms include developmental disturbances in children early age, poor growth, short stature, increased fatigue, trouble breathing, swallowing, and an increased risk of infections.
Diagnosis of mitochondrial diseases
The array of symptoms that are displayed in children suffering from mitochondrial disorders is common to many other diseases. Often, a feature of a mitochondrial disorder that distinguishes it from other diseases with similar symptoms is additional symptoms that are not usually present in a non-mitochondrial disease.
Due to the complex nature of mitochondrial disorders, physicians take multifaceted approaches to diagnosing such diseases. The process usually begins with a comprehensive medical examination, evaluation of the patient's medical and family history. Often, a neurological 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 includes the least invasive methods, such as testing a blood sample for evaluation. In some cases, the diagnosis can be made based on blood tests; in others, blood tests may indicate that further testing is needed.
Secondary evaluation. These tests may be more intense, more aggressive, and/or carry more risks. Examples include lumbar puncture, urinalysis, magnetic resonance imaging (MRI), additional blood tests, electrocardiogram (ECG).
Tertiary assessment. Complicated and/or invasive procedures such as skin testing or muscle biopsy. In some cases, tertiary tests are needed to make a definitive diagnosis.
In a certain situation, a physician 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 difficulty of testing for mitochondrial disorders, their diagnosis is not always possible.
Treatment of mitochondrial diseases
There are no specific drugs for the treatment of 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 age of the person, the affected organs, and the state of his health. Not all patients benefit from treatment.
Therapy, meanwhile, may consist of courses of vitamins, nutritional supplements, physical or occupational therapy, traditional medicines, such as:
- vitamins, such as the B vitamins (thiamin, 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 administered 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 monosodium glutamate can also exacerbate mitochondrial disorders.
In some cases, a properly designed diet is necessary to avoid worsening symptoms. Parents of a child affected by mitochondrial syndrome should consult a nutritionist to create an individualized diet. An individualized diet plan may include eating small, frequent meals, increasing or decreasing fat intake, 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 nevertheless 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 shown its effectiveness in several studies. This tool allows you to optimize energy production in mitochondria and reduce redox imbalance.
In the treatment of encephalomyelopathy (MELAS), a certain positive effect was shown by L-arginine, 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 disturbances and consciousness. This was shown in a 9-year study conducted by Japanese scientists.
Prognosis of mitochondrial disorders
The prognosis of an individual mitochondrial disease depends on many factors, including the specific disorder, mode of inheritance, age of the patient, and affected organs. 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 with different procedures, or if the progression of the disease is slow. In other cases, the disease progresses rapidly and leads to inevitable 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 a mitochondrial disease or its severity.
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 health professional.
Not so long ago, questions of mitochondrial dysfunction were of interest only to researchers and individual attending physicians. For some time now, doctors using a biomedical approach and parents of children with ASD have begun to talk about it more and more.
The mitochondrial complex is the part of the cells responsible for energy production. Mitochondrial dysfunction is seen as one of the possible causes of many manifestations of autism.
I note right away that there is simply a huge amount of data on mitochondria that need to be systematized, generalized, and a working model created. Genetics, complex chemical reactions, the movement of electrons and the permeability of cell membranes - all these issues are relevant to the problem of the efficiency of mitochondrial functioning in patients with ASD.
A large number of children with autism have similar symptoms that may be due to insufficient cell energy:
- Low activity of smooth muscles. This is especially detrimental to the work of the digestive tract, which leads to reflux (reflux of stomach contents into the esophagus), dyskinesias, constipation and yeast overgrowth due to the long stay of food in the intestines.
- General muscle weakness. This leads to clumsiness and poor gross motor skills, which in turn causes developmental delays.
- Decreased effectiveness of body detoxification. Organs that perform detoxification, such as the liver, require a very large amount of energy. . If not, then not all toxins will be processed. As a result, the body is poisoned more and more, and those coming with food and water are potentially harmful substances have an unexpectedly powerful effect.
- Insufficient supply of energy to the nervous system. This leads to distortion of the signals in the sensory system. When nerve impulses from the brain to the muscles pass with great difficulty, this further hinders the smoothness and clarity of movements.
- Decreased energy potential of brain cells. A brain deprived of sufficient energy will not be able to fully perform its functions: produce and absorb neurotransmitters, grow new cells, get rid of old ones, and transmit signals. As a result, problems with memory and concentration can be observed.
If the child exhibits the symptoms listed, then the doctor's task is to check the functioning of all body systems and decide whether laboratory studies of mitochondrial function are necessary.
Read also The influence of diet on the course of autism: where and how to look for chances for improvement
It can be assumed that not all conditions accompanying ASD are irreversible. The saturation of certain deficiencies, which include mitochondrial dysfunction, will provide the child's body with the energy that it sorely lacks.
As a result, we will be able to observe an improvement in the functioning of almost all body systems, which will increase the patient's learning ability and facilitate his integration into society.
The list of factors and substances that lead to a deterioration in the functioning of mitochondria:
- infections, especially viral ones;
- inflammatory process;
- heat;
- dehydration;
- prolonged hunger;
- extreme heat or cold;
- paracetamol;
- non-steroidal anti-inflammatory drugs;
- antipsychotics;
- antidepressants;
- antiepileptic drugs;
- anesthesia;
- heavy metals;
- insecticides;
- cigarette smoke.
Parents of children with ASD should avoid the following:
- Alcohol consumption by children
- Keeping children around cigarette smoke
- Eating meals with monosodium glutamate (almost all processed foods that can be found on supermarket shelves)
- Use at high temperature paracetamol (take ibuprofen instead, which is safer)
- Taking antipsychotics.
Here is the list antibiotics that impair the functioning of the mitochondrial system:
- Linezolid
- Rifampicin
- Tetracycline
- Chloramphenicol
- Imipenem
- Penicillin
- Cephalosporins
- Quinolones (ciprofloxacin, levofloxacin, ofloxacin)
- Macrolides (azithromycin, clarithromycin, erythromycin)
- Sulfanilamide co-trimoxazole
Mitochondrial disorders are best treated with:
- ketogenic diet ( a large number of fat, sufficient - protein, low - carbohydrates)
- Using vitamins and nutritional supplements to help remedy the situation:
- Vitamin B12 in the form of subcutaneous injections
- A complex of B vitamins, such as B-50. These are all B vitamins at 50mg each
- S-adenosylmethionine (SAM, ademethionine)
- L-cysteine and glutathione
- Coenzyme Q10
- Ginkgo biloba extract
- Complexes of antioxidants, which include vitamins A, C, E and minerals selenium and zinc
Mitochondrial diseases are a heterogeneous group of hereditary diseases that are caused by structural, genetic or biochemical defects in mitochondria, leading to disruption of energy functions in the cells of eukaryotic organisms. In humans, mitochondrial diseases primarily affect the muscular and nervous systems.
ICD-9 | 277.87 |
---|---|
MeSH | D028361 |
DiseasesDB | 28840 |
General information
Mitochondrial diseases as a separate type of pathology were identified at the end of the 20th century after the discovery of mutations in the genes responsible for the synthesis of mitochondrial proteins.
Mutations in mitochondrial DNA discovered in the 1960s and the diseases caused by these mutations are more studied than diseases caused by disturbances in nuclear-mitochondrial interactions (nuclear DNA mutations).
To date, at least 50 diseases known to medicine are associated with mitochondrial disorders. The prevalence of these diseases is 1:5000.
Kinds
Mitochondria are unique cellular structures that have their own DNA.
According to many researchers, mitochondria are the descendants of archaebacteria that have turned into endosymbionts (microorganisms that live in the body of the "owner" and benefit him). As a result of introduction into eukaryotic cells, they gradually lost or transferred to the nucleus of the eukaryotic host a large part of the genome, and this is taken into account in the classification. The participation of a defective protein in the biochemical reactions of oxidative phosphorylation is also taken into account, which makes it possible to store energy in the form of ATP in mitochondria.
There is no single generally accepted classification.
The generalized modern classification of mitochondrial diseases distinguishes:
- Diseases caused by mutations in mitochondrial DNA. Defects can be caused by point mutations in proteins, tRNAs or rRNAs (usually maternally inherited), or structural rearrangements - sporadic (irregular) duplications and deletions. These are primary mitochondrial diseases, which include pronounced hereditary syndromes - Kearns-Sayre syndrome, Leber syndrome, Pearson syndrome, NAPR syndrome, MERRF syndrome, etc.
- Diseases caused by defects in nuclear DNA. Nuclear mutations can disrupt the functions of mitochondria - oxidative phosphorylation, operation of the electron transport chain, utilization or transport of substrates. Also, mutations in nuclear DNA cause defects in enzymes that are necessary to ensure a cyclic biochemical process - the Krebs cycle, which is a key step in the respiration of all oxygen-using cells and the intersection center of metabolic pathways in the body. This group includes gastrointestinal mitochondrial disease, Luft syndrome, Friedrich's ataxia, Alpers syndrome, diseases connective tissue, diabetes, etc.
- Diseases that arise as a result of disorders in nuclear DNA and secondary changes in mitochondrial DNA caused by these disorders. Secondary defects are tissue-specific deletions or duplications of mitochondrial DNA and a decrease in the number of copies of mitochondrial DNA or their absence in tissues. This group includes liver failure, De Toni-Debre-Fanconi syndrome, etc.
Reasons for development
Mitochondrial diseases are caused by defects in organelles located in the cell cytoplasm - mitochondria. The main function of these organelles is the production of energy from the products of cellular metabolism entering the cytoplasm, which occurs due to the participation of about 80 enzymes. The released energy is stored in the form of ATP molecules, and then converted into mechanical or bioelectrical energy, etc.
The causes of mitochondrial diseases are a violation of the production and accumulation of energy due to a defect in one of the enzymes. First of all, with chronic energy deficiency, the most energy-dependent organs and tissues suffer - the central nervous system, the heart muscle and skeletal muscles, the liver, kidneys and endocrine glands. Chronic energy deficiency causes pathological changes in these organs and provokes the development of mitochondrial diseases.
The etiology of mitochondrial diseases has its own specifics - most mutations occur in the genes of mitochondria, since redox processes are intense in these organelles and DNA-damaging free radicals are formed. In mitochondrial DNA, damage repair mechanisms are imperfect, since it is not protected by histone proteins. As a result, defective genes accumulate 10-20 times faster than in nuclear DNA.
Mutated genes are transmitted during the division of mitochondria, so even in one cell there are organelles with different genome variants (heteroplasmy). When a mitochondrial gene is mutated in humans, a mixture of mutant and normal DNA is observed in any ratio, therefore, even in the presence of the same mutation, mitochondrial diseases in humans are expressed to varying degrees. The presence of 10% defective mitochondria does not have a pathological effect.
The mutation may not manifest itself for a long time, since normal mitochondria compensate at the initial stage for the insufficiency of the function of defective mitochondria. Over time, defective organelles accumulate, and pathological signs of the disease appear. With an early manifestation, the course of the disease is more severe, the prognosis may be negative.
Mitochondrial genes are transmitted only from the mother, since the cytoplasm containing these organelles is present in the egg and is practically absent in the spermatozoa.
Mitochondrial diseases, which are caused by defects in nuclear DNA, are transmitted by autosomal recessive, autosomal dominant, or X-linked inheritance patterns.
Pathogenesis
The mitochondrial genome differs from the genetic code of the nucleus and more closely resembles that of bacteria. In humans, the mitochondrial genome is represented by copies of a small circular DNA molecule (their number ranges from 1 to 8). Each mitochondrial chromosome codes for:
- 13 proteins that are responsible for the synthesis of ATP;
- rRNA and tRNA, which are involved in protein synthesis in mitochondria.
About 70 mitochondrial protein genes are encoded by nuclear DNA genes, due to which the centralized regulation of mitochondrial functions is carried out.
The pathogenesis of mitochondrial diseases is associated with processes that occur in mitochondria:
- With the transport of substrates (organic keto acid pyruvate, which is the end product of glucose metabolism, and fatty acids). Occurs under the influence of carnitine palmitoyl transferase and carnitine.
- With the oxidation of substrates, which occurs under the influence of three enzymes (pyruvate dehydrogenase, lipoate acetyltransferase and lipoamide dehydrogenase). As a result of the oxidation process, acetyl-CoA is formed, which is involved in the Krebs cycle.
- With the tricarboxylic acid cycle (Krebs cycle), which not only occupies a central place in energy metabolism, but also supplies intermediate compounds for the synthesis of amino acids, carbohydrates and other compounds. Half of the steps in the cycle are oxidative processes that release energy. This energy is accumulated in the form of reduced coenzymes (molecules of non-protein nature).
- with oxidative phosphorylation. As a result of the complete decomposition of pyruvate in the Krebs cycle, the coenzymes NAD and FAD are formed, which are involved in the transfer of electrons to the respiratory electron transport chain (ETC). ETC is controlled by the mitochondrial and nuclear genome and carries out electron transport using four multienzyme complexes. The fifth multienzyme complex (ATP synthase) catalyzes the synthesis of ATP.
Pathology can occur both with mutations in nuclear DNA genes and with mutations in mitochondrial genes.
Symptoms
Mitochondrial diseases are characterized by a significant variety of symptoms, since different organs and systems are involved in the pathological process.
The nervous and muscular systems are the most energy-dependent, so they suffer from an energy deficit in the first place.
Symptoms of damage to the muscular system include:
- decrease or loss of the ability to perform motor functions due to muscle weakness (myopathic syndrome);
- hypotension;
- pain and painful muscle spasms (cramps).
Mitochondrial diseases in children are manifested by headache, vomiting, and muscle weakness after exercise.
Damage to the nervous system manifests itself in:
- delayed psychomotor development;
- loss of previously acquired skills;
- the presence of seizures;
- the presence of periodic occurrence of apnea and;
- repeated coma and a shift in the acid-base balance of the body (acidosis);
- gait disorders.
Adolescents have headaches, peripheral neuropathies (numbness, loss of sensation, paralysis, etc.), stroke-like episodes, pathological involuntary movements, dizziness.
Mitochondrial diseases are also characterized by damage to the sense organs, which manifest themselves in:
- atrophy of the optic nerves;
- ptosis and external ophthalmoplegia;
- cataracts, clouding of the cornea, pigmentary retinal degeneration;
- visual field defect, which is observed in adolescents;
- hearing loss or sensorineural deafness.
Signs of mitochondrial diseases are also lesions of internal organs:
- cardiomyopathy and heart block;
- pathological enlargement of the liver, violations of its functions, liver failure;
- lesions of the proximal renal tubules, accompanied by increased excretion of glucose, amino acids and phosphates;
- vomiting, pancreatic dysfunction, diarrhea, celiac disease.
There is also macrocytic anemia, in which the average size of red blood cells is increased, and pancytopenia, which is characterized by a decrease in the number of all types of blood cells.
The defeat of the endocrine system is accompanied by:
- growth retardation and violation of sexual development;
- hypoglycemia and diabetes;
- hypothalamic-pituitary syndrome with GH deficiency;
- thyroid dysfunction;
- hypothyroidism, impaired metabolism of phosphorus and calcium, and.
Diagnostics
Diagnosis of mitochondrial diseases is based on:
- Anamnesis study. Because all symptoms of mitochondrial disease are nonspecific, the diagnosis is suggested by a combination of three or more symptoms.
- Physical examination, which includes endurance and strength tests.
- Neurological examination, including testing of vision, reflexes, speech and cognitive abilities.
- Specialized samples, which include the most informative test - muscle biopsy, as well as phosphorus magnetic resonance spectroscopy and other non-invasive methods.
- CT and MRI, which can detect signs of brain damage.
- DNA diagnostics, which allows you to identify mitochondrial diseases. Mutations not previously described are determined by direct mtDNA sequencing.
Treatment
Effective treatments for mitochondrial diseases are being actively developed. Attention is paid to:
- Increasing the efficiency of energy metabolism with the help of thiamine, riboflavin, nicotinamide, coenzyme Q10 (shows good results in MELAS syndrome), vitamin C, cytochrome C, etc.
- Prevention of damage to mitochondrial membranes by free radicals, for which a-lipoic acid and vitamin E (antioxidants), as well as membrane protectors (citicoline, methionine, etc.) are used.
Treatment also includes creatine monohydrate as an alternative source of energy, lactic acid reduction, and exercise.
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