Disturbances in the formation and excretion of end products of protein metabolism. Scientists managed to cure epilepsy while studying memory mechanisms

Consequences of disruption of general protein synthesis

A long-term and significant decrease in protein synthesis leads to the development of dystrophic and atrophic disorders in various organs and tissues due to insufficient renewal of structural proteins. Regeneration processes slow down. In childhood, growth, physical and mental development are inhibited.

tie. The synthesis of various enzymes and hormones (GH, antidiuretic and thyroid hormones, insulin, etc.) decreases, which leads to endocrinopathies and disruption of other types of metabolism (carbohydrate, water-salt, basal). The content of proteins in the blood serum decreases due to a decrease in their synthesis in hepatocytes. As a result, oncotic pressure in the blood decreases, which contributes to the development of edema. The production of antibodies and other protective proteins decreases and, as a result, the immunological reactivity of the body decreases. To the most pronounced extent, these disorders arise as a result of long-term disruption of the absorption of food proteins in various chronic diseases of the digestive system, as well as during prolonged protein starvation, especially if it is combined with a deficiency of fats and carbohydrates. In the latter case, the use of protein as an energy source increases.

Causes and mechanism of disruption of the synthesis of individual proteins. In most cases, these disorders are hereditary. They are based on the absence in cells of messenger RNA (mRNA), a specific matrix for the synthesis of any particular protein, or a violation of its structure due to a change in the structure of the gene on which it is synthesized. Genetic disorders, for example, the replacement or loss of one nucleotide in a structural gene, lead to the synthesis of an altered protein, often devoid of biological activity.

The formation of abnormal proteins can be caused by deviations from the norm in the structure of mRNA, mutations of transfer RNA (tRNA), as a result of which an inappropriate amino acid is added to it, which will be included in the polypeptide chain during its assembly (for example, during the formation of hemoglobin).

The translation process is complex, occurring with the participation of a number of enzymes, and dysfunction of any of them can lead to the fact that one or another mRNA does not transmit the information encoded in it.

Violation of the synthesis of individual enzyme proteins or structural proteins underlies various hereditary diseases (hemoglobinosis, albinism, phenylketonuria, galactosemia, hemophilia and many others - see section 5.1). Violation of any enzymatic function is most often associated not with the absence of the corresponding protein - enzyme, but with the formation of a pathologically altered inactive product.

Causes, mechanism and consequences of increased breakdown of tissue proteins. Along with synthesis in the cells of the body, protein degradation constantly occurs under the action of proteinases. The renewal of proteins per day in an adult is 1-2% of the total amount of protein in the body and is associated mainly with the degradation of muscle proteins, while 75-80% of the released amino acids are again used for synthesis.

Nitrogen balance- an integral indicator of the general level of protein metabolism, this is the daily difference between nitrogen entering and released from the body,

In a healthy adult, the processes of protein breakdown and synthesis are balanced, i.e. available nitrogen balance. At the same time, daily protein degradation is 30-40 g.

Nitrogen balance can be positive or negative.

Positive nitrogen balance: the intake of nitrogen into the body exceeds its excretion, i.e. protein synthesis prevails over its breakdown. It is noted during tissue regeneration, during the period of recovery after serious illnesses, during pregnancy, in childhood, with hyperproduction of growth hormone, and with polycythemia.

In pathology, protein breakdown may prevail over synthesis and less nitrogen enters the body than is excreted (negative nitrogen balance).

The causes of negative nitrogen balance are: infectious fever; extensive injuries, burns and inflammatory processes; progressive malignant tumor growth, endocrine diseases (diabetes mellitus, hyperthyroidism, hypercortisolism); severe emotional stress; dehydration, protein starvation, radiation sickness; hypovitaminosis A, C, B 1, B 2, B 6, PP, folic acid deficiency. The mechanism of increased protein breakdown in many of these conditions is the increased production of catabolic hormones.

The consequence of a negative nitrogen balance is degenerative changes in organs, weight loss, and in childhood - retarded growth and mental development.

Heat shock of the developing brain and genes that determine epilepsy

N. E. Chepurnova

Moscow State University them. M.V. Lomonosov

Etiology and pathogenesis of febrile seizures

Each new step in solving fundamental biological problems helps to understand the age-old problems of human diseases, their nature and again turns us to hereditary factors. “Inexhaustible hereditary biochemical heterogeneity cannot but entail,” wrote V.P. Efroimson, “inexhaustible hereditary mental heterogeneity...”. This is true for the severity of neurological and mental diseases.

Epilepsy manifests itself in 2-4% of the human population; it poses the greatest danger in childhood. Febrile seizures (FS) account for up to 85% of all convulsive syndromes observed in children. The total number of children aged 6 months to 6 years with FS ranges from 2 to 5% (9% in Japan), the largest number of such children is observed in Guam - 15%. More than half of FS attacks occur during the second year of a child’s life, with peak frequency occurring between 18 and 22 months. Seizures can be provoked by diseases occurring with a temperature above 39-41 ºС, but doctors have always assumed the presence of a hidden genetic predisposition in a child to paroxysmal conditions if an increase in temperature causes FS. Boys get sick four times more often than girls. Suggestions have been made about autosomal dominant inheritance, autosomal recessive inheritance of FS, but polygenic or multifactorial inheritance is not excluded. Genetic heterogeneity of epilepsy manifests itself at different levels. It is revealed in a variety of clinical features of the phenotype, heritable characteristics (patterns), primary gene products, among which may be factors for the development and differentiation of neurons, enzymes, receptor proteins, channel proteins, and finally, products of another gene. Abnormalities of the genetic code also vary, and several loci on different chromosomes may be involved.

According to the US national program (California Comprehensive Epilepsy Program), between 2 and 2.5 million Americans suffer from epilepsy. Over 10 years of studies of American families, six different loci on different chromosomes were identified in patients with epilepsy. When mapping chromosomes, it is customary to denote its number as the first digit; letters p or q shoulders, followed by numbers segments of regions (for more details, see). It was found that loci on chromosomes 6p and 15q are responsible for juvenile myoclonic epilepsy; for classic juvenile epilepsy with grand mal seizures and mixed with absence seizures on chromosome 6p (absences are sudden short-term loss of consciousness lasting 2-15 s). Two loci have been identified for childhood absence epilepsy (pycnolepsy), which occurs with severe seizures, in 8q24, and for developing into juvenile myoclonic epilepsy, in 1p. In patients in Italian families, other loci were identified: for idiopathic (from the Greek idios - own; pathos - suffering; idiopathic - primarily occurring without external causes) generalized epilepsy - in chromosome 3p, and for generalized epilepsy with febrile convulsions and absence seizures - also in chromosome 8q24.

The gene that determines the development of FS turned out to be in different regions of the 8th and 19th chromosomes than previously determined by DNA markers. Their position indicates a connection between FS and other genetically determined forms of epilepsy.

The study of families with inheritance of FS identified a genetic component and autosomal dominant inheritance. The work of Japanese geneticists, when examining 6,706 children aged three years in the Fuchu province of Tokyo with a population of about 182,000 people, showed that 654 children had FS. New interesting facts were obtained by S. Berkovich as a result of many years of research on families in Australia. It was discovered that the main PS gene is located at 8q13-21 and is associated with Na+ channel protein synthesis. Features of the immune status in Egyptian children who underwent FS suggested that genetically determined FS were observed in children with the HLA-B5 antigen, a low level of IgA immunoglobulin and a low content of T-lymphocytes. All this allows us to talk about feedback: children had not only a predisposition to FS, but also increased sensitivity to acute infections that occur with fever, which becomes the physiological cause of seizures. The combination of intrauterine encephalopathy syndromes with a hereditary family history of epilepsy only worsens the outcome of FS. Since the main condition for the occurrence of PS in a child is an increase in temperature, hyperthermia should be considered as a factor in epileptogenesis.

The role of the thermoregulatory center of the hypothalamus in the initiation of febrile seizures

Why is a prolonged increase in temperature so dangerous for a child's developing brain? The facilitation of the occurrence of PS is determined by the low level of the inhibitory mediator - gamma-aminobutyric acid (GABA) and the absence of full-fledged receptors for it, as well as a decrease in the level of ATP in the brain for one reason or another, especially under the influence of hypoxia. In a child, the level of lipid peroxidation products increases, brain microcirculation is disrupted, and brain hyperthermia is accompanied by edema. All neurochemical systems of inhibition of neurons, and primarily hypothalamic ones, are immature. In the brain, connections are just being established between brain cells responsible for the constancy of body temperature.

The temperature regulation center is located in the anterior hypothalamus. More than a third of the neurons in this area are thermoreceptors, and they receive information from peripheral thermoreceptors of the skin and internal organs via nerve pathways. Approximately a third of these cells are thermal receptors; they increase the frequency of discharges with increasing blood temperature (0.8 imp "s-1" °C-1), less than 5% of the cells are cold receptors. Recently, experiments on isolated brain slices showed that an increase in the temperature of the washing blood changes the rate of neuronal depolarization, determined by the properties of the Na+ channels of the membrane, while at the same time the interspike intervals decrease, which partly depends on the K+ channels. As a result, the frequency of cell discharges increases sharply. When the inhibitory systems are underdeveloped, this leads to hyperexcitability, the occurrence of paroxysmal excitations covering the motor cortex, and the appearance of seizures.

Heat production and heat transfer are two important physiological mechanisms for maintaining temperature in the optimal range for the body. But it is precisely these peripheral mechanisms in the child that are also immature and cannot stop the increasing hyperthermia.

Modeling of febrile seizures in newborn animals

The developed models of PS in newborn animals - rat pups - helped to identify vulnerable, critical periods of brain development, temperature thresholds at which PS occurs, to study the long-term consequences of PS, and to study the effect of anticonvulsants. Working together with Park Jin Kyu in Daejeon (South Korea), we found that systemic administration of a specific combination of ginsenosides, biologically active substances isolated from ginseng root, provides unique opportunities for preventing or reducing the severity of FS in rat pups. Of all the techniques developed by physiologists: endogenous hyperthermia, external warming with air, microwave, infrared rays, we chose simple heating with an incandescent lamp. As body temperature rises, there is a gradual development of external signs of motor seizures, the severity of which was determined according to the generally accepted scale of P. Maresh and G. Kubova. Hyperthermia was stopped when tonic-clonic convulsions with loss of posture appeared in the rat pups, and in the absence of PS, after 15 minutes. To measure infrared radiation from the intact surface of the animal’s skin, a thermal imaging method was used - an Inframetrics 522L infrared detector.

Neuroendocrine regulation of febrile seizures

The brain's response to hyperthermia involves the neurohormone arginine vasopressin (AVP). The following facts support this hypothesis of K. Pitman: in Brattleboro rats with a genetically determined deficiency of AVP and in rats passively immunized to this peptide, a convulsive response to elevated temperature occurs at higher temperatures than in animals with a normal level of its synthesis. Electrical stimulation of neurons that synthesize AVP helps to stop fever. On the one hand, clinical data indicate an increase in the level of AVP in the blood plasma of children after convulsive seizures; on the other hand, perfusion of AVP through the septum pellucidum of the brain in animals leads to a decrease in elevated body temperature. The hypothesis allows us to talk about the discovery of an endogenous antipyretic (from the Greek pyretos - heat, fever, pyretica - a drug that causes fever). Paradoxically, it turned out that the antipyretic function of the neurohormone AVP is combined with a proconvulsant effect.

In our experiments performed with Soros student A.A. Ponomarenko, new facts were obtained about the proepileptic effect of AVP using the example of PS in the early postnatal ontogenesis of the brain of rat pups. AVP actually significantly shortens the time of appearance of generalized, hyperthermic convulsions on the 3rd and 5th days after birth, their duration clearly increases compared to those in animals of the control group. On the 9th postnatal day, with a combination of hyperthermia and AVP administration in the experimental group, febrile status epilepticus lasting more than 2 hours resulted in the death of all rat pups receiving AVP. Such events leading to death cannot but be controlled at the hormonal and neurochemical levels. It was necessary to find out which regulators aggravated the effect of high temperature.

AVP is an antidiuretic hormone that conserves water in the body, so its secretion depends on water-salt balance, but, in addition, its release is controlled by a recently discovered peptide that activates pituitary adenylate cyclase (abbreviated by the first Latin letters - PACAP). The effect of the latter does not depend on an increase or decrease in the concentration of salts in the blood. Only in 1999, Nomura proved that PACAP stimulates the transcription of the AVP gene in the cells of those hypothalamic nuclei that are responsible for the regulation water-salt metabolism and drinking behavior. Our experiments have shown that when PACAP is administered to rat pups, it can act through the secretion of AVP at the time of hyperthermia (see Fig. 2). Multidirectional changes in experimental febrile seizures were found in rat pups after administration of high (0.1 μg per rat) and low (0.01 μg per rat) doses of PACAP. The effect also depends on the age of the rat, that is, the maturity of the hypothalamus.

So, AVP combines the functions of an endogenous antipyretic agent and an inducer of a convulsive motor reaction during a rapid increase in body temperature, and one of the regulators of its secretion, PACAR, can accelerate these processes. Seems likely direct action AVP and PACAR on membranes nerve cells through receptors to them (Fig. 3). But other regulatory pathways cannot be excluded, for example through the hypothalamic releasing factor – corticoliberin. Cells that synthesize PACAP send their axons to the bodies of neurosecretory cells of the hypothalamus that synthesize corticoliberin. The release of corticoliberin into the blood provokes epileptic seizures.

Intracellular protection of neurons – heat shock proteins

In some cases of genetically determined neuropathology, molecular events are secondary. Febrile seizures are no exception. A significant increase in body temperature leads to the expression of genes for a huge number of proteins called “heat shock proteins” (HSPs). Transcription of HSP begins several minutes after heating. This reaction has always been considered protective against death from heat shock. The latest evidence for this theory comes from the Cancer Institute in Copenhagen. In tissue culture, it has been shown that severe heat stress causes apoptosis (from the Greek apoptosis - falling of leaves or petals from a flower - genetically

programmed death of one or more cells, see for more details), but moderate stress (and hyperthermia is classified as moderate stress), due to the preservation of the cell’s ability to synthesize HSPs, protects them from both apoptosis and necrosis. This property will allow the use of HSPs in vivo (in the clinic) to protect the heart and brain from ischemia, the lungs from sepsis, moreover, they can be used in anti-cancer therapy. HSPs can also be used for urgent brain protection in the event of FS in children.

HSP synthesis is a nonspecific stress response. In the cells and tissues of the body, HSPs are induced by many factors in addition to hyperthermia, namely: ischemia, peroxidation, the action of cytokines (cytokines are endogenous protein regulators involved in the most effective manifestation of the immune response), muscle stress, glucose deprivation, disturbances in the level of Ca2 + and pH. Dutch physiologists in Nijmegen recently showed that protective reactions in the form of HSP expression are observed in patients with parkinsonism in the late stage of the disease with the development of dementia and in Alzheimer's disease. A direct correlation was found between HSP expression and the severity of Alzheimer's disease, especially with damage to the hippocampus.

Thus, during PS, HSP genes are expressed, but such nonspecific protection is not always sufficient to preserve inhibitory cells, especially in the hippocampus. Therefore there is a threat long-term consequences in the form of mesial hippocampal sclerosis, causing temporal lobe epilepsy. If a genetic predisposition to temporal lobe epilepsy is combined with a predisposition to FS, the prognosis of the disease is especially difficult.

The question of the consequences of FS in the form of the development of temporal lobe epilepsy is important for the subsequent fate of the child. The main discussion in the clinic revolved around the question of whether cells die as a result of PS, or whether they die for other reasons (for example, as a result of a violation of the protective synthesis of HSPs, the development of apoptosis). Molecular biological studies in the laboratory of K. Wasterline in Los Angeles showed that seizure processes in the developing brain delay its development, and in particular the growth of axons, since the seizure disrupts the expression of the gene for the marker of the axon growth cone - the GAP-43 protein.

Surgeons who operate on the temporal region to treat temporal lobe epilepsy note that many of their patients have had episodes of FS in childhood. However, this is a retrospective assessment. Recent research in Canada has shown that a positive family history and FS are inseparable factors in the development of temporal lobe epilepsy. It can be assumed that the longer the FS attacks were, the longer the generalized seizure engulfed the child’s brain and the more nerve cells died. No matter how small the percentage of such children is (only 1.5-4.6% of children with FS subsequently develop epilepsy), they will be doomed to suffering and treatment for the rest of their lives due to the death of hippocampal inhibitory cells due to hyperthermia.

Genetics of potassium and sodium channels and epilepsy

The causes of paroxysmal states may be changes in the structure and functions of Na+-, Ca2+-, Cl--, K+ channels. The channel is one protein molecule, it is characterized by strict selectivity with respect to the type of ion passed through, and has a gate device that is controlled by the potential on the membrane (Fig. 4, a). The occurrence and conduction of nerve impulses depends on the state of ion channels. For the last ten years, hereditary diseases have been studied nervous system, which received a new name - “channelopathy”. The disorders are associated with the localization of genes in chromosomes: 19q13.1 (Na+ channel), 12p13, 20q13.3, 8q24 (K+ channel), 7q (Cl- channel). The discovery of the molecular structure of the channels has helped to understand the inheritance of epilepsy.

A nerve impulse is a consequence of the movement of Na+ into the cell through membrane channels, and K+ out of the cell. Positively charged Na+ ions entering along the ion gradient create a membrane-depolarizing current, reducing the membrane potential to zero and then recharging the membrane to + 50 mV. Since the state of these channels depends on the sign of the charge on the membrane, a positive membrane potential promotes the inactivation of sodium channels and the opening of potassium channels. Now the K+ ions leaving the cell create a current that recharges the membrane and restores its resting potential. Disturbances of Na+ channels lead to changes in cell depolarization, and disturbances of K+ channels lead to disruption of polarization. The discovery in 1980 by D. Brown and P. Adams of low-threshold M-currents through non-inactivating KCNQ2/KCNQ3 potassium channels helped to understand the nature of susceptibility to epilepsy. M-currents change the excitability of the cell and prevent the occurrence of epileptic neuron activity. Disruption of the KCNQ2/KCNQ3 potassium channel genes leads to the disease “familial neonatal seizures,” which occurs in a child on the 2-3rd days after birth. The newly synthesized drug retigabine helps patients with epilepsy by opening KCNQ2/KCNQ3 channels in neuronal membranes. This is an example of how fundamental study of channels can help synthesize new drugs against channelopathies.

We have already mentioned two loci responsible for PS. New studies have shown the involvement of another region of 19q13.1, responsible for the synthesis of the b1 subunit of the Na+ channel. Mutations in this region determine the occurrence febrile seizures in combination with generalized epilepsy. The Na+ channel consists of one a- (forming a pore) and two b-subunits, the latter modulate the process of inactivation of the channel, that is, the work of the a-subunit (see Fig. 4, a). The effect of the a-subunit on the gate system depends on the structure of the extracellular domain of the b1-subunit. The SCN1B gene responsible for the b1 subunit was reasonably chosen for research, since the action of the main anticonvulsants phenytoin and carbamazepine is to inactivate sodium channels. Moreover, it was already known that mutations of this gene in muscle cells lead to paroxysmal excitations (myotonia, periodic paralysis), and in cardiac cells - to an increase in the QT interval in the ECG. It is in the region of the disulfide bridge that a mutation occurs, leading to its destruction and a change in the structure of the extracellular domain b1 (Fig. 4, b). Transfer of the gene into the Xenopus laevis oocyte and induction of the synthesis of the defective channel made it possible to electrophysiologically study the mutant channel and prove that it is inactivated more slowly (see Fig. 4, b). It is very important that in such patients there are no changes in the cells of the heart muscle and skeletal muscles, and the mutation is observed only for the neural isoform of Na+ channels. This mutation was identified as a result of research by Australian geneticists. A study was conducted of six generations of families (378 people), living mainly in Tasmania and having a family history of FS in combination with generalized epilepsy. These works opened new way for studying idiopathic forms epilepsy, which may be the result of as yet unknown forms of channelopathies.

Equally important are disturbances in the synthesis of protein receptors for mediators. Autosomal dominant inheritance of nocturnal frontal epilepsy is associated with chromosome 20 (gene localization in q13.2 - q13.3), and the manifestation of this form of epilepsy is associated with the S248F mutation of the genetic code of the a4 subunit of the H-cholinergic receptor. The “wall” of the channel protein, its transmembrane 2nd segment, in which the amino acid serine is replaced by phenylalanine, is subject to change. Disturbances in the regulation of the gene expression of the b-subunit of the NMDA receptor protein for the excitatory transmitter - glutamate, the release of which by brain cells initiates an epileptic attack, were also discovered. If, during the process of mRNA editing, glutamine is replaced by arginine in the membrane domain, the resulting disruption of alternative splicing (for more details, see) is already sufficient to significantly increase the excitability of hippocampal neurons.

Inheritance of "hot water epilepsy"

In one of the poster presentations by Indian neurologists at the Epilepsy Congress in Oslo in 1993, we suddenly saw something reminiscent of a medieval Chinese execution: hot water was dripped onto the head of a motionless rat until a severe epileptic seizure occurred. An unbiased study of this report showed that the created torment of the rat is caused by the desire to understand a serious illness, which in populous India affects almost 7% of all patients with epilepsy and accounts for 60 cases per 100 thousand diseases. This phenomenon is similar to the hyperthermia-induced convulsions discussed above.

Case of epileptic seizure while washing hair hot water was first described in New Zealand in 1945. A sick person, when washing his hair (and in Hindu traditions, this procedure is repeated every 3-15 days) with hot water at a temperature of 45-50 ° C, experiences an aura, hallucinations, ending in partial or generalized convulsions with loss of consciousness (men are 2-2.5 times more likely than women). It is possible to measure the temperature of the brain as closely as possible by inserting a special electrothermometer into the ear canal close to the eardrum. It turned out that in patients the brain temperature at the beginning of washing their hair rises very quickly (every 2 minutes by 2-3°C) and very slowly

decreases after stopping washing. Their brains “cool down” slowly (10-12 minutes), while in healthy volunteers participating in such experiments, the brain “cools down” almost instantly after stopping bathing. The question naturally arose: what deviations in thermoregulation are the cause of the disease and are they determined genetically? The true reason was revealed by twin studies and family analysis data. It turned out that in India, up to 23% of all cases of “hot water epilepsy” are repeated in subsequent generations.

PS, as we have already said, are a consequence of autosomal dominant inheritance at one chromosome locus - 8q13-21. In “hot water epilepsy,” changes in one locus are not sufficient to explain the entire complex of the disease. The appearance of the diseased phenotype (both sexes) may be associated with an autosomal recessive mutation leading to this disease. Observations of five generations of several families in India showed that the disease occurs in children of closely related parents, for example in marriages between nephews. In southern India, traditions of such closely related marriages have been preserved, which, apparently, can explain high percent patients compared to other states.

Conclusion

The neurogenetic approach has made it possible to definitively establish the genetic predisposition to febrile seizures. This is why not every child who is exposed to a very high temperature (40-41°C) for a long time experiences motor convulsions. The main PS gene is associated with the membrane mechanisms of neuron excitability, with the control of the synthesis of the protein channel through which Na+ ions pass. A depolarizing excitation of the neuron is created. It is not surprising that the “genes” of these disorders related to FS are somewhat “aloof” from the specific genes responsible for other forms of epilepsy. External cause FS is overheating, which occurs under the influence of either endogenous pyretics (for example, during an infectious disease), or actually under the influence of an increase in environmental temperature. In response to hyperthermia, physiological defense is the first to turn on - functional system maintaining the temperature in the optimal range. It is aimed at reducing body temperature. Nerve signals go to the vegetative centers - commands aimed at releasing heat and reducing heat production. The cells of the hypothalamus, having the ability to measure blood temperature, themselves use feedback mechanisms to monitor the results of these commands. Since they are neurosecretory and secrete liberins and statins, they can simultaneously trigger complex biochemical changes by regulating the secretion of pituitary hormones. Endocrine mechanisms and behavioral defense reactions are almost simultaneously connected to autonomic regulation. The release of synaptic AVP as an antipyretic substance leads to an increase in the convulsive response. The secretion of AVP, in turn, is enhanced by the neuropeptide PACAP, which activates the energy of pituitary cells. Unfortunately, this protective attempt to lower body temperature ends in provoking seizures. Genetic predisposition and low seizure threshold lead to irreversible development of events. Paroxysmal pathological convulsive activity of neurons occurs, first in the hippocampus, amygdala, associative parts of the cortex, and then in the motor cortex. For all types of seizures, the main cause remains a violation of the ratio of the release of excitatory (glutamate) and inhibitory (GABA) mediators. This violation is a pre-trigger mechanism. Unlimited excitation in the nerve networks covers the parts of the brain responsible for tone and movement, and leads to convulsions. Before this, loss of consciousness occurs, as pathological excitation covers the structures of the brain stem and thalamus. Of course, the brain also has other protective mechanisms, such as compensatory expression of early oncogenes (c-fos, c-jun), accumulation of cAMP, secretion of thyrotropin-releasing hormone, and long-term release of an inhibitory transmitter. However, the question of why these mechanisms are ineffective in the case of a genetic predisposition to PS requires further research.

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Epilepsy in inborn errors of metabolism in children/

Authors: Nicole I. WOLF, Thomas BAST, Department of Child Neurology, University Children's Hospital, Heidelberg, Germany; Robert SOURTES, Neurological Research Fellowship, Institute of Child Health, University College, London, UK

Summary

Although inborn errors of metabolism are rare enough to be considered a cause of epilepsy, seizures are common symptoms of metabolic disorders. In some of these disorders, epilepsy responds to specific treatment with diet or supplements. However, in most cases, such treatment is ineffective, and it is necessary to prescribe conventional antiepileptic therapy, which is also often ineffective. Rarely are the types of seizures specific to certain metabolic disorders, and they are usually not recorded on the EEG. In order to make a diagnosis, other symptoms and syndromes must be taken into account, and in some cases additional methods examinations. We give an overview of the most important symptoms of epilepsy caused by inborn errors of metabolism, memory, intoxications and disorders of neurotransmitter systems. We also review vitamin-sensitive epilepsy and a variety of other metabolic disorders that may be similar in pathogenesis, and the importance of their symptoms for diagnosis and treatment.

Keywords

inborn errors of metabolism, memory disorders, neurotransmitters, vitamin-sensitive epilepsy, epilepsy.

Seizures are a common symptom for a large number of metabolic disorders occurring in the neonatal period and childhood. Sometimes attacks occur only until adequate treatment is prescribed, or are a consequence of an acute decompensated metabolic disorder, such as hyperammonemia or hypoglycemia. In other cases, seizures are the main manifestation of the disease and can lead to drug-resistant epilepsy, as in one of the creatinine deficiency syndromes and guanidine acetate methyltransferase (GAMT) deficiency. In some cases of metabolic disorders, epilepsy can be prevented by early initiation of individually tailored “metabolic” treatment, which has been introduced following screening of newborns with phenylketonuria (PKU) or biotinidase deficiency in some countries. For some disorders, such as celiac aciduria type 1 (GA 1), “metabolic” therapy should be prescribed in conjunction with conventional antiepileptic drugs; however, for many metabolic disorders, the only means of eliminating seizures is monotherapy with antiepileptic drugs.

Epilepsy due to inborn errors of metabolism can be classified in different ways. One of the correct options is to use pathogenetic mechanisms for classification: attacks can be caused by a lack of energy expenditure, intoxication, memory impairment, damage to neurotransmitter systems with cases of excitation or lack of inhibition, or may be associated with cerebral vascular malformations (Table 1). Other classifications take into account clinical manifestations with an emphasis on the semiotics of seizures, epileptic syndromes and their manifestations on the EEG (Table 2) or the age at which the disease began (Table 3). Organizing these types of epilepsies means identifying those that do and do not respond to the same treatment as metabolic disorders (Table 4). In this review, we will focus on pathogenesis and its role in diagnosis and treatment.

Epilepsy due to congenital disorders of energy metabolism

Mitochondrial disorders

Mitochondrial disorders are often combined with epilepsy, although there is little accurate data in this area, there are only a few publications on this subject. In the neonatal period and childhood, epilepsy is detected in 20-60% of cases of all mitochondrial disorders. In the general subgroup, with Leigh's syndrome, epilepsy is detected in half of all patients. In our experience, epilepsy is a common disease with early onset and severe psychomotor delay, which is less common in older adults. mild flow disease, and in which there are predominant white inclusions on MRI. All attacks manifest clinically.

Decreased production of ATP, the main biochemical downstream of the disrupted respiratory chain, is likely to cause unstable membrane potential and nervous system alertness because about 40% of neurons require Na-K-ATPase to produce ATP and to maintain membrane potential. One of the mutations in mitochondrial DNA (mtDNA) causes myoclonic epilepsy with intermittent red waves (MERW), with damaged calcium metabolism leading to increased convulsive readiness. Another possible mechanism is currently being discussed, and the importance of mitochondrial glutamate has been shown to mediate early myoclonic encephalopathy (EME), which may also be due to an imbalance of excitatory neurotransmitters. One of the first mitochondrial disorders to be described, MEPLE, is caused by a mutation in the mitochondrial tRNA for lysine, present in the second decade or later as progressive myoclonic epilepsy with typical EEG changes of high-amplitude somatosensory potentials and photosensitivity. Clinically, patients experience cortical myoclonus as well as other types of seizures. Another mitochondrial disorder caused by a mutation in the mitochondrial tRNA for leucine, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELIE), also often leads to seizures, especially during acute stroke-like episodes when focal seizures occur in the involved cortical areas (Figure 1). , leading to focal epistatus. This marked epileptic activity is also responsible for the spreading damage seen in some acute episodes.

At the onset of mitochondrial encephalopathy in the neonatal period or in childhood, myoclonic seizures are frequent, sometimes with rare isolated clinical manifestations (tremor of the eyelids) and profound mental retardation. EEG patterns range from suppressive bursts to irregular polyspike-wave paroxysms during myoclonus. However, other types of seizures may occur - tonic, tonic-clonic, partial, hypo- and hypermotor seizures or infantile spasms. One study found that 8% of all children with infantile spasms had mitochondrial disorders. Epistatus has also been observed with or without seizures. Long-lasting partial epilepsy, such as focal epilepsy, is common in Alpers disease, some cases of which are caused by a mutation in mitochondrial DNA polymerase gamma caused by mitochondrial depletion. Alpers disease should be suspected in children with this symptom and should be differentiated from Ramussen encephalitis.

Non-convulsive epistatus or the development of hypoarrhythmia can lead to gradually developing dementia, which may be mistaken for the constant and untreatable progression of the underlying disease, but they must be treated.

Disorders of creatine metabolism

Disorders of creatine metabolism include three different defects: impaired transport of creatine into the brain due to a defect in the coupled creatine transporter, and impaired creatine synthesis due to defects in GAMT (guanidinium acetate methyltransferase) and AGAT (arginine glycine amidine transferase). Only GAMT deficiency is consistently associated with epilepsy that is resistant to conventional treatment (Fig. 2). Creatine supplementation often results in improvement. However, in some patients, reducing the toxic components of guanidine acetate by limiting arginine intake and supplementing with ornithine has been able to control epilepsy. In addition, preventive treatment makes it possible to prevent the onset of neurological symptoms. There are many types of seizures, they are varied. Newborns are characterized by West syndrome with atypical absences, astatic and generalized tonic-clonic seizures, followed by general generalization. Such findings may be normal even in adult patients, but some patients have an abnormal signal from the basal ganglia. The diagnosis of GAMT deficiency may be questioned by biochemical detection of increased urinary excretion of guanidine constituents; All three disorders are allowed when proton magnetic resonance spectroscopy of the brain or SMPS reveals the absence of free creatine or creatine phosphate.

GLUT-1 deficiency

Impaired transport of glucose into the brain through the blood is caused by a mutation in the dominant gene for glucose transporter 1 (GLUT-1). The mutation usually occurs de novo, although autosomal dominant inheritance has been described in some families. Clinical manifestations of drug-resistant epilepsy begin in the first year of life and are complemented by the development of microcephaly and intellectual impairment. Ataxia is a common finding, and movement disorders such as dystonia also occur. Symptoms may develop rapidly, and the EEG may reveal increased generalized or local epileptiform changes that regress after eating. Cerebral imaging is normal. This diagnosis should be suspected if low blood glucose levels are detected (< 0,46). Диагноз должен быть подтвержден исследованием транспорта глюкозы через мембрану эритроцита (эритроциты переносят также транспортер глюкозы) и анализом генных мутаций. Лечение целесообразно и включает в себя кетогенную диету, так как кетоновые тела являются альтернативной энергетических субстратов для мозга. Различные антиконвульсанты, особенно фенобарбитал, хлоргидрат и диазепам, могут в дальнейшем снижать ГЛУТ-1 и не должны использоваться при этом заболевании.

Hypoglycemia

Hypoglycemia is a common and easily correctable metabolic disorder leading to attacks and should therefore be excluded in all patients with attacks. Prolonged attacks caused by hypoglycemia can cause hippocampal sclerosis and subsequently parietal lobe epilepsy; in newborns, damage to the temporal lobe predominates. Hypoglycemia can also cause certain metabolic diseases, such as defects in gluconeogenesis, so further testing is necessary. Every child with hypoglycemia should have blood glucose, beta-hydroxybutyrate, amino acids, acylcarnitine, ammonium, insulin, growth hormone, cortisol, ketone bodies in the brain, organic acids.

Nervous system dysfunction caused by memory impairment

Many memory disorders are associated with epilepsy and are difficult to treat. Epilepsy is the leading symptom of Ty-Sachs disease with myoclonus, atypical absence seizures and motor seizures.

Type 1 sialidosis leads to the development of progressive myoclonic epilepsy; the characteristic symptom is the retinal “cherry pit” sign. In various neuronal seroid lipofuscinoses (NSL, Batten disease), epilepsy occurs in most cases. In infantile forms (NSL-1), seizures begin and end in the first year of life and manifest themselves in the form of myoclonic, atopic and tonic-clonic seizures. The EEG shows early deep depression. The diagnosis is confirmed by rapidly progressing dementia and the development of a complex of movement disorders almost immediately after the development of epilepsy. MRI with NSL reveals atrophy of the cortex, cerebellum and white matter and a secondary pathological signal from the white matter (Fig. 3). Electroretinograms are very sparse, and evoked potentials disappear quickly. Milder variants are similar to late-onset juvenile forms of the disease.

Clinical manifestations of late infantile forms (LID-2) usually occur in the second year of life. A transient slowing of speech function develops, but this development of seizures prompted further research. Seizures can be generalized, tonic-clonic, atonic and myoclonic; Children may have a clinical picture of myoclonic-astatic epilepsy. The EEG reveals spikes with slow photostimulation (Fig. 4). High-amplitude potentials with visually evoked and somatosensory responses are detected. Attacks are often resistant to treatment. Early clinical diagnostic symptom is the presence of active myoclonus, which can be mistaken for cerebellar ataxia.

Diagnosis of NSL-1 and NSL-2 is currently based on the determination of the activity of enzymes such as palmiteyl protein thioesterase (PTP-1) or tripeptidyl peptidase (PTP-2) in blood spots or white blood cells or by gene mutation assays ( NSL-1, NSL-2, and in late infantile variants SLN-5, SLN-6, SLN-8). The juvenile form (NSL-3) also causes the development of epilepsy, although it does not develop immediately and is not one of the early clinical symptoms.

Toxic effects

Urea cycle disorder

During the early development of hyperammonemia, seizures often develop before deep coma sets in, especially in newborns. With good metabolic control, epilepsy is a rare symptom in such disorders.

Amino acid metabolism disorders

With untreated phenylketonuria, epilepsy develops in approximately a quarter to half of all patients. West syndrome with hypsarrhythmia and infantile seizures is the most common syndrome in newborns, which completely regresses when prescribed symptomatic therapy. Seizures may accompany maple syrup disease in the neonatal period; The EEG reveals a “comb-like” rhythm, similar to the rhythm in the central regions of the brain. When an adequate diet is prescribed, epilepsy does not develop. In some rare disorders of amino acid metabolism, epilepsy may be one of the main symptoms.

Organic acid metabolism disorders

Various organic acidurias can lead to attacks or episodes of acute decompensation. The most important are methylmalonic acidemia and propionic acidemia. With adequate treatment, seizures are rare and reflect persistent brain damage. In glutaric aciduria type 1, attacks may develop in acute cases, but they subside after the initiation of adequate treatment. In 2-methyl-3-hydroxybutyrate-CoA dehydrogenase deficiency, which has recently been described as a congenital acid disorder responsible for brachiocephalic obesity and a disorder of isoleucine metabolism, severe epilepsy is common.

Disorders of purine and pyrimidine metabolism

In cases of adenylsuccinate deficiency, whose de novo effects induce purine synthesis, epilepsy often develops in the first year of life or in the neonatal period. Patients additionally exhibit severe psychomotor impairment and autism. The modified Bratton-Marshall test is used to test urine. There is no adequate treatment for this disease, so the prognosis in most cases is unfavorable. Seizures also develop in half of all patients with dihydropyrimidine dehydrogenase deficiency.

Disorders of neurotransmitter systems

Non-ketotic hyperglycemia

Typically, this disorder of insufficient breakdown of glycine manifests itself early in the neonatal period with lethargy, hypotension, hiccups (which are detected before birth), ophthalmoplegia and autonomic disturbances. As the coma worsens, apnea and frequent focal myoclonic jerks develop. Over the next 5 months (usually more than 3), severe, difficult-to-treat epilepsy with myoclonic seizures develops, in most cases including infantile spasms or partial motor seizures. The development of severe mental retardation and tetraplegia has also been proven. In the first days and weeks, the EEG shows normal background activity, but areas of epileptic sharp waves (so-called suppressive bursts) appear, followed by high-amplitude slow activity and then hypsarrhythmia within 3 months if the newborn survives. Diagnosis is based on a high concentration of glycine in all body fluids and cerebrospinal fluid (> 0.08), which is confirmed by reduced activity of the hepatic glycine breakdown system. MRI may show a normal appearance or agenesis or hypoplasia of the corpus callosum. Glycine is one of the major inhibitors of neurotransmitters in the brain and spinal cord. Excessive inhibition of the structures of the brain and spinal cord gives the appearance of the first symptoms in the clinic of the disease. However, glycine can also be a co-antagonist of the exotoxic glutamate NMDA receptor. Under physiological conditions, the coantagonist is not completely located on the NMDA receptor, and its binding is prerequisite for the ion to pass through the receptor. It is hypothesized that excess glycine saturates the coantagonist-binding site of the NMDA receptor, causing overexcitation of neurotransmission and postsynaptic toxicity. The excitatory toxic effect of an overactive NMDA receptor is obviously the cause of epilepsy and partly tetraplegia and mental retardation. Specific treatment is not appropriate, although lowering glycine levels with sodium benzoate provides survival. Some patients present with NMDA antagonist therapeutic trials with some EEG manifestations and frequent seizures. Severe epilepsy in surviving patients is usually treated with conventional antiepileptic drugs. Valproic acid is not used in theory because it inhibits the hepatic glycine breakdown system.

GABA Metabolism Disorders

GABA transaminase deficiency is a rather rare pathology, described in only 3 patients. Convulsions are noted from birth. The level of GABA in the CSF and plasma increases. Only 2 patients survived to adulthood. There is no treatment plan for this disease yet. Succinate semialdehyde dehydrogenase deficiency causes severe mental retardation. Almost half of patients develop epilepsy and other neurological symptoms, mainly ataxia. A biochemical sign is the accumulation of 4-hydroxybutyrate in body fluids. The antiepileptic drug vagabatrin, which irreversibly inhibits GABA transaminase, is effective in many patients but may cause worsening of the condition in some.

Malformations in the brain

Among peroxisomal disorders, severe Zellweger syndrome is characterized by malformations in the cerebral cortex. Polymicrogyria of the frontal and opercular regions is common, and pachygyria is also occasionally found. Congenital cysts in the caudothalamic ganglia are typical (Fig. 5). Epilepsy in Zellweger syndrome typically involves partial motor seizures, which are treatable with standard antiepileptic drugs and indicate in which area of ​​the brain the malformation is present. Impaired O-glycosylation (Walker-Warburg syndrome, eye muscle disease, brain disease, Fukuyama muscular dystrophy) leads to brain malformations, including lissencephaly (Fig. 6). Patients often have seizures that are unresponsive to treatment. The EEG shows abnormal beta activity.

Vitamin-dependent epilepsy

Pyridoxine-dependent epilepsy and pyridox(am)ine phosphate oxygenase deficiency

The phenomenon of pyridoxine-dependent epilepsy has been known since 1954, but its molecular basis still had to be elucidated. A possible metabolic marker for this disease seemed to be pipecolic acid in plasma and CSF, which increased before pyridoxine and decreased during treatment, although still below normal. When studying genetics, a chain was identified in some families, including chromosome 5q-31.

The classification of pyridoxine-dependent epilepsy is divided into typical, early-onset, appearing in the first days of life, and atypical, late-onset, manifesting itself by the age of 34. If onset is early, there may be prenatal seizures occurring around 20 weeks of gestation. Neonatal encephalopathy with increased anxiety, irritability and sensitivity to external stimuli is common (in 1/3 of cases). It may be accompanied by systemic damage such as respiratory distress syndrome, nausea, abdominal disorders, metabolic acidosis. Many attacks begin in the first days of life and do not respond to standard treatment. Structural brain abnormalities, such as hypoplasia of the posterior part of the corpus callosum, cerebral hypoplasia or hydrocephalus, and other disorders, such as hemorrhages or organic lesions of the white matter of the brain, may be observed. A clear (up to minutes) reaction is detected in the form of cessation of convulsive activity to the intravenous administration of 100 mg of pyridoxine. However, in 20% of newborns with pyridoxine-dependent epilepsy, the first dose of pyridoxine can cause depression: newborns become hypotonic and sleep for several hours, apnea, dysfunction of the cardiovascular system and an isoelectric pattern on the EEG are less likely to develop. Cerebral depression from the first dose of pyridoxine is more common when anticonvulsants are prescribed to newborns.

On the contrary, with late-onset pyridoxine-dependent epilepsy, encephalopathy and structural brain disorders do not develop. In children over 3 years of age, seizures develop at any year of life. They often develop in the context of febrile conditions and can transform into epistatus. Usually antiepileptic drugs have a positive effect, but then it still becomes difficult to control these seizures. Pyridoxine in a daily dose of 100 mg per os ensures the cessation of convulsive activity for a 2-day period. With late-onset pyridoxine-dependent epilepsy, cerebral depression is not observed.

Currently, the only confirmation of the diagnosis of pyridoxine-dependent epilepsy is the cessation of seizures when pyridoxine is prescribed. Treatment is lifelong, and the daily dose of pyridoxine is 15-500 mg/kg. A persistent symptom of pyridoxine-dependent epilepsy is learning difficulties, especially when learning languages. Stopping treatment for several months or years causes the development of severe movement disorders, learning difficulties, and sensory disturbances. Every newborn with seizures, even those with diagnosed perinatal asphyxia or sepsis, must be prescribed pyridoxine.

Pyridox(am)ine phosphate oxidase (PPO) catalyzes the conversion of pyridoxine phosphate to the active cofactor, pyridoxal phosphate. PPO deficiency causes neonatal seizures, similar to those in early-onset pyridoxine-deficient epilepsy, but they cannot be treated with pyridoxine, but are treated with pyridoxal phosphate at a daily dose of 10-50 mg/kg. Pyridoxal phosphate is a cofactor for various enzymes in the synthesis of neurotransmitters and the breakdown of threonine and glycine. A biochemical marker of the disease is a decrease in the concentration of homovanillic acid and 5-hydroxyindole acetate (a breakdown product of dopamine and serotonin) and an increase in the concentration of 3-methoxytyrosine, glycine and threonine in the cerebrospinal fluid. The prognosis for treatment of PPO deficiency is unclear. It is assumed that if left untreated, death will occur.

Folate-dependent seizures

This is a rare disease that is treated with folic acid. Molecular basis this pathology is not clear. In all cases to date, an unidentified substance has been detected in the cerebrospinal fluid. Newborns with folate-dependent epilepsy need a trial of folic acid if there is no effect of pyridoxine and pyridoxal phosphate.

Biotinidase and holocarboxylase synthase deficiency

Biotinidase is a cofactor for various carboxylases. Various metabolites accumulate in the urine and lactic acidosis often develops. With biotinidase deficiency, endogenous disorders of biotin metabolism develop. Epilepsy usually begins after 3–4 months of age, and infantile spasms, optic atrophy, and hearing loss are common. The key to diagnosis is the presence of alopecia and dermatitis. Attacks are usually stopped when biotin is prescribed at a dose of 5-20 mg/day. With holocarboxylase synthase deficiency, symptoms appear in the neonatal period. Convulsions are observed in only 25-50% of patients. Biotin is effective at the dosage described above, although higher doses may be necessary in some children.

Mixed violations

Deficiency of molybdenum cofactor and sulfite oxidase

These rare inborn errors of metabolism usually present in the neonatal period with encephalopathy, intractable seizures (usually myoclonic), and lens displacement. MRI reveals cysts in the white matter of the brain and severe atrophy. The easy screening test is a simple sulfite strip test performed by dipping it into a sample of freshly collected urine. Fibroblasts exhibit a deficiency of various enzymes. There are no treatment regimens for this pathology yet.

Menkes disease

Children with this recessive X chromosome defect always suffer from epilepsy, often with treatment-resistant infantile spasms. The diagnosis is confirmed by detecting low levels of copper and ceruloplasmin in the blood serum. Subcutaneous administration of copper histidinate can cause the cessation of attacks and stop the development of the disease.

Serine biosynthesis deficiency

Serine biosynthesis is impaired by a deficiency of two enzymes: 3-phosphate glycerate dehydrogenase and 3-phosphoserine phosphatase. Only one case of this pathology occurring in an older age group has been described. In general, this is a fairly rare disease. Children with this pathology are born with microcephaly. They develop attacks in the first year of life, most often West syndrome. Seizures regress with oral serine supplementation. The key to a correct diagnosis is the detection of low levels of serine in the cerebrospinal fluid. MRI reveals brain white matter atrophy and demyelination.

Congenital disorders of glycosylation (CDG)

In children with SUD type 1a (phosphomannomutase deficiency), epilepsy is rare, sometimes only in the form of acute stroke-like episodes. However, this is a common syndrome in type 1 CNG. In patients with other subtypes of type 1 CNG, isolated cases seizures. The clinical picture of attacks varies depending on subgroups. Treatment with standard antiepileptic drugs is carried out depending on the clinical picture of the attacks. The diagnosis is made on the basis of isoelectric focusing of transferrin, which is part of the examination of children with unspecified epilepsy and mental retardation.

Congenital disorders of brain excitability

The concept behind inborn errors of metabolism is that the name implies an impairment in the flow of substances across cell membranes. Neuronal excitability ends with the appearance of a membrane potential, which is maintained by an energy-dependent ion pump (Na-K-ATPase and K/Cl transporter) and modulated by ion flow through protein channels. They are constantly closed and opened (thus allowing the flow of ions across the membrane) in response to the action of ligands (such as neurotransmitters) or changes in membrane potential. Genetic defects ion channels may be the cause of various epileptic syndromes. Thus, in some cases, such as as a result of metabolic disorders, primary epilepsy may develop.

Genetic defects in alpha-2 subunit-Na-K-ATPase 1 are one of the causes of familial migratory hemiplegia in children. In both cases, the likelihood of epilepsy is high. In one family they tried to find out whether familial spasms were an isolated disease or whether they were combined with migratory hemiplegia. Genetic defects in K/Cl transporter 3 are one of the causes of Andermann syndrome (Charlevox disease, or agenesis of the corpus callosum in combination with peripheral neuropathy). Epilepsy also often develops with this disease.

Ligand disruption of gated ion channels can also result in episyndrome. Genetic defects in the neural receptors for nicotinic acetylcholine (alpha 4 or beta 2 subunits) are one of the causes of autosomal dominant frontal lobe epilepsy. Inherited defects in the alpha 1 subunit of the GABA-A receptor are one of the causes of myoclonic juvenile epilepsy. Mutations in the gene code for the gamma 2 subunit of this receptor cause generalized epileptic febrile plus seizures (GEFS+), severe myoclonic epilepsy of the newborn (SMEN) and absence seizures in children.

Other congenital channelopathies can also manifest as episyndromes. Defects in voltage-gated potassium channels are one of the causes of familial neonatal spasms. Disturbances in voltage-gated chloride channels are one of the causes of juvenile absence seizures, juvenile myoclonic epilepsy and generalized epilepsy with grand-mal seizures. Mutations in the genes encoding various alpha subunits of voltage-gated potassium channels in the brain cause neonatal infantile spasms (type II alpha subunit), GEPS+ and TMEN. Since GEPS+ and TMEN– allelic disorders are at two different loci and both forms of epilepsy can occur in members of the same family, TMEN is considered the most severe phenotype in the spectrum of GEPS+ epilepsy.

Conclusion

Inborn errors of metabolism rarely present with epilepsy. However, epileptic syndrome is often characteristic of other metabolic disorders. Which patients need a screening examination and in the presence of what metabolic disorders? The answer to this question is, of course, not simple. Metabolic disorders should be suspected if epilepsy is resistant to standard treatment and if there are symptoms such as mental retardation and movement disorders. Sometimes the findings of a patient examination are characteristic of a particular metabolic disorder, for example, a typical MRI picture for mitochondrial disorders. If the first attack occurs in adulthood, the spectrum of metabolic disorders is narrower than in children.

In children, certain diagnostic methods are used depending on age. In the neonatal period, everyone should be prescribed pyridoxine or pyridoxal phosphate for diagnostic purposes, even if the attacks are caused by sepsis or perinatal asphyxia. If seizures do not respond to standard antiepileptic drugs, a trial of folic acid is necessary. In the presence of congenital myoclonic encephalopathy, an inborn error of metabolism is often assumed, although sometimes its nature cannot be clarified. Additional examinations are prescribed if deterioration is detected on the preprandial EEG (GLUT-1 deficiency), movement disorders (creatine deficiency), changes in the skin and hair (Menkes disease and biotinidase deficiency), dysmorphological symptoms (Zellweger syndrome), other disorders (mitochondrial diseases). Patients with partial epilepsy (unless Ramussen's syndrome) and AED-resistant epilepsy should be evaluated for mitochondrial disorders, especially mitochondrial DNA depletion, which is common in Alpers disease. Basic metabolic examinations should include tests such as serum and cerebrospinal fluid glucose levels, blood and cerebrospinal fluid lactate, ammonium and amino acid levels, and uric acid levels.

The diagnosis of a metabolic disorder in a patient with seizures makes it possible to choose the right treatment and thereby improve the patient's condition. Often, no matter what, antiepileptic drugs must be prescribed. If it is not possible to prescribe specific treatment, nonspecific antiepileptic drugs are prescribed; in some types of attacks, it is advisable to prescribe any of the antiepileptic drugs, except valproic acid. It is not used in cases of mitochondrial disorders, disorders of the urea cycle and is prescribed with caution in many other metabolic disorders. Clarifying the diagnosis not only helps determine treatment tactics, but also makes it possible to tell the patient’s family members what is most important in changing the patient’s condition.

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It is known that proteins undergo hydrolysis under the influence of endo- and exopeptidases formed in the stomach, pancreas and intestines. Endopeptidases (pepsin, trypsin and chymotrypsin) cause the breakdown of protein in its middle part into albumin and peptones. Exopeptidases (carbopeptidase, aminopeptidase and dipeptidase), formed in the pancreas and small intestine, ensure the cleavage of the terminal sections of protein molecules and their breakdown products into amino acids, the absorption of which occurs in the small intestine with the participation of ATP.

Protein hydrolysis disorders can be caused by many reasons: inflammation, tumors of the stomach, intestines, pancreas; resection of the stomach and intestines; general processes such as fever, overheating, hypothermia; with increased peristalsis due to disorders of neuroendocrine regulation. All of the above reasons lead to a deficiency of hydrolytic enzymes or acceleration of peristalsis when peptidases do not have time to ensure the breakdown of proteins.

Undigested proteins enter the large intestine, where, under the influence of microflora, putrefaction processes begin, leading to the formation of active amines (cadaverine, tyramine, putrescine, histamine) and aromatic compounds such as indole, skatole, phenol, cresol. These toxic substances are neutralized in the liver by combining with sulfuric acid. In conditions of a sharp increase in decay processes, intoxication of the body is possible.

Absorption disorders are caused not only by breakdown disorders, but also by ATP deficiency associated with inhibition of the coupling of respiration and oxidative phosphorylation and blockade of this process in the wall of the small intestine during hypoxia, poisoning with phloridzin, monoiodoacetate.

Impaired breakdown and absorption of proteins, as well as insufficient intake of proteins into the body, lead to protein starvation, impaired protein synthesis, anemia, hypoproteinemia, a tendency to edema, and immune deficiency. As a result of activation of the hypothalamic-pituitary-adrenal cortex system and the hypothalamic-pituitary-thyroid system, the formation of glucocorticoids and thyroxine increases, which stimulate tissue proteases and protein breakdown in the muscles, gastrointestinal tract, and lymphoid system. In this case, amino acids can serve as an energy substrate and, in addition, are intensively excreted from the body, ensuring the formation of a negative nitrogen balance. Protein mobilization is one of the causes of dystrophy, including in muscles, lymph nodes, and the gastrointestinal tract, which aggravates the disruption of protein breakdown and absorption.

When absorbing unsplit protein, allergization of the body is possible. So, artificial feeding children often leads to allergization of the body in relation to cow's milk protein and other protein products. The causes, mechanisms and consequences of disorders of protein breakdown and absorption are presented in Scheme 8.

Scheme 8. Disorders of protein hydrolysis and absorption
	Hydrolysis disorders	Absorption disorders
Causes	Inflammation, tumors, resection of the stomach and intestines, increased peristalsis (nervous influences, decreased stomach acidity, ingestion of poor quality food)
Mechanisms	Deficiency of endopeptidases (pepsin, trypsin, chymotrypsin) and exopeptidases (carbo-, amino- and dipeptidases)	ATP deficiency (absorption of amino acids is an active process and occurs with the participation of ATP)
Consequences	Protein starvation -> hypoproteinemia, edema, anemia; immunity disorder -> tendency to infectious processes; diarrhea, disruption of hormone transport. Activation of protein catabolism -> atrophy of muscles, lymph nodes, gastrointestinal tract with subsequent aggravation of disturbances in the processes of hydrolysis and absorption of not only proteins, vitamins, but also other substances; negative nitrogen balance. Absorption of unsplit protein -> allergization of the body. When undigested proteins enter the large intestine, the processes of bacterial breakdown (putrefaction) increase with the formation of amines (histamine, tyramine, cadaverine, putrescine) and aromatic toxic compounds (indole, phenol, cresol, skatole)

This type of pathological processes includes insufficiency of synthesis, increased breakdown of proteins, and disturbances in the conversion of amino acids in the body.

• Disturbance of protein synthesis.

  Protein biosynthesis occurs on ribosomes. With the participation of transfer RNA and ATP, a primary polypeptide is formed on ribosomes, in which the sequence of amino acids is determined by DNA. The synthesis of albumin, fibrinogen, prothrombin, alpha and beta globulins occurs in the liver; Gamma globulins are formed in the cells of the reticuloendothelial system. Disorders of protein synthesis are observed during protein starvation (as a result of starvation or impaired breakdown and absorption), with liver damage (circulatory disorders, hypoxia, cirrhosis, toxic-infectious lesions, deficiency of anabolic hormones). An important reason is hereditary damage to the B-immune system, in which the formation of gamma globulins in boys is blocked (hereditary agammaglobulinemia).

  Insufficiency of protein synthesis leads to hypoproteinemia, impaired immunity, degenerative processes in cells, and a possible slowdown in blood clotting due to a decrease in fibrinogen and prothrombin.

  An increase in protein synthesis is caused by excess production of insulin, androgens, and somatotropin. Thus, with a pituitary tumor involving eosinophilic cells, an excess of somatotropin is formed, which leads to activation of protein synthesis and increased growth processes. If excessive formation of somatotropin occurs in an organism with incomplete growth, then the growth of the body and organs increases, manifesting itself in the form of gigantism and macrosomia. If increased secretion of somatotropin occurs in adults, then an increase in protein synthesis leads to the growth of protruding parts of the body (hands, feet, nose, ears, brow ridges, lower jaw, etc.). This phenomenon is called acromegaly (from the Greek acros - tip, megalos - large). With a tumor of the reticular zone of the adrenal cortex, a congenital defect in the formation of hydrocortisone, as well as a tumor of the testes, the formation of androgens is enhanced and protein synthesis is activated, which is manifested in an increase in muscle volume and the early formation of secondary sexual characteristics. Increased protein synthesis is the cause of positive nitrogen balance.

  An increase in the synthesis of immunoglobulins occurs during allergic and autoallergic processes.

  In some cases, it is possible to distort protein synthesis and form proteins that are not normally found in the blood. This phenomenon is called paraproteinemia. Paraproteinemia is observed in myeloma, Waldenström's disease, and some gammopathies.

  With rheumatism, severe inflammatory processes, myocardial infarction, hepatitis, a new, so-called C-reactive protein is synthesized. It is not an immunoglobulin, although its appearance is due to the body's reaction to the products of cell damage.

• Increased protein breakdown.

  With protein starvation, an isolated increase in the formation of thyroxine and glucocorticoids (hyperthyroidism, syndrome and Cushing's disease), tissue cathepsins and protein breakdown are activated, primarily in the cells of striated muscles, lymphoid nodes, and the gastrointestinal tract. The resulting amino acids are excreted in excess in the urine, which contributes to the formation of a negative nitrogen balance. Excessive production of thyroxine and glucocorticoids also manifests itself in impaired immunity and an increased susceptibility to infectious processes, dystrophy of various organs (striated muscles, heart, lymphoid nodes, gastrointestinal tract).

  Observations show that in three weeks in the body of an adult, proteins are renewed by half through the use of amino acids received from food and through breakdown and resynthesis. According to McMurray (1980), at nitrogen equilibrium, 500 g of proteins are synthesized daily, i.e., 5 times more than what comes from food. This can be achieved through the reuse of amino acids, including those formed during the breakdown of proteins in the body.

  The processes of enhancing protein synthesis and breakdown and their consequences in the body are presented in Schemes 9 and 10.

  Scheme 10. Nitrogen imbalance
  	Positive nitrogen balance	Negative nitrogen balance
  Causes	An increase in synthesis and, as a consequence, a decrease in the excretion of nitrogen from the body (tumors of the pituitary gland, reticular zone of the adrenal cortex).	The predominance of protein breakdown in the body and, as a result, the release of nitrogen in larger quantities compared to intake.
  Mechanisms	Strengthening the production and secretion of hormones that provide protein synthesis (insulin, somatotropin, androgenic hormones).	Increased production of hormones that stimulate protein catabolism by activating tissue cathepeins (thyroxine, glucocorticoids).
  Consequences	Acceleration of growth processes, premature puberty.	Dystrophy, including the gastrointestinal tract, impaired immunity.

• Disturbances in the conversion of amino acids.

  During interstitial metabolism, amino acids undergo transamination, deamination, and decarboxylation. Transamination is aimed at the formation of new amino acids by transferring an amino group to a keto acid. The acceptor of amino groups of most amino acids is alpha-ketoglutaric acid, which is converted into glutamic acid. The latter can again donate an amino group. This process is controlled by transaminases, the coenzyme of which is pyridoxal phosphate, a derivative of vitamin B 6 (pyridoxine). Transaminases are found in the cytoplasm and mitochondria. The donor of amino groups is glutamic acid, located in the cytoplasm. From the cytoplasm, glutamic acid enters the mitochondria.

  Inhibition of transamination reactions occurs during hypoxia, vitamin B6 deficiency, including suppression of intestinal microflora by sulfonamides and ftivazide, which partially synthesizes vitamin B6, as well as during toxic-infectious liver lesions.

  In case of severe damage to cells with symptoms of necrosis (infarction, hepatitis, pancreatitis), transaminases from the cytoplasm enter large quantities into the blood. Thus, in acute hepatitis, according to McMurray (1980), the activity of glutamate-allanine transferase in the blood serum increases 100 times.

  The main process leading to the destruction of amino acids (their degradation) is non-amination, in which, under the influence of amino oxidase enzymes, ammonia and keto acid are formed, which undergo further conversion in the tricarboxylic acid cycle to C0 2 and H 2 0. Hypoxia, hypovitaminosis C, PP, B 2 , B 6 blocks the breakdown of amino acids along this pathway, which contributes to their increase in the blood (aminoacidemia) and excretion in the urine (aminoaciduria). Usually, when deamination is blocked, some amino acids undergo decarboxylation with the formation of a number of biologically active amines - histamine, serotonin, gama-amino-butyric acid, tyramine, DOPA, etc. Decarboxylation is inhibited by hyperthyroidism and excess glucocorticoids.

As a result of deamination of amino acids, ammonia is formed, which has a strong cytotoxic effect, especially for cells of the nervous system. A number of compensatory processes have been formed in the body to ensure the binding of ammonia. The liver synthesizes urea from ammonia, which is a relatively harmless product. In the cytoplasm of cells, ammonia is bound to glutamic acid to form glutamine. This process is called amidation. In the kidneys, ammonia combines with a hydrogen ion and is excreted in the urine in the form of ammonium salts. This process, called ammoniogenesis, is also an important physiological mechanism aimed at maintaining acid-base balance.

Thus, as a result of deamination and synthetic processes in the liver, such end products of nitrogen metabolism as ammonia and urea are formed. During the transformation in the tricarboxylic acid cycle of the products of interstitial protein metabolism - acetyl coenzyme-A, alpha-ketoglutarate, succinyl coenzyme-A, fumarate and oxaloacetate - ATP, water and CO 2 are formed.

The end products of nitrogen metabolism are excreted from the body in different ways: urea and ammonia - mainly with urine; water through urine, through the lungs and by sweating; CO 2 - mainly through the lungs and in the form of salts in urine and sweat. These non-protein substances containing nitrogen constitute residual nitrogen. Normally, its content in the blood is 20-40 mg% (14.3-28.6 mmol/l).

The main phenomenon of disturbances in the formation and excretion of end products of protein metabolism is an increase in non-protein nitrogen in the blood (hyperazotemia). Depending on the origin, hyperazotemia is divided into production (hepatic) and retention (renal).

Productive hyperazotemia is caused by liver damage (inflammation, intoxication, cirrhosis, circulatory disorders), hypoproteinemia. In this case, the synthesis of urea is disrupted, and ammonia accumulates in the body, producing a cytotoxic effect.

Retention hyperazotemia occurs when the kidneys are damaged (inflammation, circulatory disorders, hypoxia), or impaired urine outflow. This leads to a delay and increase in residual nitrogen in the blood. This process is combined with the activation of alternative pathways for the release of nitrogenous products (through the skin, gastrointestinal tract, lungs). With retention hyperazotemia, the increase in residual nitrogen occurs mainly due to the accumulation of urea.

Disturbances in the formation of urea and the release of nitrogenous products are accompanied by disorders of water and electrolyte balance, dysfunction of organs and body systems, especially the nervous system. The development of hepatic or uremic coma is possible.

The causes of hyperazotemia, mechanisms and changes in the body are presented in Diagram 11.

Scheme 11. Disturbances in the formation and excretion of end products of protein metabolism
HYPERAZOTEMIA
	Hepatic (productive)	Renal (retention)
Causes	Liver damage (intoxication, cirrhosis, circulatory disorders), protein starvation	Impaired urea formation in the liver
Mechanisms	Inflammation of the kidneys, circulatory disorders, disturbances in the outflow of urine	Insufficient excretion of nitrogenous products in urine
Changes in the body	Consequences- Dysfunction of organs and systems, especially the nervous system. The development of hepatic or uremic coma is possible. Compensation Mechanisms- Amidation in cells, ammoniogenesis in the kidneys, release of nitrogenous products by alternative routes (through the skin, mucous membranes, gastrointestinal tract)

Source: Ovsyannikov V.G. Pathological physiology, typical pathological processes. Tutorial. Ed. Rostov University, 1987. - 192 p.

Providing the body with proteins from several sources determines the diverse etiology of protein metabolism disorders. The latter can be primary or secondary in nature.

One of the most common reasons general disorders of protein metabolism is quantitative or qualitative protein deficiencyprimary (exogenous) origin. Defects associated with this are caused by limited intake of exogenous proteins during complete or partial starvation, low biological value of food proteins, and deficiency of essential amino acids (valine, isoleucine, leucine, lysine, methionine, threonine, tryptophan, phenylalanine, histidine, arginine).

In some diseases, disturbances in protein metabolism can develop as a result of disorders of digestion and absorption of protein products (with gastroenteritis, ulcerative colitis), increased breakdown of protein in tissues (with stress, infectious diseases), increased loss of endogenous proteins (during blood loss, nephrosis, injuries), impaired protein synthesis (during hepatitis). The consequence of these violations is oftensecondary (endogenous) protein deficiency with a characteristic negative nitrogen balance.

With prolonged protein deficiency, the biosynthesis of proteins in various organs is sharply disrupted, which leads to pathological changes in metabolism as a whole.

Protein deficiency can develop even if there is sufficient protein intake from food, but if protein metabolism is disrupted.

It may be due to:

• violation of the breakdown and absorption of proteins in the gastrointestinal tract;
• slowing down the flow of amino acids into organs and tissues;
• disruption of protein biosynthesis; violation of intermediate amino acid metabolism;
• changing the rate of protein breakdown;
• pathology of the formation of end products of protein metabolism.

Disturbances in the breakdown and absorption of proteins.

In the digestive tract, proteins are broken down under the influence of proteolytic enzymes. At the same time, on the one hand, protein substances and other nitrogenous compounds that make up food lose their specific characteristics, on the other hand, amino acids are formed from proteins, from nucleic acids- nucleotides, etc. Nitrogen-containing substances with a small molecular weight formed during the digestion of food or contained in it are absorbed.

There are primary (in various forms of pathology of the stomach and intestines - chronic gastritis, peptic ulcer, cancer) and secondary (functional) disorders of the secretory and absorption functions of the epithelium as a result of swelling of the mucous membrane of the stomach and intestines, impaired digestion of proteins and absorption of amino acids in the gastrointestinal tract .

The main causes of insufficient protein breakdown consist in a quantitative decrease in the secretion of hydrochloric acid and enzymes, a decrease in the activity of proteolytic enzymes (pepsin, trypsin, chymotrypsin) and the associated insufficient formation of amino acids, a decrease in the time of their action (acceleration of peristalsis). Thus, when the secretion of hydrochloric acid is weakened, the acidity of gastric juice decreases, which leads to a decrease in the swelling of food proteins in the stomach and a weakening of the conversion of pepsinogen into its active form - pepsin. Under these conditions, part of the protein structures passes from the stomach to the duodenum in an unchanged state, which impedes the action of trypsin, chymotrypsin and other intestinal proteolytic enzymes. Deficiency of enzymes that break down proteins plant origin, leads to intolerance to cereal proteins (rice, wheat, etc.) and the development of celiac disease.

Insufficient formation of free amino acids from food proteins can occur if the flow of pancreatic juice into the intestine is limited (with pancreatitis, compression, blockage of the duct). Insufficiency of pancreatic function leads to a deficiency of trypsin, chymotrypsin, carbonic anhydrase A, B and other proteases that act on long polypeptide chains or cleave short oligopeptides, which reduces the intensity of cavity or parietal digestion.

Insufficient action of digestive enzymes on proteins can occur due to the accelerated passage of food masses through the intestines with increased peristalsis (with enterocolitis) or with a decrease in the absorption area (with surgical removal of large sections of the small intestine). This leads to a sharp reduction in the time of contact of the chyme contents with the apical surface of enterocytes, incompleteness of the processes of enzymatic breakdown, as well as active and passive absorption.

Causes of amino acid malabsorption are damage to the wall of the small intestine (swelling of the mucous membrane, inflammation) or uneven absorption of individual amino acids over time. This leads to a disruption (imbalance) of the ratio of amino acids in the blood and protein synthesis in general, since essential amino acids must enter the body in certain quantities and ratios. Most often there is a lack of methionine, tryptophan, lysine and other amino acids.

In addition to the general manifestations of amino acid metabolism disorders, there may bespecific disorders associated with the lack of a specific amino acid. Thus, a lack of lysine (especially in a developing organism) retards growth and general development, lowers the content of hemoglobin and red blood cells in the blood. When there is a lack of tryptophan in the body, hypochromic anemia. Arginine deficiency leads to impaired spermatogenesis, and histidine deficiency leads to the development of eczema, growth retardation, and inhibition of hemoglobin synthesis.

In addition, insufficient protein digestion in upper sections the gastrointestinal tract is accompanied by an increase in the transfer of products of its incomplete breakdown into the large intestine and an acceleration of the process of bacterial breakdown of amino acids. As a result, the formation of toxic aromatic compounds (indole, skatole, phenol, cresol) increases and general intoxication of the body with these decay products develops.

Slowing down the flow of amino acids into organs and tissues.

Amino acids absorbed from the intestines enter directly into the blood and partially into lymphatic system, representing a reserve of various nitrogenous substances, which then participate in all types of metabolism. Normally, amino acids absorbed into the blood from the intestines circulate in the blood for 5–10 minutes and are very quickly absorbed by the liver and partly by other organs (kidneys, heart, muscles). An increase in the time of this circulation indicates a violation of the ability of tissues and organs (primarily the liver) to absorb amino acids.

Since a number of amino acids are the starting material for the formation of biogenic amines, their retention in the blood creates conditions for the accumulation of corresponding proteinogenic amines in the tissues and blood and their manifestation pathogenic action on various organs and systems. An increased level of tyrosine in the blood promotes the accumulation of tyramine, which is involved in the pathogenesis of malignant hypertension. A prolonged increase in histidine content leads to an increase in the concentration of histamine, which contributes to impaired blood circulation and capillary permeability. In addition, an increase in the content of amino acids in the blood is manifested by an increase in their excretion in the urine and the formation of a special form of metabolic disorders - aminoaciduria. The latter can be general, associated with an increase in the concentration of several amino acids in the blood, or selective - with an increase in the content of any one amino acid in the blood.

Violation of protein synthesis.

The synthesis of protein structures in the body is the central link in protein metabolism. Even small disturbances in the specificity of protein biosynthesis can lead to profound pathological changes in the body.

Among the reasons causing disturbances in protein synthesis, an important place is occupied by various types of nutritional deficiency (complete, incomplete fasting, lack of essential amino acids in food, violation of the quantitative relationships between essential amino acids entering the body). If, for example, tryptophan, lysine, and valine are contained in tissue protein in equal ratios (1:1:1), and these amino acids are supplied with food protein in the ratio (1:1:0.5), then tissue protein synthesis will be ensured at this is only half of it. If at least one of the 20 essential amino acids is absent in cells, protein synthesis as a whole stops.

An impairment in the rate of protein synthesis may be due to a disorder in the function of the corresponding genetic structures on which this synthesis occurs (DNA transcription, translation, replication). Damage to the genetic apparatus can be either hereditary or acquired, arising under the influence of various mutagenic factors (ionizing radiation, ultraviolet irradiation, etc.). Some antibiotics can disrupt protein synthesis. Thus, errors in reading the genetic code can occur under the influence of streptomycin, neomycin and some other antibiotics. Tetracyclines inhibit the addition of new amino acids to the growing polypeptide chain. Mitomycin inhibits protein synthesis due to DNA alkylation (the formation of strong covalent bonds between its chains), preventing the splitting of DNA strands.

One of the important reasons causing disruption of protein synthesis may be dysregulation of this process. The intensity and direction of protein metabolism are regulated by the nervous and endocrine systems, the action of which is probably their influence on various enzyme systems. Clinical and experimental experience show that disconnection of organs and tissues from the central nervous system leads to local disruption of metabolic processes in denervated tissues, and damage to the central nervous system causes disorders of protein metabolism. Removal of the cerebral cortex in animals leads to a decrease in protein synthesis.

The growth hormone of the pituitary gland, sex hormones and insulin have a stimulating effect on protein synthesis. Finally, the cause of protein synthesis pathology can be a change in the activity of cell enzyme systems involved in protein biosynthesis. In extreme cases, we are talking about a blockage of metabolism, which is a type of molecular disorder that forms the basis of some hereditary diseases.

The result of the action of all of these factors is a break or decrease in the rate of synthesis of both individual proteins and the protein as a whole.

There are qualitative and quantitative disorders of protein biosynthesis. About. what significance can qualitative changes in protein biosynthesis have in pathogenesis? various diseases, can be judged by the example of some types of anemia with the appearance of pathological hemoglobins. Replacement of only one amino acid residue (glutamine) in the hemoglobin molecule with valine leads to a serious disease - sickle cell anemia.

Of particular interest are quantitative changes in the biosynthesis of proteins in organs and blood, leading to a shift in the ratios of individual protein fractions in the blood serum - dysproteinemia. There are two forms of disproteinemia: hyperproteinemia (increased content of all or individual types of proteins) and hypoproteinemia (decreased content of all or individual proteins). Thus, a number of liver diseases (cirrhosis, hepatitis), kidney diseases (nephritis, nephrosis) are accompanied by a pronounced decrease in albumin content. A number of infectious diseases accompanied by extensive inflammatory processes lead to an increase in the content of γ-globulins.

The development of dysproteinemia is usually accompanied by serious changes in the body's homeostasis (impaired oncotic pressure, water metabolism). A significant decrease in the synthesis of proteins, especially albumins and γ-globulins, leads to a sharp decrease in the body's resistance to infection and a decrease in immunological resistance. The significance of hypoproteinemia in the form of hypoalbuminemia is also determined by the fact that albumin forms more or less strong complexes with various substances, ensuring their transport between different organs and transfer through cell membranes with the participation of specific receptors. It is known that iron and copper salts (extremely toxic to the body) are poorly soluble at blood serum pH and their transport is possible only in the form of complexes with specific serum proteins (transferrin and ceruloplasmin), which prevents intoxication with these salts. About half of the calcium is retained in the blood in a form bound to serum albumin. In this case, a certain dynamic balance is established in the blood between the bound form of calcium and its ionized compounds.

In all diseases accompanied by a decrease in albumin content (kidney disease), the ability to regulate the concentration of ionized calcium in the blood is also weakened. In addition, albumins are carriers of some components of carbohydrate metabolism (glycoproteins) and the main carriers of free (non-esterified) fatty acids, a number of hormones.

With damage to the liver and kidneys, some acute and chronic inflammatory processes (rheumatism, infectious myocarditis, pneumonia), the body begins to synthesize special proteins with altered properties or unusual ones. A classic example of diseases caused by the presence of pathological proteins are diseases associated with the presence of pathological hemoglobin (hemoglobinosis), blood clotting disorders with the appearance of pathological fibrinogens. Unusual blood proteins include cryoglobulins, which can precipitate at temperatures below 37 °C, leading to thrombus formation. Their appearance is accompanied by nephrosis, cirrhosis of the liver and other diseases.

Pathology of intermediate protein metabolism (disorder of amino acid metabolism).

The main pathways of intermediate protein metabolism are the reactions of transamination, deamination, amidation, decarboxylation, remethylation, and transsulfurization.

The central place in the intermediate metabolism of proteins is occupied by the transamination reaction, as the main source of the formation of new amino acids.

Transamination disorder may result from a deficiency of vitamin B6 in the body. This is explained by the fact that the phosphorylated form of vitamin B 6 - phosphopyridoxal - is an active group of transaminases - specific transamination enzymes between amino and keto acids. Pregnancy and long-term use of sulfonamides inhibit the synthesis of vitamin B6 and can cause disturbances in amino acid metabolism.

Pathological enhancement transamination reactions are possible in conditions of liver damage and insulin deficiency, when the content of free amino acids increases significantly. Finally, a decrease in transamination activity can occur as a result of inhibition of transaminase activity due to impaired synthesis of these enzymes (during protein starvation) or impaired regulation of their activity by certain hormones. Thus, tyrosine (an essential amino acid), supplied with food proteins and formed from phenylalanine, is partially oxidized in the liver to fumaric and acetoacetic acids. However, this oxidation of tyrosine occurs only after its reamplification with α-ketoglutaric acid. With protein depletion, the transamination of tyrosine is noticeably weakened, as a result of which its oxidation is impaired, which leads to an increase in the tyrosine content in the blood. The accumulation of tyrosine in the blood and its excretion in the urine may also be associated with a hereditary defect in tyrosine aminotransferase. The clinical condition that develops as a result of these disorders is known as tyrosinosis. The disease is characterized by cirrhosis of the liver, rickets-like bone changes, hemorrhages, and damage to the kidney tubules.

The processes of transamination of amino acids are closely related to the processesoxidative deamination . during which the enzymatic cleavage of ammonia from amino acids occurs. Deamination determines the formation of final products of protein metabolism and the entry of amino acids into energy metabolism. Weakening of deamination may occur due to disruption of oxidative processes in tissues (hypoxia, hypovitaminosis C, PP, B 2). However, the most severe disruption of deamination occurs when the activity of amino oxidases decreases, either due to a weakening of their synthesis (diffuse liver damage, protein deficiency), or as a result of a relative insufficiency of their activity (increased content of free amino acids in the blood). Due to a violation of the oxidative deamination of amino acids, urea formation is weakened, the concentration of amino acids increases and their excretion in the urine increases (aminoaciduria).

The intermediate exchange of a number of amino acids occurs not only in the form of transamination and oxidative deamination, but also through theirdecarboxylation (loss of CO 2 from the carboxyl group) with the formation of the corresponding amines, called “biogenic amines”. Thus, when histidine is decarboxylated, histamine is formed, tyrosine - tyramine, 5-hydroxytryptophan - serotonin, etc. All these amines are biologically active and have a pronounced pharmacological effect on blood vessels. If normally they are formed in small quantities and are destroyed quite quickly, then if decarboxylation is disrupted, conditions arise for the accumulation of the corresponding amines in the tissues and blood and the manifestation of their toxic effect. The reasons for the disruption of the decarboxylation process may be increased activity of decarboxylases, inhibition of the activity of amine oxidases and impaired binding of amines to proteins.

Changing the rate of protein breakdown.

The body's proteins are constantly in a dynamic state: in the process of continuous breakdown and biosynthesis. Violation of the conditions necessary for the implementation of this dynamic balance can also lead to the development of general protein deficiency.

Typically, the half-life of different proteins varies from several hours to many days. Thus, the biological time for human serum albumin to decrease by half is about 15 days. The magnitude of this period largely depends on the amount of protein in food: with a decrease in retention of proteins, it increases, and with increase, it decreases.

A significant increase in the rate of breakdown of tissue and blood proteins is observed with an increase in body temperature, extensive inflammatory processes, severe injuries, hypoxia, malignant tumors, which is associated either with the action of bacterial toxins (in case of infection), or with a significant increase in the activity of proteolytic enzymes in the blood (in case of hypoxia ), or the toxic effect of tissue breakdown products (in case of injuries). In most cases, the acceleration of protein breakdown is accompanied by the development of a negative nitrogen balance in the body due to the predominance of protein breakdown processes over their biosynthesis.

Pathology of the final stage of protein metabolism.

The main end products of protein metabolism are ammonia and urea. Pathology of the final stage of protein metabolism can manifest itself as a violation of the formation of final products or a violation of their excretion.

Rice. 9.3. Diagram of urea synthesis disorder

The binding of ammonia in the tissues of the body is of great physiological importance, since ammonia has a toxic effect primarily on the central nervous system, causing its sharp excitation. In the blood of a healthy person, its concentration does not exceed 517 µmol/l. The binding and neutralization of ammonia is carried out using two mechanisms: in the liver byurea formation, and in other tissues - by adding ammonia to glutamic acid (via amination) withglutamine formation .

The main mechanism for ammonia binding is the process of urea formation in the citrulline-argininornithine cycle (Fig. 9.3).

Disturbances in the formation of urea can occur as a result of a decrease in the activity of enzyme systems involved in this process (with hepatitis, cirrhosis of the liver), and general protein deficiency. When urea formation is impaired, ammonia accumulates in the blood and tissues and the concentration of free amino acids increases, which is accompanied by the developmenthyperazotemia . In severe forms of hepatitis and cirrhosis of the liver, when its urea-forming function is sharply impaired, a pronouncedammonia intoxication (dysfunction of the central nervous system with the development of coma).

Impaired urea formation may be caused by hereditary defects in enzyme activity. Thus, an increase in the concentration of ammonia (ammonemia) in the blood may be associated with blocking carbamyl-phosphate synthetase and ornithine carbamoyltransferase. catalyzing the binding of ammonia and the formation of ornithine. With a hereditary defect of arginine succinate synthetase, the concentration of citrulline in the blood sharply increases, as a result of which citrulline is excreted in the urine (up to 15 g per day), i.e. developscitrullinuria .

In other organs and tissues (muscles, nervous tissue), ammonia binds in the reactionamidation with the addition of free dicarboxylic amino acids to the carboxyl group. The main substrate is glutamic acid. Disruption of the amidation process can occur when the activity of the enzyme systems that provide the reaction (glutaminase) decreases, or as a result of intensive formation of ammonia in quantities exceeding the possibilities of its binding.

Another end product of protein metabolism formed during the oxidation of creatine (the nitrogenous substance of muscles) iscreatinine . The normal daily creatinine content in urine is about 1-2 g.

Creatinuria - increased creatinine levels in urine - observed in pregnant women and children during periods of intensive growth.

During fasting, vitamin E deficiency, feverish infectious diseases, thyrotoxicosis and other diseases in which metabolic disorders in the muscles are observed, creatinuria indicates a violation of creatine metabolism.

Another common form of disruption of the final stage of protein metabolism occursin case of impaired excretionend products of protein metabolism in kidney pathology. With nephritis, urea and other nitrogenous products are retained in the blood, residual nitrogen increases and developshyperazotemia. The extreme degree of impairment of the excretion of nitrogenous metabolites isuremia.

With simultaneous damage to the liver and kidneys, a violation of the formation and release of the final products of protein metabolism occurs.

Along with general violations protein metabolism in case of protein deficiency may also occurspecific disorders in the metabolism of individual amino acids. For example, with protein deficiency, the function of enzymes involved in the oxidation of histidine is sharply weakened, and the function of histidine decarboxylase, as a result of which histamine is formed from histidine, not only does not suffer, but, on the contrary, increases. This entails a significant increase in the formation and accumulation of histamine in the body. The condition is characterized by skin lesions, cardiac dysfunction and gastrointestinal tract function.

Of particular importance for medical practice arehereditary aminoacidopathies , the number of which today is about 60 different nosological forms. According to the type of inheritance, almost all of them are autosomal recessive. Pathogenesis is caused by a deficiency of one or another enzyme that carries out the catabolism and anabolism of amino acids. A common biochemical sign of aminoaidopathies is tissue acidosis and aminoaciduria. The most common hereditary metabolic defects are four types of enzymopathy, which are interconnected by a common pathway of amino acid metabolism: phenylketonuria, tyrosinemia, albinism, alkaptonuria.