home Folk remedies Amino acid metabolism disorder. Disorders of amino acid metabolism with accumulation of metabolites in tissues

Amino acid metabolism disorder. Disorders of amino acid metabolism with accumulation of metabolites in tissues

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 causes of general disorders of protein metabolism is quantitative or qualitative protein deficiency primary (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 ones (with various forms pathologies 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 gastrointestinal tract.

The main causes of insufficient protein breakdown consist in a quantitative decrease in 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 weakens, acidity decreases gastric juice, 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 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 prompt removal large areas 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 digestion of protein in the upper gastrointestinal tract is accompanied by an increase in the transfer of products of its incomplete breakdown to 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 the manifestation of their pathogenic effect 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 causes of protein synthesis disorders, an important place is occupied by different kinds nutritional deficiency (complete or 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, valine are contained in tissue protein in equal proportions (1:1:1), and with food protein These amino acids are supplied in the ratio (1:1:0.5), then the synthesis of tissue protein will be ensured only by half. 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 important reasons, causing disruption of protein synthesis, may result in disruption of the regulation 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're talking about about a metabolic block, 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 qualitative changes in protein biosynthesis can have in the pathogenesis of 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 dysproteinemia: hyperproteinemia (an increase in the content of all or individual species 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 various organs and transport 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.

For liver and kidney damage, 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. So, tyrosine ( essential amino acid), which comes with food proteins and is 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 pharmachologic effect on the 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 increased 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 (with hypoxia), or with the toxic effect of tissue breakdown products (with 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 in relation to the central nervous system, causing her sudden arousal. In blood 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, nerve tissue) ammonia is bound 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.

Other general shape disturbances in the final stage of protein metabolism occurin 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. Extreme degree disturbances in 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 disorders of protein metabolism, protein deficiency may also causespecific 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 havehereditary 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.

Human gene diseases

Gene diseasesThis is a clinically diverse group of diseases caused by mutations of single genes.

The number of currently known monogenic hereditary diseases is about 4500. These diseases occur with a frequency of 1: 500 - 1: 100,000 and less often. Monogenic pathology is detected in approximately 3% of newborns and is the cause of 10% of infant mortality.

Inherited monogenic diseases according to Mendel's laws.

The onset of the pathogenesis of any gene disease is associated with the primary effect of the mutant allele. It can manifest itself in the following ways: lack of protein synthesis; synthesis of abnormal protein; quantitatively excess protein synthesis; quantitatively insufficient protein synthesis.

A pathological process resulting from a mutation of a single gene manifests itself simultaneously at the molecular, cellular and organ levels in one individual.

There are several approaches to the classification of monogenic diseases: genetic, pathogenetic, clinical, etc.

Classification based on genetic principles: according to it, mono gene diseases can be divided into types of inheritance: autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, Y-linked (holandric). This classification is the most convenient, because allows you to navigate in relation to family situation and prognosis of offspring.

The second classification is based on clinical principle, i.e. on assigning a disease to one group or another depending on the organ system most involved in pathological process, - monogenic diseases of the nervous, respiratory, cardiovascular systems, visual organs, skin, mental, endocrine, etc.

The third classification is based on the pathogenetic principle. According to it, all monogenic diseases can be divided into three groups:

hereditary metabolic diseases;
monogenic multiple syndromes birth defects development;
combined forms.

Let's look at the most common monogenic diseases.

Amino acid metabolism disorder.

Hereditary diseases caused by disorders of amino acid metabolism make up a significant part genetic pathology children early age. Most of them begin after a fairly short period of successful development of the child, but later lead to severe damage to the intellect and physical indicators. There is also an acute course of these diseases, when the condition of the newborn sharply worsens on the 2-5th day of life. In such a situation, there is a high probability of death even before the diagnosis is clarified.

The vast majority of these diseases are inherited in an autosomal recessive manner. The probability of re-birth of a sick child in families where this pathology has already been registered is 25%.

Phenylketonuria (PKU)the most common disease caused by a disorder of amino acid metabolism. It was first described in 1934. This disease is inherited in an autosomal recessive manner.

In Western Europe, one patient with PKU is found among 10,000-17,000 newborns; in Belarus and Russia, the frequency of PKU ranges between 1 case per 6,000-10,000 newborns. PKU is very rare among blacks and Ashkenazi Jews in Japan.

The main cause of PKU is a defect in the enzyme phenylalanine 4-hydroxylase, which converts the amino acid phenylalanine into tyrosine. Phenylalanine is a vital amino acid that is not synthesized in the body, but comes from food containing protein. Phenylalanine is a component of many human proteins and has great importance for the maturation of the nervous system.

The gene that determines the structure of phenylalanine 4-hydroxylase is localized on the long arm of chromosome 12 and contains 70,000 nucleobase pairs. Most often, the mutation of this gene is caused by the replacement of a single nucleotide (90% of all cases of the disease).

An enzyme defect in PKU leads to disruption of the reaction that converts phenylalanine to tyrosine. As a result, an excess amount of phenylalanine and its derivatives accumulate in the patient’s body: phenylpyruvic, phenyllactic, phenylacetic, etc. At the same time, with PKU, a deficiency of reaction products is formed in the patient’s body: tyrosine, which is an important part of the metabolism of neurotransmitters (catecholamines and serotonin), and melanin , which determines the coloring of human skin and hair.

An excess of phenylalanine and its derivatives has a direct damaging effects on the nervous system, liver function, protein metabolism and other substances in the body.

Pregnancy and childbirth with PKU in the fetus usually does not have any specific features. A newborn baby looks healthy, since during fetal development the mother's metabolism ensures a normal level of phenylalanine in the fetus. After birth, the baby begins to receive protein from the mother's milk. A defect in phenylalanine hydroxylase interferes with the metabolism of protein breast milk phenylalanine, which begins to gradually accumulate in the patient’s body.

The first clinical manifestations of PKU can be noticed in a 2-4 month old child. Skin and hair begin to lose pigmentation. The eyes become blue. Eczema-like changes often appear skin: redness, weeping and peeling of the cheeks and folds of the skin, brownish crusts in the scalp area. A specific odor appears and then intensifies, described as “mouse-like.”

The child becomes lethargic and loses interest in his surroundings. From 4 months, a delay in motor and mental development becomes noticeable. The child begins to sit and walk much later and is not always able to learn to talk. The severity of damage to the nervous system varies, but in the absence of treatment, profound mental retardation is usually recorded. Approximately a quarter of sick children experience seizures in the second half of life. Particularly characteristic are short-term attacks accompanied by head tilts (“nods”). Children with PKU over 1 year of age are usually disinhibited and emotionally unstable.

Diagnosis of PKU is based not only on clinical examination and genealogical data, but also on the results of laboratory tests (determination of phenyl pyruvic acid in urine). To clarify the diagnosis, it is necessary to determine the level of phenylalanine in the child’s blood (normally, the content of phenylalanine in the blood is no more than 4 mg%, in a patient with PKU it exceeds 10, and sometimes 30 mg%).

Because the main reason Damage to the nervous system in the classical form of PKU is an excess of phenylalanine, then limiting its intake from food into the patient’s body makes it possible to prevent pathological changes. For this purpose, a special diet is used that provides only the minimum age-related requirement for phenylalanine for the child. This amino acid is included in the structure of most proteins, so they are excluded from the patient’s diet. high protein foods: meat, fish, cottage cheese, egg white, bakery products, etc.

Early introduction of a diet (in the 1st month of life) and its regular adherence ensures almost normal development of the child.

Strict dietary therapy is recommended up to 10-12 years of age. After this volume regular products nutrition for patients with PKU is gradually increasing, and patients are switched to a vegetarian diet. In case of increased physical or mental stress, it is recommended to use protein substitutes in food.

In adulthood, a strict diet is necessary for women with PKU who are planning childbearing. If a pregnant woman's blood FA level exceeds normal, then her child will have microcephaly, congenital heart disease and other anomalies.

Metabolic disorder connective tissue.

The vast majority of these diseases are inherited in an autosomal dominant manner. At this type inheritance patients occur in every generation; sick parents give birth to a sick child; the probability of inheritance is 100% if at least one parent is homozygous, 75% if both parents are heterozygous, and 50% if one parent is heterozygous.

Marfan syndrome.This is one of the hereditary forms of congenital generalized connective tissue pathology, first described in 1886 by V. Marfan. Frequency in population 1: 10000-15000.

The etiological factor of Marfan syndrome (SM) is a mutation in the fibrillin gene, localized in the long arm of chromosome 15.

Patients with Marfan syndrome have a characteristic appearance: they are tall, have an asthenic physique, the amount of subcutaneous fat is reduced, the limbs are elongated mainly due to the distal parts, the arm span exceeds the length of the body (normally these indicators are the same). Long thin fingers are noted arachnids (arachnodactyly), a “symptom” is often observed thumb", in which the long 1st finger of the hand in a transverse position reaches the ulnar edge of the narrow palm. When the 1st and 5th fingers cover the wrist of the other hand, they necessarily overlap (wrist symptom). Half of the patients have deformity chest(funnel-shaped, keel-shaped), spinal curvature (kyphosis, scoliosis), joint hypermobility, clinodactyly of the little fingers, sandal cleft. From the cardiovascular system, the most pathognomonic are dilation of the ascending aorta with the development of an aneurysm, and prolapse of the heart valves. On the part of the visual organs, the most typical are subluxations and dislocations of the lenses, retinal detachment, myopia, heterochromia of the iris. Half of the patients have inguinal, diaphragmatic, umbilical and femoral hernias. Polycystic kidney disease, nephroptosis, hearing loss, and deafness may be observed.

The mental and mental development of patients does not differ from the norm.

The prognosis of life and health is determined primarily by the state of the cardiovascular system. Average duration life during expressed form Marfan syndrome is about 27 years old, although some patients live to a very old age.

When managing pregnant women with SM, it is necessary to remember the possibility of dissection of the aortic aneurysm and its subsequent rupture. These complications usually occur when late stages pregnancy.

US President Abraham Lincoln and violinist Nicolo Paganini suffered from Marfan syndrome.

Disorders of carbohydrate metabolism.

These diseases develop with congenital deficiency of enzymes or transport systems of cell membranes, which are necessary for the metabolism of any carbohydrate.

The clinical manifestations of these pathological conditions are very diverse. But many of them are characterized by the onset of the disease after the corresponding carbohydrate enters the child’s body. Thus, galactosemia develops from the first days of a child’s life after he begins to eat milk, fructosemia usually after the introduction of juices, sugar and complementary foods. Impaired carbohydrate metabolism is often accompanied by impaired absorption in the intestine (malabsorption syndrome). Sugar accumulating in the intestinal lumen increases the water content in small intestine. All this leads to diarrhea (diarrhea), bloating and pain in the abdomen, and regurgitation.

However, with defects in carbohydrate metabolism, damage to other organs is also determined: the nervous system, liver, eyes, etc.

These diseases are relatively rare. The exception is congenital lactase deficiency.

Galactosemia this is a pathology for the first time was described in 1908. The gene for this disease is localized on the short arm of chromosome 9.

The cause of the classic form of galactosemia is a deficiency of the enzyme galactose-1-phosphouridyltransferase, which leads to the accumulation of galactose-1-phosphate in the tissues of the sick child. This disease is inherited in an autosomal recessive manner and occurs with a frequency of 1: 15,000-50,000.

Galactose is the main enzyme in milk, including women's milk. Therefore, pathological changes occur from the first days of a child’s life, as soon as he begins to be fed milk.

First there is vomiting, diarrhea, yellowing of the skin, which does not disappears after the neonatal period. Subsequently, the liver and spleen enlarge. When a child eats dairy food, a low level of glucose in the blood is recorded. IN In the first months of a child’s life, clouding of the lenses of the eyes (cataracts) develops, and kidney function is impaired. Gradually, mental and mental retardation becomes noticeable. physical development, convulsions may occur, even the death of a child against the background of very low level blood glucose or liver cirrhosis.

The main thing in the treatment of this metabolic defect is the appointment of a special diet that does not contain products with galactose. Early initiation of such therapy prevents liver and kidney damage and severe neurological changes in such patients. Cataract resorption is possible. Blood glucose levels are normalized. However, even in patients who receive a special diet from the neonatal period, some signs of damage to the nervous system and ovarian hypofunction in girls may be recorded.

Currently, other types of galactosemia are known that are not accompanied by severe health problems. Thus, with atypical variants of the disease associated with galactokinase and uridine diphosphogalactose-4-epimerase deficiency, clinical manifestations are usually absent. When the galactokinase enzyme is deficient, the only symptom is cataracts. Therefore, children with congenital cataract it is necessary to examine the level of galactose in urine and blood. With this disease, early dietary therapy also helps restore the transparency of the lens.

Violation of hormone metabolism.

Congenital hypothyroidismone of the most common metabolic defects. This disease is found in approximately 1 in 4000 newborns in Europe and North America. This pathology occurs somewhat more often in girls.

The cause of the disease is a complete or partial deficiency of thyroid hormones, which is accompanied by a decrease in the rate of metabolic processes in organism. Such changes lead to inhibition of the child’s growth and development.

Congenital hypothyroidism is divided into primary, secondary and tertiary.

Primary hypothyroidism accounts for about 90% of all cases of the disease. It is caused by damage to the thyroid gland itself. In most cases, its absence (aplasia) or underdevelopment (hypoplasia) is detected. Often thyroid turns out not in the usual place (at the root of the tongue, in the trachea, etc.) This form of the disease is usually recorded as the only case in the family. However, autosomal recessive and autosomal dominant types of inheritance of thyroid malformation have been described.

Approximately 10% of all cases of primary hypothyroidism are caused by a defect in the formation of hormones. With this form of the disease, there is an increase in the size of the thyroid gland in the child (congenital goiter). This pathology is inherited autosomal recessively.

Secondary and tertiary hypothyroidism is recorded only in 3-4% of cases. These forms of the disease are caused by dysfunction of the pituitary gland and hypothalamus and are inherited in an autosomal recessive manner.

IN last years Cases of congenital hypothyroidism caused by tissue insensitivity to the action of thyroid hormones have been described. This disorder is also characterized by an autosomal recessive mode of inheritance.

A lack of thyroid hormones leads to a delay in brain differentiation, a decrease in the number of neurons, neurotransmitters and other substances. All this causes depression of the central nervous system function and delayed mental development of the child.

In addition, with hypothyroidism, the activity of enzyme systems and the rate of oxidative processes decrease, and the accumulation of under-oxidized metabolic products occurs. As a result, the growth and differentiation of virtually all tissues of the child’s body (skeleton, muscles, cardiovascular and immune systems, endocrine glands etc.)

The clinical picture of all forms of hypothyroidism is almost the same. Only the severity of the disease differs. It is possible to have both a mild, asymptomatic course with partially preserved thyroid hormone function, and a very serious condition of the patient.

Congenital hypothyroidism develops gradually during the first months of a child's life. Somewhat later, the disease manifests itself in breastfed children, since breast milk contains thyroid hormones.

In 10-15% of sick children, the first signs of hypothyroidism can be detected already in the first month of life. The birth of such a child usually occurs after 40 weeks (post-term pregnancy). Newborns with this condition have a large body weight, often above 4 kg. When examining such a child, one may note swelling of the facial tissues, a large tongue lying on the lips, and swelling in the form of “pads” on the dorsum of the hands and feet. Later, a rough voice is observed when crying.

A sick child does not retain heat well and sucks sluggishly. Often, yellowing of the skin lasts up to 1 month or more.

The clinical picture usually reaches full development by 3-6 months. The child begins to lag behind in growth, does not gain weight well, and sucks lazily. The patient's skin becomes dry, yellowish-pale, thickened, and often peels off. A large tongue, a low hoarse voice, brittle, dry hair, usually cold hands and feet, and constipation are detected. Muscle tone reduced. During this period, the features of the facial skeleton are formed: a wide sunken bridge of the nose, widely spaced eyes, a low forehead.

After 5-6 months, an increasing delay in the psychomotor and physical development of the sick child becomes noticeable. The child begins to sit and walk much later, and mental retardation develops. The proportions of the skeleton change: the neck, limbs and fingers are shortened, thoracic kyphosis And lumbar lordosis, hands and feet become wide. The child begins to lag significantly in growth. Facial deformation, waxy pallor and thickening of the skin, and a low, rough voice persist and worsen. Muscle tone is reduced. Patients suffer from constipation. On examination, attention is drawn to enlargement of the heart chambers, dullness of its sounds, bradycardia, bloated belly, umbilical hernia. Laboratory research reveals a violation of age-related differentiation of the skeleton, anemia, hypercholesterolemia.

The diagnosis of hypothyroidism is confirmed by testing the pituitary thyroid-stimulating hormone (TSH), thyroid hormones: triiodothyronine (T3) and thyroxine (T4) in the blood. Patients are characterized by a decrease in the level of T3 and T4 in the blood. TSH level is increased in the primary form of the disease and is low in secondary and tertiary hypothyroidism.

The main thing in the treatment of children with congenital hypothyroidism is constant, lifelong therapy with thyroid hormones. If a child begins to take these medications in the first month of life, then a reverse development of all pathological changes in the nervous system is possible. Provided early initiation of treatment and constant intake of the required dose of thyroid hormones under control of their blood levels, in the vast majority of cases, the psychomotor and physical development of sick children is within normal limits.

Features of caring for patients with hereditary pathology.

Patients with hereditary pathology require constant monitoring by medical professionals. Chronic progressive course of the disease makes it necessary long stay in hospitals different profiles, frequent visits to outpatient facilities.

Caring for such patients is challenging. Often you have to deal not with one person, but with an entire family, since even physically healthy relatives may need psychological support, assistance, and sometimes preventive treatment.

The daily routine of a patient with a hereditary pathology should be as close as possible to the usual for the corresponding age. Organization of walks, games, studies, communication with peers contributes to social adaptation patients and their families. For diseases characterized by impaired mental development, it is important to ensure frequent communication with the child, a variety of toys and aids, and developmental activities. Regular exercise helps develop motor skills physical therapy and massage.

The diet of patients should be balanced in terms of main ingredients and appropriate for their age. In cases where feeding through a tube is necessary due to problems with chewing and swallowing, children should receive pureed meat, vegetables and fruits in accordance with their age, and not just milk and cereals. If such a child is fed only milk and cereals, he will lag behind in weight and body length, anemia and an immunodeficiency state will occur.

Special attention special dietary therapy for certain metabolic diseases (phenylketonuria, galactosemia, hypercholesterolemia, etc.) deserves constant assistance to parents and families of patients in organizing nutrition. In addition, such dietary therapy should be accompanied by regular monitoring of the child’s weight and body length: in the first year of life monthly, up to three years once every 3 months until adolescence every six months.

Children with hereditary pathology often suffer from disruption of natural functions. To prevent constipation, foods rich in fiber and juices are introduced into the diet of patients. If there is no independent stool, you need to give a cleansing enema. Some metabolic diseases and malformations of the gastrointestinal tract are accompanied by frequent bowel movements. In such cases, you need to especially carefully monitor the dryness of the child’s skin. The child must be washed every time warm water, blot the skin with a soft cloth and treat the folds of the skin with vegetable oil or baby cream.

Hereditary diseases may be accompanied by urinary problems. With this pathology, the amount of liquid drunk is taken into account. For bladder atony caused by damage to the nervous system, catheterization is used.

Patients with hereditary pathology need to create optimal conditions for temperature and humidity in the rooms where they are located, since such children often suffer from impaired thermoregulation and are prone to overheating and hypothermia.

In addition, the rooms in which the child spends time must be free of dangerous objects (piercing, cutting, very hot, etc.)

Patients forced long time carried out in a lying position may cause bedsores. In order to prevent them, it is necessary: frequent change underwear and bed linen; smoothing out wrinkles on fabric in contact with the patient’s skin; use of special rubber pads or fabric mattresses; systematic change of the patient’s body position. In such cases, the patient’s skin must be treated camphor alcohol or cologne 2-3 times a day and then sprinkle with talcum powder.

The most important part of caring for patients with hereditary pathologies is working with their relatives. A friendly attitude towards the patient, explaining to parents the essence of the disease, freeing them from the feeling of guilt towards the child, creating a positive attitude towards treatment - all this reduces anxiety in the family and improves the results of rehabilitation measures.

The intermediate metabolism of amino acids consists of the reactions of deamination, transamination and decarboxylation.

Rice. 21. Metabolism of amino acids.

Deamination. This is the stage of interstitial amino acid metabolism, during which the formation of keto acids and ammonia occurs. Deamination is carried out by the enzyme amine oxidase, the coenzyme of which is FAD or NAD.

L-glutamate →N.H. 3 + α -ketoglutarate

Deamination is a universal process in the formation of amino acids, when amino acids not used for protein synthesis lose amino groups and are converted into nitrogen-free products. Ammonia is formed from the amino group, and keto acids are formed from the nitrogen-free part.

Thanks to education α -ketoglutarate deamination ensures the functioning of the Krebs cycle, and thanks to the formation ammonium ions in the renal tubules – participates in the regulation of the acid-base state (ammoniogenesis).

Causes and consequences of deamination deficiency.

This process is weakened with liver damage, with hypoxia, with vitamin deficiencies C, PP and B2.

Violation of deamination leads to a weakening of urea formation and an increase in amino acids in the blood ( aminoacidemia), which is accompanied aminoaciduria.

Also, the consequences of a decrease in deamination are: a decrease in protein synthesis due to insufficiency of adjacent transamination reactions, suppression of the activity of the Krebs cycle, energy production, acidosis, hyperammonemia.

Causes and consequences of excess deamination.

The reasons for the increase in deamination may be: fasting, when the body's energy needs are satisfied by protein.

The consequences of increased deamination are an increase in the formation of α-ketoglutarate, leading to an increase in energy production and the formation of keto acids, a decrease in protein synthesis, an increase in ammonia synthesis and an increase in urea formation.

Transamination(transamination) is a reversible transfer of an amino group from an amino acid to a keto acid without the intermediate formation of ammonia to form a new keto acid (KA) and a new non-essential amino acid. Amino acids are amino group donors, and keto acids are acceptors.

Transamination occurs in the presence of a coenzyme, the role of which is played by pyridoxal phosphate (vitamin B 6).

Transamination supplies keto acids (oxaloacetic acid) to the Krebs cycle, thereby supporting energy metabolism, and pyruvic acid to ensure gluconeogenesis and the synthesis of non-essential amino acids.

When the amino group is transferred to α-ketoglutarate, the collector substance L-glutamate is formed:

A-ta +α -ketoglutarate ↔ KK (PC, SHUK) +L-glutamate

L-glutamate is used in the synthesis of urea.

Reasons for decreased transamination:

hypovitaminosis B6 due to insufficient vitamin content in food, with a high need during pregnancy, with a violation of its absorption and phosphorylation during treatment with ftivazide, with suppression of the intestinal microflora that partially synthesizes the vitamin, under the influence of long-term use of sulfonamide drugs.

restriction of protein synthesis (with fasting and severe liver diseases, with insufficiency of the adrenal cortex and thyroid gland).

Consequences of reducing transamination:

reduction in the synthesis of non-essential amino acids (alanine from pyruvic acid, asparagine from oxaloacetic acid);

hypoglycemia due to decreased gluconeogenesis;

aminoacidemia due to decreased urea synthesis;

acidosis in the muscles due to an increase in pyruvic acid (PA) in the muscles (due to impaired transport to the liver)

PC+L-glutamate →α -Alanine +α -ketoglutarate

formation of toxic substances due to activation of decarboxylation.

During the transamination process, nicotinic acid is formed from tryptophan. The absence of phosphopyridoxal leads to disruption of the synthesis of nicotinic acid, resulting in the development of pellagra.

For a number of reasons (excess of keto acids (PC, α-ketoglutarate, increase in glucocorticoids), an increase in transamination is noted.

Consequences of increased transamination:

reduction in the content of essential amino acids

decreased protein synthesis,

increased urea synthesis and hyperazotemia.

If necrosis occurs in individual organs (pancreatitis, hepatitis, myocardial or pulmonary infarction), then due to cell destruction, tissue transaminases enter the blood and an increase in activity in the blood is one of the diagnostic tests. Increased levels of aspartate aminotransferase (AST) are characteristic of heart disease and alanine aminotransferase (ALT) - characteristic of liver disease.

Decarboxylation. This is the process of removing carboxyl groups from amino acids in the form of CO 2 .

Amino acid → Amines (biogenic) + CO 2

Primary amines are formed by decarboxylation of amino acids. All amino acids enter into this reaction. The decarboxylation process is carried out by specific decarboxylases, the coenzyme of which is phosphopyridoxal (vitamin B 6).

Only some amino acids undergo decarboxylation to form biogenic amines and carbon dioxide.

histidine → histamine

The histamine content increases with allergic diseases (bronchial asthma, Quincke's edema, etc.), with burns, tumor disintegration, with shocks (anaphylactic, traumatic and blood transfusion), with poisonous insect bites, with nervous excitement, oxygen starvation. Excess histamine increases vascular permeability, causes dilatation, disrupts microcirculation, and causes spasm of smooth muscles.

tryptophan → tryptamine → serotonin

Serotonin is produced in the mitochondria of chromaffin cells in the intestine. It is destroyed mainly in the lungs by the enzyme amine oxidase. Serotonin increases smooth muscle tone, vascular tone and resistance, is a mediator of nerve impulses in the central nervous system, and reduces aggressiveness. The content of serotonin in the blood increases with intestinal carcinoid, with exacerbation of chronic pancreatitis, and immobilization stress in rats.

glutamic acid → gamma-aminobutyric acid (GABA)

Gamma-aminobutyric acid (GABA) inhibits synaptic transmission of the superficial layers of the cerebral cortex.

tyrosine → tyramine (false transmitter)

DOPA → dopamine

cystine → taurine

The reasons for the increase in the content of biogenic amines may be not only an increase in the decarboxylation of the corresponding amino acids, but also the inhibition of the oxidative breakdown of amines and the disruption of their connection with proteins. For example, under hypoxic conditions, ischemia, tissue destruction (trauma, radiation, etc.), oxidative processes are weakened, which reduces the conversion of amino acids along the path of their usual breakdown and enhances decarboxylation.

The appearance of large amounts of biogenic amines in tissues (especially histamine and serotonin) can cause significant disturbances in local circulation, increased vascular permeability and damage to the nervous system.

A decrease in decarboxylation activity is observed during hypoxia and vitamin B6 deficiency.

Hypoxia and acidosis reduce the production of GABA, a deficiency of which causes seizures; insufficient formation of the neurotransmitter serotonin causes emotional disturbances.

Most of the amino acids in the body are bound in proteins; a much smaller portion can act as neurotransmitters (glycine, y-aminobutyric acid), serve as precursors of hormones (phenylalanine, tyrosine, tryptophan, glycine), coenzymes, pigments, purines and pyrimidines.

Modern ideas about congenital diseases metabolism are based on the results of studying disorders of amino acid metabolism. Currently, more is known 70 congenital aminoacidopathies. Each of these disorders is rare. Their frequency ranges from 1:10,000 (phenylketonuria) to 1:200,000 (alkaptonuria). In some defects, an excess of the precursor amino acid is determined, while in others, its breakdown products accumulate. The nature of the disorder depends on the location of the enzymatic block, the reversibility of reactions occurring above the damaged link, and the existence alternative paths“leakage” of metabolites.

Aminoacidopathies are characterized by biochemical and genetic heterogeneity: There are 4 forms of hyperphenylalaninemia, 3 types of homocystinuria, 5 types of methylmalonic acidemia. The clinical manifestations of many aminoacidopathies can be prevented or reduced by early diagnosis and timely start adequate treatment: restriction of protein and amino acids in the diet, supplementation of vitamins. This is why newborns are screened for aminoacidopathy using a variety of chemical and microbiological blood or urine tests. In addition, to diagnose congenital disorders of amino acid metabolism, the following is used:

Direct enzymatic method using extracts of leukocytes, erythrocytes, fibroblast culture;

DNA-DNA blot hybridization using amniotic fluid cell culture.

The most common aminoacidopathies include phenylketonuria - one of the types of hyperphenylalaninemia caused by a violation of the conversion of phenylalanine to tyrosine due to a decrease in the activity of phenylalanine hydroxylase. The defect is inherited in an autosomal recessive manner and is widespread among Caucasians and Easterners. Phenylalanine hydroxylase was found in noticeable quantities only in the liver and kidneys. A direct consequence of impaired hydroxylation of phenylalanine is its accumulation in the blood and urine and a decrease in the formation of tyrosine.

The concentration of phenylalanine in plasma reaches a level high enough (more than 200 mg/l) to activate alternative metabolic pathways with the formation of phenylpyruvate, phe. nyl acetate, phenyllactate and other derivatives that undergo renal clearance and are excreted in the urine. An excess of phenyllanine in body fluids inhibits the absorption of other amino acids in the gastrointestinal tract, and this deprives the brain of other amino acids necessary for protein synthesis, accompanied by impaired formation or stabilization of polyribosomes, decreased myelin synthesis and insufficient synthesis of norepinephrine and serotonin.

Phenylalanine - a competitive inhibitor of tyrosinase, which is a key enzyme in the pathway of melanin synthesis. Blockage of this pathway, along with a decrease in the availability of the melanin precursor (tyrosine), causes insufficient pigmentation of hair and skin.

In newborns, no abnormalities are noted, but children left untreated with classic phenylketonuria are developmentally delayed; their brain dysfunctions progress. Hyperactivity and convulsions, progressive dysfunction of the brain and basal ganglia cause a sharp lag in mental development, chorea, hypotension, and muscle rigidity. Due to the accumulation of phenylalanine, there is a “mousy” odor of the skin, hair and urine, a tendency to hypopigmentation and eczema. Despite early diagnosis and standard treatment, children die in the first few years of life from secondary infection.

In a newborn, the level of phenylalanine in plasma can be within the normal range for all 4 types of hyperphenylalaninemia, but after the start of protein feeding, the level of phenylalanine in the blood increases rapidly and usually already exceeds the norm on the 4th day.

Classic phenylketonuria can be diagnosed prenatally by restriction fragment length polymorphisms identified using DNA-DNA blot hybridization, and after birth by determining the concentration of phenylalanine in the blood using the Guthrie method (bacterial growth inhibition).

A sharp impairment of tyrosine catabolism due to homogentisic acid oxidase enzyme deficiency determines the development alkaptonuria(alkaptone is a colored polymer of homogentisic acid oxidation products). A defect in this enzyme causes increased excretion of homogentisic acid in the urine and accumulation of oxidized homogentisic acid in the connective tissue (ochronosis). Over time, ochronosis causes the development of degenerative arthritis.

Homogentisic acid is an intermediate in the conversion of tyrosine to fumarate and acetoacetate. With a decrease in the activity of homogentisic acid oxidase in the liver and kidneys, the opening of the phenolic ring of tyrosine is disrupted with the formation of maleylacetoacetic acid. As a result, homogentisic acid accumulates in liquid media and body cells. This acid and especially its oxidized polymers are bound by collagen, which leads to increased accumulation of gray or blue-black pigment (ochronosis) with the development dystrophic changes in cartilage, intervertebral discs and other connective tissue formations.

The disease is inherited in an autosomal recessive manner.

Alkaptonuria may remain unrecognized until the development of dystrophic joint damage. Symptoms such as the ability of patients' urine to darken when standing and slight discoloration of the sclera and ears, for a long time may go unnoticed, although these are the earliest external signs of the disease. Then foci of gray-brown pigmentation of the sclera and generalized darkening of the auricles, antihelix and helix appear. The ear cartilage becomes fragmented and thickened. Ochronous arthritis appears with symptoms of pain and stiffness, especially in the hip, knee and shoulder joints.

The amino acid tyrosine, which comes from food proteins and is formed from phenylalanine, can be converted into:

1) to phenylpyruvate after transamination with α-ketoglutarate, the oxidation of which leads to the formation of homogentisic acid; the latter, oxidizing, turns into fumaric, then acetoacetic acid, which is included in the Krebs cycle;

2) DOPA (n-dioxyphenylalanine) with the participation tyrosinase in norepinephrine and melanin;

3) into tetra- and gryodothyronine after iodization;

4) undergo decarboxylation.

Violation various stages The oxidative transformation of tyrosine with the participation of tyrosinase and, consequently, the formation of melanin from it causes the development of albinism. Delay in tyrosine oxidation at the stage of hydroxyphenylpyruvic acid (with a lack of vitamin C and damage to the liver parenchyma) induces tyrosinosis, which manifests itself in increased urinary excretion of hydroxyphenylpyruvate. The intermediate metabolism of tryptophan is characterized by the fact that it is relatively little involved in transamination and deamination reactions. Most of the tryptophan is converted into nicotinic acid (vitamin PP), and at this stage a number of intermediate products are formed: kynurenine, xanthurenic acid, oxyantranilic acid and others. An increase in their concentration in the blood has a general toxic effect; xanthurenic acid interferes with the formation of insulin. The pathology of tryptophan metabolism may be associated with a deficiency of specific enzymes, coenzymes and vitamin B6 involved in its metabolism, as well as with focal and diffuse liver damage, with infectious diseases, and during treatment with anti-tuberculosis drugs.

A peculiar disorder of amino acid metabolism is aminoaciduria - their increased excretion in the urine. Causes of aminoaciduria: impaired deamination of amino acids with liver damage and impaired reabsorption of amino acids in the renal tubules with kidney damage.

In acute liver dystrophy or terminal stage In cirrhosis, the loss of amino acids in the urine is quite significant. Aminoaciduria also occurs in other pathological processes (cachexia, extensive trauma, muscle atrophy, hyperthyroidism), the course of which is characterized by increased breakdown of tissue proteins and an increase in the content of amino acids in the blood.

Sometimes there is an increased content of cystine in the urine - cystinuria as a congenital metabolic abnormality, which is characterized by the formation of cystine stones in the urinary tract. More severe cystine metabolism disorder - cystinosis, which is accompanied by general aminoaciduria, deposition of cystine crystals in tissues and is characterized by early death.

In general, the basis for disturbances in the interstitial metabolism of amino acids is the pathology of enzymatic systems (congenital abnormalities of enzyme synthesis, general protein deficiency, dystrophic processes) or deficiency of certain vitamins, hypoxia, pH shifts, etc.

The pathophysiological significance of disorders of the interstitial link of protein metabolism is that with these disorders, toxic metabolic products appear and the quantitative relationships between amino acids are disrupted, which ultimately creates conditions for disruption of the processes of protein synthesis, formation and excretion of the final products of protein metabolism.

Human gene diseases

Gene diseases – This is a clinically diverse group of diseases caused by mutations of single genes.

The number of currently known monogenic hereditary diseases is about 4500. These diseases occur with a frequency of 1: 500 - 1: 100,000 and less frequently. Monogenic pathology is detected in approximately 3% of newborns and is the cause of 10% of infant mortality.

Monogenic diseases are inherited in accordance with Mendel's laws.

A pathological process resulting from a mutation of a single gene manifests itself simultaneously at the molecular, cellular and organ levels in one individual.

There are several approaches to the classification of monogenic diseases: genetic, pathogenetic, clinical, etc.

Classification based on the genetic principle: according to it, monogenic diseases can be divided into types of inheritance - autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, Y-linked (holandric). This classification is the most convenient, because allows you to navigate the situation in the family and the prognosis of the offspring.

The second classification is based on clinical principle, i.e. on assigning a disease to one group or another depending on the organ system most involved in the pathological process - monogenic diseases of the nervous, respiratory, cardiovascular systems, visual organs, skin, mental, endocrine, etc.

The third classification is based on the pathogenetic principle. According to it, all monogenic diseases can be divided into three groups:

hereditary metabolic diseases;

monogenic syndromes of multiple congenital malformations;

combined forms.

Let's look at the most common monogenic diseases.

Amino acid metabolism disorder.

Hereditary diseases caused by disorders of amino acid metabolism constitute a significant part of the genetic pathology of young children. Most of them begin after a fairly short period of successful development of the child, but later lead to severe damage to intelligence and physical indicators. There is also an acute course of these diseases, when the condition of the newborn sharply worsens on the 2-5th day of life. In such a situation, there is a high probability of death even before the diagnosis is clarified.

The vast majority of these diseases are inherited in an autosomal recessive manner. The probability of re-birth of a sick child in families where this pathology has already been registered is 25%.

Phenylketonuria (PKU) – the most common disease caused by a disorder of amino acid metabolism. It was first described in 1934. This disease is inherited in an autosomal recessive manner.

The main cause of PKU is a defect in the enzyme phenylalanine 4-hydroxylase, which converts the amino acid phenylalanine into tyrosine. Phenylalanine is a vital amino acid that is not synthesized in the body, but comes from food containing protein. Phenylalanine is a component of many human proteins and is of great importance for the maturation of the nervous system.

Excess of phenylalanine and its derivatives has a direct damaging effect on the nervous system, liver function, protein metabolism and other substances in the body.

Pregnancy and childbirth with PKU usually do not have any specific features in the fetus. A newborn baby looks healthy, since during fetal development the mother's metabolism ensures a normal level of phenylalanine in the fetus. After birth, the baby begins to receive protein from the mother's milk. A defect in phenylalanine hydroxylase interferes with the metabolism of phenylalanine contained in breast milk protein, which gradually begins to accumulate in the patient’s body.

The first clinical manifestations of PKU can be noticed in a 2-4 month old child. Skin and hair begin to lose pigmentation. The eyes become blue. Eczema-like changes in the skin often appear: redness, weeping and peeling of the cheeks and folds of the skin, brownish crusts in the scalp area. A specific odor appears and then intensifies, described as “mouse-like.”

Diagnosis of PKU is based not only on clinical examination and genealogical data, but also on the results of laboratory tests (determination of phenylpyruvic acid in urine). To clarify the diagnosis, it is necessary to determine the level of phenylalanine in the child’s blood (normally, the content of phenylalanine in the blood is no more than 4 mg%, in a patient with PKU it exceeds 10, and sometimes 30 mg%).

Since the main cause of damage to the nervous system in the classical form of PKU is an excess of phenylalanine, limiting its intake from food into the patient’s body makes it possible to prevent pathological changes. For this purpose, a special diet is used that provides only the minimum age-related requirement for phenylalanine for the child. This amino acid is included in the structure of most proteins, so high-protein foods are excluded from the patient’s diet: meat, fish, cottage cheese, egg whites, baked goods, etc.

Early introduction of a diet (in the 1st month of life) and its regular adherence ensures almost normal development of the child.

Strict dietary therapy is recommended up to 10-12 years of age. After this, the amount of regular food for patients with PKU is gradually increased, and patients are switched to a vegetarian diet. In case of increased physical or mental stress, it is recommended to use protein substitutes in food.

Connective tissue metabolism disorder.

The vast majority of these diseases are inherited in an autosomal dominant manner. With this type of inheritance, patients occur in every generation; sick parents give birth to a sick child; the probability of inheritance is 100% if at least one parent is homozygous, 75% if both parents are heterozygous, and 50% if one parent is heterozygous.

Marfan syndrome. This is one of the hereditary forms of congenital generalized connective tissue pathology, first described in 1886 by V. Marfan. Frequency in the population – 1: 10000-15000.

The etiological factor of Marfan syndrome (SM) is a mutation in the fibrillin gene, localized in the long arm of chromosome 15.

Patients with Marfan syndrome have a characteristic appearance: they are tall, have an asthenic physique, the amount of subcutaneous fat is reduced, the limbs are elongated mainly due to the distal parts, the arm span exceeds the length of the body (normally these indicators are the same). Long, thin, spider-like fingers are noted (arachnodactyly); the “thumb symptom” is often observed, in which the long 1st finger of the hand in a transverse position reaches the ulnar edge of the narrow palm. When the 1st and 5th fingers cover the wrist of the other hand, they necessarily overlap (wrist symptom). Half of the patients have chest deformity (funnel-shaped, keel-shaped), spinal curvature (kyphosis, scoliosis), joint hypermobility, clinodactyly of the little fingers, and sandal-shaped cleft. From the cardiovascular system, the most pathognomonic are dilation of the ascending aorta with the development of an aneurysm, and prolapse of the heart valves. On the part of the visual organs, the most typical are subluxations and dislocations of the lenses, retinal detachment, myopia, heterochromia of the iris. Half of the patients have inguinal, diaphragmatic, umbilical and femoral hernias. Polycystic kidney disease, nephroptosis, hearing loss, and deafness may be observed.

The mental and mental development of patients does not differ from the norm.

The prognosis of life and health is determined primarily by the state of the cardiovascular system. The average life expectancy for a severe form of Marfan syndrome is about 27 years, although some patients live to a very old age.

US President Abraham Lincoln and violinist Nicolo Paganini suffered from Marfan syndrome.

Disorders of carbohydrate metabolism.

These diseases develop with congenital deficiency of enzymes or transport systems of cell membranes, which are necessary for the metabolism of any carbohydrate.

The clinical manifestations of these pathological conditions are very diverse. But many of them are characterized by the onset of the disease after the corresponding carbohydrate enters the child’s body. Thus, galactosemia develops from the first days of a child’s life after he begins to eat milk, fructosemia - usually after the introduction of juices, sugar and complementary foods. Impaired carbohydrate metabolism is often accompanied by impaired absorption in the intestine (malabsorption syndrome). Sugar accumulating in the intestinal lumen increases the water content in the small intestine. All this leads to diarrhea (diarrhea), bloating and pain in the abdomen, and regurgitation.

However, with defects in carbohydrate metabolism, damage to other organs is also determined: the nervous system, liver, eyes, etc.

These diseases are relatively rare. The exception is congenital lactase deficiency.

Galactosemia– this pathology was first described in 1908. The gene for this disease is localized on the short arm of chromosome 9.

Galactose is the main enzyme in milk, including women's milk. Therefore, pathological changes occur from the first days of a child’s life, as soon as he begins to be fed milk.

First, vomiting, diarrhea, and yellowing of the skin appear, which does not disappear even after the neonatal period. Subsequently, the liver and spleen enlarge. When a child eats dairy food, a low level of glucose in the blood is recorded. In the first months of a child’s life, clouding of the lenses of the eyes (cataracts) develops, and kidney function is impaired. Gradually, a delay in mental and physical development becomes noticeable, seizures may occur, and even the death of the child against the background of very low blood glucose levels or cirrhosis of the liver.

Currently, other types of galactosemia are known that are not accompanied by severe health problems. Thus, with atypical variants of the disease associated with galactokinase and uridine diphosphogalactose-4-epimerase deficiency, clinical manifestations are usually absent. When the galactokinase enzyme is deficient, the only symptom is cataracts. Therefore, in children with congenital cataracts, it is necessary to examine the level of galactose in urine and blood. With this disease, early dietary therapy also helps restore the transparency of the lens.

Violation of hormone metabolism.

Congenital hypothyroidism– one of the most common metabolic defects. This disease is found in approximately 1 in 4000 newborns in Europe and North America. This pathology occurs somewhat more often in girls.

The cause of the disease is a complete or partial deficiency of thyroid hormones, which is accompanied by a decrease in the rate of metabolic processes in the body. Such changes lead to inhibition of the child’s growth and development.

Congenital hypothyroidism is divided into primary, secondary and tertiary.

Primary hypothyroidism accounts for about 90% of all cases of the disease. It is caused by damage to the thyroid gland itself. In most cases, its absence (aplasia) or underdevelopment (hypoplasia) is detected. Often the thyroid gland is not in the usual place (at the root of the tongue, in the trachea, etc.) This form of the disease is usually recorded as the only case in the family. However, autosomal recessive and autosomal dominant types of inheritance of thyroid malformation have been described.

In recent years, cases of congenital hypothyroidism caused by tissue insensitivity to the action of thyroid hormones have been described. This disorder is also characterized by an autosomal recessive mode of inheritance.

A sick child does not retain heat well and sucks sluggishly. Often, yellowing of the skin lasts up to 1 month or more.

The clinical picture usually reaches full development by 3-6 months. The child begins to lag behind in growth, does not gain weight well, and sucks lazily. The patient's skin becomes dry, yellowish-pale, thickened, and often peels off. A large tongue, a low hoarse voice, brittle, dry hair, usually cold hands and feet, and constipation are detected. Muscle tone is reduced. During this period, the features of the facial skeleton are formed: a wide sunken bridge of the nose, widely spaced eyes, a low forehead.

After 5-6 months, an increasing delay in the psychomotor and physical development of the sick child becomes noticeable. The child begins to sit and walk much later, and mental retardation develops. The proportions of the skeleton change: the neck, limbs and fingers shorten, thoracic kyphosis and lumbar lordosis increase, the hands and feet become wide. The child begins to lag significantly in growth. Facial deformation, waxy pallor and thickening of the skin, and a low, rough voice persist and worsen. Muscle tone is reduced. Patients suffer from constipation. On examination, attention is drawn to enlargement of the heart chambers, dullness of its sounds, bradycardia, bloated abdomen, and umbilical hernia. Laboratory research reveals a violation of age-related differentiation of the skeleton, anemia, hypercholesterolemia.

The diagnosis of hypothyroidism is confirmed by testing the pituitary thyroid-stimulating hormone (TSH), thyroid hormones: triiodothyronine (T3) and thyroxine (T4) in the blood. Patients are characterized by a decrease in the level of T3 and T4 in the blood. The TSH level is increased in the primary form of the disease and is low in secondary and tertiary hypothyroidism.

Features of caring for patients with hereditary pathology.

Patients with hereditary pathology require constant monitoring by medical professionals. The chronic progressive course of the disease necessitates long-term stays in hospitals of various profiles and frequent visits to outpatient clinics.

The daily routine of a patient with a hereditary pathology should be as close as possible to the usual for the corresponding age. Organization of walks, games, studies, and communication with peers contributes to the social adaptation of patients and their families. For diseases characterized by impaired mental development, it is important to ensure frequent communication with the child, a variety of toys and aids, and developmental activities. Regular exercise therapy and massage help develop motor skills.

Special dietary therapy for certain metabolic diseases (phenylketonuria, galactosemia, hypercholesterolemia, etc.) deserves special attention. Constant assistance is needed for parents and families of patients in organizing nutrition. In addition, such dietary therapy should be accompanied by regular monitoring of the child’s weight and body length: at the first stage of life - monthly, up to three years - once every 3 months, until adolescence - every six months.

Children with hereditary pathology often suffer from disruption of natural functions. To prevent constipation, foods rich in fiber and juices are introduced into the diet of patients. If there is no independent stool, you need to give a cleansing enema. Some metabolic diseases and malformations of the gastrointestinal tract are accompanied by frequent bowel movements. In such cases, you need to especially carefully monitor the dryness of the child’s skin. Each time, the child must be washed with warm water, blot the skin with a soft cloth and treat the folds of the skin with vegetable oil or baby cream.

In addition, the rooms in which the child spends time must be free of dangerous objects (piercing, cutting, very hot, etc.)

Patients forced to spend long periods of time in a lying position may develop bedsores. In order to prevent them, it is necessary: frequent change of underwear and bed linen; smoothing out wrinkles on fabric in contact with the patient’s skin; use of special rubber pads or fabric mattresses; systematic change of the patient’s body position. In such cases, the patient’s skin must be treated with camphor alcohol or cologne 2-3 times a day and then sprinkled with talcum powder.

Book >> Medicine, health

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Abstract >> Biology

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