Amino acid metabolism disorders. Hereditary disorders of amino acid metabolism

Hyperaminoaciduria. Hyperaminoaciduria is said to occur when the excretion of one or more amino acids in the urine exceeds physiological values.
Depending on the origin, we can distinguish: 1. metabolic or prerenal and 2. renal aminoaciduria.

With metabolic aminoaciduria, one or more amino acids are formed more than normal, or less of them are metabolized. The excess exceeds the reabsorption capacity of the tubules, so amino acids “overflow” and are excreted in the urine. In these cases, along with increased aminoaciduria, an increased concentration of the corresponding amino acids in the blood is detected.

Symptomatic forms of metabolic aminoacidurias can be encountered when severe lesions liver.

However, in most cases, metabolic aminoacidurias are hereditary enzymopathies: the interstitial metabolism of any amino acid is disrupted due to a lack of a certain enzyme. Metabolic products formed before the enzymatic block accumulate in the blood and are excreted in large quantities in the urine.

In renal aminoaciduria, amino acids are synthesized in normal quantities, but due to congenital or acquired damage to the renal tubules, they are excreted in large quantities in the urine. These abnormalities are described in more detail in the chapter on kidney diseases. Only congenital metabolic aminoacidurias will be addressed here.

Phenylketonuria. Phenylpyruvic oligophrenia (Völling's disease). Enzymopathy inherited in an autosomal recessive manner. Its biochemical essence is the impossibility of converting phenylalanine into tyrosine due to the absence of the enzyme phenylalanine oxidase. Clinical manifestations this anomaly is associated with severe brain damage accompanied by mental retardation. This common disease- one of the most common reasons oligophrenia. Among the population it occurs with a frequency of 1:10,000-1:20,000.

Pathogenesis. Due to the absence of the enzyme involved in the metabolism of phenylalanine - phenylalanine oxidase, phenylalanine and the product of its metabolism - phenylpyruvic acid - accumulate in the blood. The accumulation of these substances is the cause of the leading clinical symptom - brain damage, apparently caused by the inhibitory effect of these metabolites on other enzymatic processes in the brain. In addition, disruption of the normal synthesis of tyrosine, which is the main material for the production of adrenaline, norepinephrine and diiodotyrosine, also plays a certain role in the formation of the disease.

Clinical picture. The leading symptom of phenylketonuria is mental retardation, which manifests itself in early infancy and rapidly progresses. Muscle hypertension is common, and in some cases epileptiform convulsions are observed.

Among other changes associated with metabolic defects, insufficient pigmentation of patients should be mentioned. Many of them are blue-eyed, have fair skin and blond hair. Brachycephaly and hypertaylorism are common. Arterial pressure usually low. The sweat of patients has an unpleasant (“mouse”) odor.

Diagnosis. Due to the possibility of treating the disease great importance has early recognition of carriers of the anomaly. Phenylalanine and its metabolic products can be found in blood and urine. The concentration of phenylalanine in the blood is many times higher than the upper limit of normal (1.5 mg%). In urine, using the Fölling test, the presence of phenylpyruvic acid can be qualitatively demonstrated: when a solution of ferric chloride is added, the urine acquires a dark green color.

However, this test becomes positive only at the age of 3-4 weeks and, moreover, is not specific. More accurate results are obtained already at the end of the first week by the Guthrie test: a microbiological method based on the effect that phenylalanine has on the growth of Bacillus subtilis. Of course, this method is most suitable for examining a population of infants. Its disadvantage is the need to draw blood, which is still difficult to carry out on a large scale. Until this analysis becomes universal, it is necessary to perform a ferrochloride test at 3-4 weeks of age and, in suspicious cases, confirm the diagnosis by examining the spectrum of amino acids in blood and urine using paper chromatography. In case of a family history, a blood test should be performed already in the first week of life.

Treatment . If therapy is started early, if possible as early as the neonatal period, success can be achieved by reducing the phenylalanine content in the diet to a minimum. However, the use of casein hydrolysate, which forms the basis of the diet, providing phenylalanine limitation, is difficult and expensive. Currently offered special drugs for the treatment of phenylketonuria - berlofen, lofenalac, minafen, hypophenate, which are satisfactorily tolerated by patients. Treatment started in late infancy can only achieve cessation further progression idiocy.

Alkaptonuria. The disease is characterized by dark brown color of urine, which appears when standing in the air. Hereditary enzymopathy, patients lack the enzyme homogentisinase. Homogentisic acid, released in larger quantities, is oxidized in air, acquiring Brown color. The baby's diapers and underwear are also stained, making the diagnosis easier.

In addition to the urine feature described above, with this anomaly there are only two other symptoms: appearing in more late age arthropathy and bluish discoloration of cartilage, easily detected on the auricle. There is no treatment.

Albinism is also a hereditary abnormality of aromatic amino acid metabolism. At the same time, there is no enzyme tyrosinase, which catalyzes the conversion of tyrosine into DOPA - dioxyphenylalanol. Since DOPA is the basis for the synthesis of melanin, carriers of the anomaly are fair-skinned, fair-haired people, in whom a reddish vascular network is visible through the iris, which is devoid of pigmentation.

Albinism is incurable. Patients should avoid direct sunlight.

Maple syrup disease. Recessively inherited rare enzymopathy. This disease lacks a specific decarboxylase, which is necessary for the metabolism of three important amino acids: valine, leucine and isoleucine. These amino acids and their metabolites accumulate in the blood and are excreted in significant quantities in the urine. Metabolic products give urine a special smell, reminiscent of the smell of syrup made from maple sap.

The main manifestation of the disease is brain damage, accompanied by seizures, developing in the first weeks of life and ending in death in early infancy.

When making a diagnosis, the Fölling test is important, because if it is positive, it indicates the direction further research; An accurate diagnosis is established by examining blood and urine amino acids using paper chromatography.

For treatment Attempts are being made to improve metabolism using a synthetic diet.

Hartnup disease. A very rare hereditary disease that is accompanied by renal hyperaminoaciduria. A large amount of indican found in the urine indicates a disorder in tryptophan metabolism. Clinically characterized cerebellar ataxia and skin changes resembling pellagra.

Oxalosis. Rare hereditary disease. Due to an enzymatic block in glycocol metabolism, a large amount of oxalic acid is formed, which accumulates in the body and is excreted in the urine.

Clinically, the leading signs are pain due to kidney stones, blood and pus in the urine. In addition to the kidneys, calcium oxalate crystals are deposited in the brain, spleen, lymph nodes and bone marrow.

Diagnosis is based on the detection of hyperoxaluria and oxalate crystals in the bone marrow and lymph nodes.

In treatment- Along with symptomatic therapy, constant intake of sodium benzoate, which forms hippuric acid together with glycocol and reduces the production of oxalic acid, seems promising.

Cystinosis. Hereditary, autosomal recessive disease, which is based on the accumulation of cystine crystals in the reticuloendothelium and individual bodies and severe nephropathy developing in connection with this.

Pathogenesis The disease is not clear enough; apparently, we are talking about a metabolic block in the catabolism of cystine.

Clinical symptoms. Among the initial changes is an increase in the size of the spleen and liver, which develops in the first months of life. Nephropathy, which decides the fate of the patient, manifests itself in the second half of life. Signs appear indicating initial tubular damage: hyperaminoaciduria, glycosuria, proteinuria. Later, the situation is aggravated by polyuria, renal tubular acidosis, as well as hypokalemia and hypophosphatemia of renal origin. Polyuria causes exicosis and hyperthermia, phosphate diabetes causes rickets and dwarfism, potassium deficiency manifests itself in paralysis. In the final stage of the disease, glomerular failure joins tubular failure, and uremia develops.

Diagnosis. Tubular insufficiency, glycosuria, acidosis, hyperaminoaciduria, hyperphosphaturia, accompanied by osteopathy and dwarfism, in the advanced phase of the disease together give a characteristic picture. These changes correspond to the picture of De Toni-Debreu-Fanconi syndrome, which, however, may have a different origin.

In the differential diagnosis, the detection of cystine crystals in the cornea using a slit lamp or in a biopsy specimen of the lymph glands is crucial.

For treatment prescribe a diet with restriction of methionine and cystine. For the purpose of symptomatic therapy they are used high doses vitamin D introduction alkaline solutions and compensation for the lack of potassium, an increased amount of water in the child’s diet and, finally, penicillamine.

Forecast bad.

Homocystinuria. The clinical symptoms of the anomaly are characterized by oligophrenia varying degrees, ectopia of the lenses, blond hair attracts attention. The content of methionine and homocystine in the blood is increased, with the help of special methods Homocystine is detected in the urine.

Treatment- a diet poor in methionine, but it is not very effective.
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This is the largest group of hereditary metabolic diseases. Almost all of them are inherited in an autosomal recessive manner. The cause of diseases is the deficiency of one or another enzyme responsible for the synthesis of amino acids. The disease is accompanied by vomiting and dehydration, lethargy or agitation and convulsions. At a later age, the decline of mental and physical development manifests itself.

Hereditary diseases with impaired amino acid metabolism include phenylketonuria, albinism, etc.

Phenylketonuria (PKU) was first described by A. Fehling in 1934. In patients, the conversion of the amino acid phenylalanine into tyrosine is impaired due to a sharp decrease in the activity of the enzyme phenylalanine hydroxylase. As a result, the content of phenylalanine in the blood and urine of patients increases significantly. Next, phenylalanine is converted into phenylpyruvic acid, which is a neurotropic poison and disrupts the formation of the myelin sheath around the axons of the central nervous system.

Phenylketonuria occurs on average worldwide with a frequency of 1 in 1000 births. However, there are significant differences between populations in this indicator: 1:2600 in Turkey, 1:4500 in Ireland, 1:30,000 in Sweden, 1:119,000 in Japan. The frequency of heterozygous carriage in most European populations is 1:100.

The locus (phenylhydroxylase) is located on the long arm of chromosome 12. Currently, molecular genetic diagnosis and identification of heterozygous carriage are possible for most families. The disease is inherited in an autosomal dominant manner. There are several forms of phenylketonuria, which differ in the severity of the disease. This is due to the presence of 4 alleles of the gene and their combinations.

A child with phenylketonuria is born healthy, but in the very first weeks, due to the intake of phenylalanine in the body through mother’s milk, increased excitability, convulsive syndrome, and a tendency to dermatitis develop; the urine and sweat of patients have a characteristic “mouse” smell, but the main symptoms of PKU are seizures and mental retardation.

Most patients are blondes with light skin and blue eyes, which is determined by insufficient synthesis of the melanin pigment. The diagnosis of the disease is established on the basis of clinical data and the results of a biochemical analysis of urine (for phenylpyruvic acid) and blood (for phenylalanine). For this purpose, a few drops of blood on filter paper are subjected to chromatography and the phenylalanine content is determined. Sometimes the Felling test is used - 10 drops of a 5% solution of ferric chloride and acetic acid are added to 2.5 ml of fresh urine of a child. The appearance of a blue-green color indicates the presence of the disease.

The treatment of phenylketonuria is now well developed. It consists of prescribing a diet to the patient (vegetables, fruits, jam, honey) and specially processed protein hydrolysates with low content phenylalanine (lofelac, ketonyl, minafen, etc.). Prenatal diagnostic methods have now been developed. Early diagnosis and preventive treatment prevent the development of the disease.

Albinism (oculocutaneous) described in 1959. The disease is caused by the lack of synthesis of the enzyme tyrosinase. It is characterized by discoloration of the skin, hair, eyes, regardless of race and age. The skin of patients is pink-red and does not tan at all. Has a predisposition to malignant neoplasms. Hair is white or yellowish. The iris is gray-blue in color, but may also be pinkish due to the reflection of light from the fundus of the eye. Patients are characterized by severe photophobia, their vision is reduced and does not improve with age.

Albinism occurs with a frequency of 1 in 39,000 and is inherited in an autosomal recessive manner. The gene is localized on the long arm of chromosome 11.

Hereditary diseasesrelated to violation

carbohydrate metabolism

It is known that carbohydrates are part of a number of biologically active substances - hormones, enzymes, mucopolysaccharides, which perform energy and structural functions. As a result of impaired carbohydrate metabolism, glycogen storage disease, galactosemia, etc. develop.

Glycogen storage disease associated with a violation of the synthesis and decomposition of glycogen - animal starch. Glycogen is formed from glucose during fasting; Normally, it turns back into glucose and is absorbed by the body. When these processes are disrupted, a person develops serious diseases - Various types glycogenosis. These include Gierke's disease, Pompe disease, etc.

Glycogenosis (type I - Gierke's disease). In patients, large amounts of glycogen accumulate in the liver, kidneys and intestinal mucosa. Its conversion into glucose does not occur, because the enzyme gluco-6-phosphatase, which regulates blood glucose levels, is missing. As a result, the patient develops hypoglycemia, and glycogen accumulates in the liver, kidneys and intestinal mucosa. Gierke's disease is inherited in an autosomal recessive manner.

Immediately after birth, the main symptoms of the disease are glycemic seizures and hepatomegaly (enlarged liver). From the 1st year of life, growth retardation is noted. Characteristic appearance of the patient: big head, “doll face”, short neck, protruding belly. In addition, nosebleeds, delayed physical and sexual development, and muscle hypotension are noted. The intelligence is normal. The level of uric acid in the blood rises, so gout can develop with age.

Diet therapy is used as treatment: frequent meals, increased carbohydrate content and limited fat in the diet.

Glycogenosis (type II - Pompe disease) occurs in a more severe form. Glycogen accumulates both in the liver and in skeletal muscles, myocardium, lungs, spleen, adrenal glands, vascular walls, in neurons.

In newborns, after 1-2 months, muscle weakness appears, deficiency of 1,4-glucosidase in the liver and muscles. During the same period, cardiomegaly (enlargement of the heart) and macroglossia (pathological enlargement of the tongue) occur. Often, patients develop a severe form of pneumonia due to the accumulation of secretions in the respiratory tract. Children die in the first year of life.

The disease is inherited in an autosomal recessive manner. The gene is localized on the long arm of chromosome 17. Diagnosis of the disease is possible even before the birth of the child. For this purpose, the activity of the enzyme 1,4-glucosidase in the amniotic fluid and its cells is determined.

Galactosemia. With this disease, galactose accumulates in the patient’s blood, which leads to damage to many organs: the liver, nervous system, eyes, etc. Symptoms of the disease appear in newborns after drinking milk, since galactose is a component milk sugar lactose. The hydrolysis of lactose produces glucose and galactose. The latter is necessary for the myelination of nerve fibers. When there is an excess of galactose in the body, it is normally converted into glucose using the enzyme galactose-1-phosphate-uridyltransferase. When the activity of this enzyme decreases, galactose-1-phosphate accumulates, which is toxic to the liver, brain, and eye lens.

The disease manifests itself from the first days of life with digestive disorders and intoxication (diarrhea, vomiting, dehydration). In patients, the liver enlarges, liver failure and jaundice develop. Cataracts (clouding of the lens of the eye) and mental retardation are detected. In children who died in the first year of life, cirrhosis of the liver was discovered at autopsy.

The most accurate methods for diagnosing galactosemia are to determine the activity of the enzyme galactose-1-phosphate-uridyltransferase in red blood cells, as well as galactose in the blood and urine, where its levels are increased. If milk (a source of galactose) is excluded from the diet and the diet is started early, sick children can develop normally.

The type of inheritance of galactosemia is autosomal recessive. The gene is localized on the short arm of chromosome 9. The disease occurs with a frequency of 1 in 16,000 newborns.

Hereditary diseases associated with the disorder

lipid metabolism

Hereditary diseases of lipid metabolism (lipidoses) are divided into two main types:

1) intracellular, in which lipids accumulate in the cells of various tissues;

2) diseases with impaired metabolism of lipoproteins contained in the blood.

The most studied hereditary diseases of lipid metabolism of the first type include Gaucher disease, Niemann-Pick disease and amaurotic idiocy (Tay-Sachs disease).

Gaucher disease characterized by the accumulation of cerebrosides in the cells of the nervous and reticuloendothelial system, caused by a deficiency of the enzyme glucocerebrosidase. This leads to the accumulation of glucocerebroside in the cells of the reticuloendothelial system. Large Gaucher cells are found in the cells of the brain, liver, and lymph nodes. The accumulation of cerebroside in the cells of the nervous system leads to their destruction.

There are childhood and juvenile forms of the disease. Children's disease manifests itself in the first months of life with delayed mental and physical development, enlargement of the abdomen, liver and spleen, difficulty swallowing, and spasm of the larynx. Respiratory failure, infiltration (thickening of the lungs by Gaucher cells) and convulsions are possible. Death occurs in the first year of life.

The most common form of Gaucher disease is the juvenile form. She amazes the children of various ages and is chronic. The disease usually appears in the first year of life. Skin pigmentation (brown spots), osteoporosis (decreased bone density), fractures, and bone deformation occur. The tissues of the brain, liver, spleen, and bone marrow contain large amounts of glucocerebrosides. In leukocytes, liver and spleen cells, glucosidase activity is reduced. The type of inheritance is autosomal recessive. The gene is localized on the long arm of chromosome 1.

Niemann-Pick disease caused by a decrease in the activity of the enzyme sphingomyelinase. As a result, sphingomyelin accumulates in the liver cells, spleen, brain, and reticuloendothelial system. Due to the degeneration of nerve cells, the activity of the nervous system is disrupted.

There are several forms of the disease that differ clinically (time of onset, course and severity of neurological manifestations). However, there are also symptoms common to all forms.

The disease most often manifests itself in early age. The child's lymph nodes, abdomen, liver and spleen are enlarged; Vomiting, refusal to eat, muscle weakness, decreased hearing and vision are noted. In 20-30% of children, a cherry-colored spot is found on the retina of the eye (the “cherry pit” symptom). Damage to the nervous system leads to delayed neuropsychic development, deafness, and blindness. Resistance to infectious diseases decreases sharply. Children die at an early age. Inheritance of the disease is autosomal recessive.

Diagnosis of Niemann-Pick disease is based on the detection of increased levels of sphingomyelin in the blood plasma and cerebrospinal fluid. In the peripheral blood, large granular foam cells of Pick are detected. Treatment is symptomatic.

Amaurotic idiocy (disease Tay-Sachs) also refers to diseases associated with lipid metabolism disorders. It is characterized by the deposition of ganglioside lipid in the cells of the brain, liver, spleen and other organs. The reason is a decrease in the activity of the enzyme hexosaminidase A in the body. As a result, the axons of nerve cells are destroyed.

The disease manifests itself in the first months of life. The child becomes lethargic, inactive, and indifferent to others. Delayed mental development leads to a decrease in intelligence to the point of idiocy. There is muscle hypotonia, cramps, and a characteristic “cherry pit” symptom on the retina. By the end of the first year of life, blindness occurs. The cause is atrophy of the optic nerves. Later, complete immobility develops. Death occurs at 3-4 years. The type of inheritance of the disease is autosomal recessive. The gene is localized on the long arm of chromosome 15.

Hereditary diseasesconnective tissue

Connective tissue in the body performs supporting, trophic and protective functions. The complex structure of connective tissue is determined genetically. Pathology in its system is the cause of various hereditary diseases and is caused, to one degree or another, by disturbances in the structure of structural proteins - collagens.

Most connective tissue diseases are associated with defects of the musculoskeletal system and skin. These include Marfan syndrome and mucopolysaccharidoses.

Marfan syndrome is one of the hereditary metabolic diseases and is characterized by systemic damage to connective tissue. It is inherited in an autosomal dominant manner with high penetrance and varying degrees of expressivity. This is associated with significant clinical and age-related polymorphism. The syndrome was first described by V. Marfan in 1886. The cause of the disease is a mutation in the gene responsible for the synthesis of the protein of connective tissue fibers, fibrillin. Blocking its synthesis leads to increased extensibility of connective tissue.

Patients with Marfan syndrome are distinguished by tall stature, long fingers, chest deformity (funnel-shaped, keeled, flattened), and flat feet. Often there are femoral and inguinal hernias, hypoplasia (underdevelopment) of muscles, muscle hypotonia, blurred vision, changes in the shape and size of the lens, myopia (up to retinal detachment), heterochromia (different coloring of areas of the iris); lens subluxation, cataract, strabismus.

In addition to the above, Marfan syndrome is characterized by congenital heart defects, dilatation of the aorta with the development of an aneurysm. Often there are respiratory disorders, lesions gastrointestinal tract and urinary system.

Treatment is mainly symptomatic. Massage, physical therapy, and in some cases surgical intervention have a positive effect. Early diagnosis of the disease is of great importance. The frequency of Marfan syndrome in the population is 1:10,000 (1:15,000).

US President Abraham Lincoln and the great Italian violinist and composer Nicolo Paganini suffered from Marfan syndrome.

Mucopolysaccharidoses are represented by a whole group of hereditary connective tissue diseases. They are characterized by a violation of the metabolism of acid glycosaminoglycans in the body, which is associated with a deficiency of lysosomal enzymes. As a result, pathological metabolic products are deposited in the connective tissue, liver, spleen, cornea and cells of the central nervous system. The first information about mucopolysaccharidoses appeared in 1900, and then in 1917-1919.

Mucopolysaccharidoses affect the musculoskeletal system, internal organs, eyes, and nervous system. Clinical signs of the disease are: slower growth, short neck and torso, bone deformation, decreased intelligence, coarse facial features with large lips and tongue, umbilical and inguinal hernias, heart defects, impaired mental development with a lag from the norm.

The type of inheritance of the disease is autosomal recessive. The gene is mapped to the short arm of chromosome 4.

In total, there are 8 main types of mucopolysaccharidoses, depending on the decrease in the activity of various enzymes and the characteristics of clinical signs. To determine the type of disease, the biochemical parameters of acid glycosaminoglucans in the blood and urine of patients are examined.

Treatment: diet therapy, physiotherapy (electrophoresis, magnetotherapy, massage, physical therapy, etc.), hormonal and cardiovascular medications.

Hereditary disordersexchange in red blood cells

Hemolytic anemia include diseases caused by a decrease in hemoglobin levels and a shortening of the lifespan of red blood cells. In addition, the cause of the disease may be:

Damage to the red blood cell membrane.

Violation of the activity of erythrocyte enzymes (enzymes, glycolysis of the pentose phosphate cycle, etc.).

Violation of the structure or synthesis of hemoglobin.

The most common form of hereditary hemolytic anemia in humans is hereditary microspherocytosis. - hemolytic anemia Minkow Ski-Shoffar. The disease was described in 1900. In approximately half of cases it occurs in newborns. The diagnosis is made at the age of 3-10 years. The disease is caused by genetic abnormalities of red blood cells and is associated with congenital deficiency of lipids in their membrane. As a result of increased membrane permeability, sodium ions enter the cell and ATP is lost. Red blood cells take on a spherical shape. The altered red blood cells are destroyed in the spleen with the formation of a toxic protein - bilirubin.

With this disease, jaundice, anemia, splenomegaly (rupture of the spleen), and skeletal changes are noted. The disease can occur in two forms - chronic and acute, in which hemolysis increases, causing anemia.

Children often experience “kernicterus” in the first months of life. The reason is damage to the nuclei of the brain due to the high content of bilirubin. At an older age, high levels of bilirubin lead to the formation of stones and the development of cholelithiasis.

Patients are characterized by an enlarged spleen and liver, skeletal deformation, and abnormal alignment of teeth.

The type of inheritance is autosomal dominant with incomplete penetrance. The gene is mapped to the short arm of chromosome 8.

Hereditary anomaliescirculating proteins.Hemoglobinopathies- these are diseases associated with a hereditary disorder of hemoglobin synthesis. There are quantitative (structural) and qualitative forms. The former are characterized by changes in the primary structure of hemoglobin proteins, which can lead to disruption of its stability and function. In high-quality forms, the structure of hemoglobin remains normal, only the rate of synthesis of globin chains is reduced.

Thalassemia. This pathology is caused by a decrease in the rate of synthesis of polypeptide chains of normal hemoglobin A. The disease was first described in 1925. Its name comes from the Greek “Talas” - Mediterranean Sea. It is believed that the origin of most thalassemia gene carriers is associated with the Mediterranean region.

Thalassemia occurs in homo- and heterozygous forms. According to the clinical picture, it is customary to distinguish between large, intermediate, small and minimal forms. Let's focus on one of them.

Homozygous (large) thalasse Mia, aka Cooley's anemia caused by a sharp decrease in the formation of hemoglobin HbA 1 and an increase in the amount of hemoglobin F.

Clinically, the disease manifests itself towards the end of the child’s first year of life. It is characterized by a Mongoloid face, a tower type of skull, and retarded physical development. With this pathology, target-shaped erythrocytes with a low HB content, shortened life expectancy and increased osmotic resistance are found in the patient’s blood. Patients have an enlarged spleen and, less commonly, liver.

Depending on the severity of the disease, there are several forms of thalassemia. Severe thalassemia ends in rapid death in the first months of a child’s life. In chronic cases, sick children live up to 5-8 years, and in mild forms, patients live until adulthood.

Sickle cell anemia - the most common hereditary disease caused by a change in the structure of the hemoglobin molecule. People with sickle cell disease usually die before reaching adulthood. Under conditions of low partial pressure of oxygen, their red blood cells take on a sickle shape. The patient's parents' red blood cells have a slightly altered shape, but they do not suffer from anemia.

This disease was first discovered in 1910 by J. Herrick in a student who suffered from severe anemia. In the patient's blood, he identified red blood cells of an unusual sickle shape.

In 1946, Nobel laureate L. Pauling and colleagues conducted a biochemical and genetic analysis of the hemoglobin of patients and healthy people and showed that hemoglobins of normal and sickle cell erythrocytes differ in mobility in an electric field and solubility. It turned out that the hemoglobin in people with sickle cell traits is a mixture of equal amounts of both normal and mutant hemoglobin. It became clear that the mutation that causes sickle cell anemia is associated with a change in the chemical structure of hemoglobin. Further studies showed that in the case of sickle cell anemia, glutamic acid is replaced by valine in the sixth nucleotide pair of the gene encoding the beta chain of human hemoglobin. In heterozygotes, altered hemoglobin is 20-45%, in homozygotes - 60-99% of total hemoglobin.

With this pathology, pale skin and mucous membranes and jaundice are noted. 60% of children have an enlarged liver. There are also murmurs in the heart area, etc. The disease occurs in the form of alternating crises and remissions.

There are no special treatment methods. It is important to protect the patient from exposure to factors that provoke the development of the disease (hypoxia, dehydration, cold, etc.).

Human chromosomal diseases

Chromosomal diseases are large group congenital hereditary diseases with multiple congenital malformations. They are based on chromosomal or genomic mutations. These two different types of mutations are collectively called “chromosomal abnormalities” for short.

The identification of at least three chromosomal diseases as clinical syndromes of congenital developmental disorders was made before their chromosomal nature was established.

The most common disease, trisomy 21, was clinically described in 1866 by the English pediatrician L. Down and was called “Down syndrome.” Subsequently, the cause of the syndrome was repeatedly subjected to genetic analysis. Suggestions have been made about a dominant mutation, a congenital infection, or a chromosomal nature.

The first clinical description of X-chromosome monosomy syndrome as a separate form of the disease was made by the Russian clinician N.A. Shereshevsky in 1925, and in 1938. G. Turner also described this syndrome. Based on the names of these scientists, monosomy on the X chromosome is called Shereshevsky-Turner syndrome.

Anomalies in the sex chromosome system in men (trisomy XXY) were first described as a clinical syndrome by G. Klinefelter in 1942. The listed diseases became the object of the first clinical and cytogenetic studies conducted in 1959.

The etiological factors of chromosomal pathology are all types of chromosomal mutations and some genomic mutations. Although genomic mutations in the animal and plant world are diverse, only 3 types of genomic mutations are found in humans: tetraploidy, triploidy and aneuploidy. Of all the variants of aneuploidy, only trisomy for autosomes, polysomy for sex chromosomes (tri-, tetra- and pentasomy) are found, and of monosomy, only monosomy X is found.

As for chromosomal mutations, all types of them have been found in humans (deletions, duplications, inversions, translocations). Chromosomal diseases include diseases caused by genomic mutations or structural changes in individual chromosomes.

The classification of chromosomal pathology is based on 3 principles that make it possible to accurately characterize the form of chromosomal pathology.

The first principle is etiological - characteristic of chromosomal or genomic mutations (triploidy, simple trisomy on chromosome 21, partial monosomy, etc.) taking into account a specific chromosome. For each form of chromosomal pathology, it is established which structure is involved in the pathological process (chromosome, segment) and what the genetic disorder is (lack or excess of chromosomal material). Differentiation of chromosomal pathology based on the clinical picture is not significant, since different chromosomal abnormalities are characterized by a large commonality of developmental disorders.

Second principle - determination of the type of cells in which it arose la mutation (in gametes or zygote). Gametic mutations lead to complete forms of chromosomal diseases. In such individuals, all cells carry a chromosomal abnormality inherited from the gamete. If a chromosomal abnormality occurs in the zygote or in the early stages of cleavage (such mutations are called somatic, as opposed to gametic), then an organism develops with cells of different chromosomal constitutions (two types or more). Such forms of chromosomal diseases are called mosaic. For the appearance of mosaic forms, the clinical picture of which coincides with the full forms, at least 10% of cells with an abnormal set are needed.

The third principle is identifying the generation in which it arose la mutation : it arose anew in the gametes of healthy parents (sporadic cases) or the parents already had such an anomaly (inherited, or familial, forms). No more than 3-5 are passed on from generation to generation % of them. Chromosomal abnormalities account for approximately 50% of spontaneous abortions and 7% of all stillbirths.

All chromosomal diseases are usually divided into two groups.

Diseases associated with abnormalitiesnumber of chromosomes

This group includes three subgroups:

Diseases caused by number disorders

Diseases associated with an increase or decrease in the number of sex X and Y chromosomes.

3. Diseases caused by polyploidy

A multiple increase in the haploid set of chromosomes.

Diseases associated with structuralviolations

(aberrations)chromosomes

Their reasons are:

Translocations are exchange rearrangements between non-homologous chromosomes.

Deletions are the loss of a section of a chromosome.

Inversions are rotations of a chromosome section by 180 degrees.

Duplications - doubling of a chromosome section

Isochromosomy - chromosomes with repeated genetic material in both arms.

The appearance of ring chromosomes (connection of two terminal deletions in both arms of a chromosome).

Currently, more than 700 diseases caused by structural abnormalities of chromosomes are known in humans. Available data show that about 25% are due to autosomal trisomies, 46% are due to pathology of sex chromosomes. Structural adjustments account for 10.4%. Among chromosomal rearrangements, translocations and deletions are the most common.

Diseases associated with chromosome aberrations

Down syndrome (trisomy 21 chromosome). The most common disease with a quantitative chromosome disorder is trisomy 21 (the presence of 47 chromosomes instead of 46 due to an extra chromosome of the 21st pair). Trisomy 21, or Down Syndrome, occurs with a frequency of 1 in 700-800 births, does not have any temporal, ethnic or geographical difference when the parents are the same age. This disease is one of the most common and studied human pathologies. The frequency of births of children with Down syndrome depends on the age of the mother and, to a lesser extent, on the age of the father.

With age, the likelihood of having children with Down syndrome increases significantly. So, in women aged 45 years it is about 3%. A high incidence of children with Down syndrome (about 2%) is observed in women who give birth early (before 18 years of age). Therefore, for population comparisons of the frequency of births of children with Down syndrome, it is necessary to take into account the distribution of women giving birth by age (the proportion of women giving birth after 30-35 years, in the total number of women giving birth). This distribution sometimes changes within 2-3 years for the same population (for example, with a sharp change in the economic situation in the country). The increase in the incidence of Down syndrome with increasing maternal age is known, but the majority of children with Down syndrome are still born to mothers under 30 years of age. This is due to the higher number of pregnancies in this age group compared to older women.

The literature describes the “bundling” of births of children with Down syndrome at certain periods of time in some countries (cities, provinces). These cases can be explained more by stochastic fluctuations in the spontaneous level of chromosome nondisjunction than by the influence of putative etiological factors (viral infection, low doses of radiation, chlorophos).

Clinically, Down syndrome was described in 1866. Its genetic nature was deciphered much later - in 1959, when Lejeune and his colleagues discovered an extra chromosome 21 in the karyotype of these patients. Rarer cytogenetic variants of Down syndrome - translocation and mosaic - have also been described. The translocation variant accounts for about 3% of cases. The number of chromosomes in the karyotype of such patients is normal - 46, since the additional 21st chromosome is translocated (moved) to another autosome. Mosaic variants account for 2% of all cases of the disease.

The ratio of boys to girls with Down syndrome is 1:1.

The clinical symptoms of Down syndrome are varied: these include congenital malformations, disorders of postnatal development of the nervous system, secondary immunodeficiency, etc. Children with Down syndrome are born at term, but with moderate prenatal hypoplasia (8-10% below average). Many symptoms of Down syndrome are noticeable at birth and become more pronounced later on. A qualified pediatrician installs correct diagnosis Down syndrome in the maternity hospital in at least 90% of cases. Craniofacial dysmorphias include Mongoloid eye shape (for this reason Down syndrome has long been called Mongoloidism), brachycephaly, round flattened face, flat dorsum of the nose, epicanthus, large (usually protruding) tongue, and deformed ears. Muscular hypotonia is combined with joint laxity. Congenital heart defects and typical changes in dermatoglyphics (four-finger, or “monkey”, fold in the palm, two skin folds instead of three on the little finger) are common. Gastrointestinal defects are rare.

The diagnosis of Down syndrome is made based on a combination of several symptoms. The presence of 4-5 of them reliably indicates Down syndrome: 1) flattening of the facial profile (90%); 2) absence of sucking reflex (85%); 3) muscle hypotonia (80%); 4) Mongoloid section of the palpebral fissures (80%); 5) excess skin on the neck (80%); 6) joint laxity (80%); 7) dysplastic pelvis (70%); 8) dysplastic (deformed) ears (60%); 9) clinodactyly of the little finger (60%); 10) four-finger flexion fold (transverse line) of the palm (45%). The height of adult patients is 20 cm below average.

The reaction of children with Down syndrome to environmental influences is often pathological due to weak cellular and humoral immunity, decreased DNA repair, insufficient production of digestive enzymes, and limited compensatory capabilities of all systems. For this reason, children with Down syndrome often suffer from pneumonia and have severe childhood infections. They are underweight and have severe hypovitaminosis.

Congenital defects of internal organs and reduced adaptability of children with Down syndrome often lead to death in the first 5 years. The consequence of altered immunity and insufficiency of repair systems (for damaged DNA) are leukemias, which often occur in patients with Down syndrome.

The mental development of patients with Down syndrome lags behind. Mental retardation can reach the level of imbecility without special teaching methods. Coefficient mental development(English IQ) for different children can range from 25 to 75. Children with Down syndrome are affectionate, attentive, obedient, and patient when learning.

Diagnosis of this syndrome does not cause any particular difficulties. An important problem at present is a radical change in public opinion and the opinion of specialists regarding the learning ability of these children, the need for developmental education and integration into the environment of healthy peers, the importance of developing and implementing special programs for their social adaptation and creative development.

90% of children with Down syndrome born in Russia are left by their parents in the care of the state. Parents often do not know that with proper training, such children can become full-fledged members of society.

Therapeutic care for children with Down syndrome is multifaceted and nonspecific. Congenital heart defects are eliminated promptly. General strengthening treatment is constantly carried out. Nutrition should be complete. Attentive care for a sick child and protection from harmful environmental factors (colds, infections) are necessary. Great successes in preserving the lives of children with Down syndrome and their development are provided by special teaching methods, strengthening physical health from early childhood, and some forms of drug therapy aimed at improving the functions of the central nervous system. Many patients with trisomy 21 are now able to lead an independent life, master simple professions, and start families.

Patau syndrome (trisomy 13 chromosome) described in 1960 in children with multiple congenital malformations. Occurs in newborns with a frequency of 1:5000 - 1:7000. The disease is caused by trisomy on chromosome 13 in 80-85% of patients with Patau syndrome. Chromosome nondisjunction in meiosis occurs most often in the mother. Boys and girls with Patau syndrome are born at the same rate.

A characteristic complication of pregnancy when carrying a fetus with Patau syndrome is polyhydramnios: it occurs in almost 50% of cases. Patau syndrome is accompanied by multiple birth defects development of the brain and face. This is a pathogenetically unified group of early (and, therefore, severe) disorders of brain formation, eyeballs, bones of the brain and facial parts of the skull. Skull circumference is usually reduced. The forehead is sloping, low; the palpebral fissures are narrow, the bridge of the nose is sunken, the ears are low and deformed. A typical sign of Patau syndrome is clefts. upper lip and palate (usually bilateral). Defects of several internal organs are always found in different combinations: heart septal defects, incomplete intestinal rotation, kidney cysts, anomalies of the internal genital organs (in girls this is a duplication of the uterus and vagina, in boys - cryptorchidism - retention of the testicle when descending into the scrotum), pancreatic defects glands. As a rule, polydactyly is observed (usually bilateral and on the hands). Deafness is detected in 80-85% of patients. At birth, sick children are characterized by low weight, although they are born at term.

Due to severe congenital malformations, most children with Patau syndrome die in the first weeks or months of life (95% die before 1 year of age). However, some patients live for several years. Moreover, in developed countries there is a tendency to increase the life expectancy of patients with Patau syndrome to 5 years (about 15% of patients) and even up to 10 years (2-3% of patients).

Therapeutic care for children with Patau syndrome is nonspecific: operations for congenital malformations (for health reasons), restorative treatment, careful care, prevention of colds and infectious diseases. Children with Patau syndrome are almost always profound idiots.

Edwards syndrome (trisomy) 18th chromosome). Described in 1960 Edwards. The frequency of patients among newborns is 1:5000 - 1:7000. The ratio of boys to girls with Edwards syndrome is 1:3. The reasons for the predominance of sick girls are not yet known. In almost all cases, Edwards syndrome is caused by a simple trisomic form (a gametic mutation in one of the parents).

With Edwards syndrome, there is a pronounced delay in prenatal development with a normal duration of pregnancy (delivery at term). The most characteristic features of the syndrome are multiple congenital malformations of the facial part of the skull, heart, skeletal system, and genital organs. The skull is dolichocephalic (elongated) in shape; lower jaw and the opening of the mouth is small; palpebral fissures are narrow and short; the ears are deformed and low-set. Other external signs include a flexor position of the hands, an abnormal foot (the heel protrudes, the arch sags), the first toe is shorter than the second toe. Spina bifida and cleft lip are rare (5% of Edwards syndrome cases).

Children with Edwards syndrome die at an early age (90% before 1 year) from complications caused by congenital malformations (asphyxia, pneumonia, intestinal obstruction, cardiovascular failure).

Syndromes caused byintrachromosomal

perestroikas

This type of chromosome rearrangements (along with deletions, duplications and inversions) includes partial trisomies and autosomal monosomies.

Cry of the cat syndrome associated with deletion short shoulder 5th chromosome. It was first described by J. Lejeune in 1963. Its sign is the unusual crying of children, reminiscent of the meowing or cry of a cat. This is due to pathology of the larynx or vocal cords. However, with age, this cry disappears.

The clinical picture of the syndrome varies significantly. The most typical, in addition to the “cry of a cat,” is mental and physical underdevelopment, microcephaly (an abnormally small head).

The appearance of patients is peculiar: moon-shaped face, microgenia (small size of the upper jaw), epicanthus (vertical fold of skin at the inner corner of the palpebral fissure), high palate, flat dorsum of the nose, strabismus. The ears are low and deformed. Congenital heart defects, pathology of the musculoskeletal system, syndactyly of the feet (complete or partial fusion of adjacent toes), flat feet, clubfoot, etc., and muscle hypotonia are also noted.

Most children die at an early age. However, descriptions of patients over 50 years of age are known. The population frequency of “cry the cat” syndrome is 1:40000 - 1:50000 newborns. The size of the deletion varies from case to case.

Wolf-Hirschhorn syndrome first described in 1965. In 80% of newborns suffering from it, the cytological basis of this syndrome is a deletion of the short arm of chromosome 4. It is noted that most deletions arise anew, about 13% occur as a result of translocations in the parents. Less commonly, in the genome of patients, in addition to translocation, there are also ring chromosomes. Along with chromosome divisions, pathology in newborns can be caused by inversions, duplications, and isochromosomes.

The disease is characterized by numerous congenital malformations and delayed mental and psychomotor development.

Newborns have a low weight during a normal pregnancy. Among the external signs are: microcephaly, beak-shaped nose, epicanthus, anti-Mongoloid eye shape (drooping of the outer corners of the palpebral fissures), abnormal ears, cleft lip and palate, small mouth, deformed feet, etc.

The frequency of this syndrome is low - 1:100,000 births.

The vitality of children is sharply reduced, most die before the age of 1 year. Only 1 patient aged 25 years is described.

Syndromes with numbersabnormalities of sex chromosomes

Shereshevsky-Turner syndrome first described by N.A. Shereshevsky in 1925, and later, in 1938, Kh.Kh. Turner. The cause of the disease is a violation of the divergence of sex chromosomes. Only women are affected; they are missing one X chromosome (45 XO).

The incidence of the syndrome is 1:3000 newborn girls. It is noted that only 20% of women remain pregnant with a diseased fetus until the end and a live child is born. In other cases, spontaneous abortion or stillbirth occurs.

The syndrome is characterized by: short stature, sexual infantilism, somatic disorders. Children experience growth retardation already in the first year of life, which becomes most clearly noticeable by the age of 9-10 years. The average height of sick adult women is 135 cm. They have anomalies in skeletal development: a short neck with lateral skin folds, a short and wide chest, excessive mobility of the elbow and knee joints, shortening of the 4th-5th fingers. The appearance of patients is characteristic: micrognathia (underdevelopment of the lower jaw), epicanthus, low-set deformed ears, high hard palate, etc. Strabismus, cataracts, hearing defects, anomalies of the urinary system (doubling of the kidneys, urinary tract) are often noted.

An important feature of this disease is sexual infantilism. The internal and external genitalia are underdeveloped, during puberty secondary sexual characteristics are absent or poorly developed, the vagina and uterus are underdeveloped, there are no menstruation, patients are infertile. However, in the literature there is data on the birth of children in women with Shereshevsky-Turner syndrome.

In 50% of cases, patients suffer from mental retardation, they are passive, prone to psychogenic reactions and psychosis.

Life expectancy is close to normal. Treatment is aimed at stimulating growth and reducing sexual infantilism (long courses of sex hormones, etc.).

X-chromosomy polysomy syndrome meh in women. The syndrome includes trisomy (karyotype 47, XXX), tetrasomy (48, XXXX), pentasomy (49, XXXXX). Trisomy is the most common - 1 in 1000 girls born. The clinical picture is quite varied. There is a slight decrease in intelligence, an increased likelihood of developing psychosis and schizophrenia with an unfavorable type of course. The fertility of such women suffers to a lesser extent.

With tetra- and pentasomy - X, the degree of mental retardation increases, somatic anomalies and underdevelopment of the genitals are noted. Diagnosis of polysomy X syndrome includes determination of sex chromatin and examination of the patient's karyotype. There is no rational treatment.

Klinefelter syndrome described in 1942 by N. Klinefelter. Only boys get sick. The frequency of occurrence is 2 out of 1000 newborn boys. It has been established that patients have an extra X chromosome (karyotype 47, XXY, instead of 46, XY). Along with this, there are polysomy variants with a large number of X and Y chromosomes, which are also classified as Klinefelter syndrome.

The disease is not clinically diagnosed before birth. Genetic abnormalities manifest themselves during puberty in the form of underdevelopment of the testes and secondary sexual characteristics.

Men with Klinefelter syndrome are characterized by tall stature, eunuchoid body type (wide pelvis, narrow shoulders), gynecomastia (more than normal development of the mammary glands), poor hair growth on the face, armpits and pubic area. The testicles are reduced in size, sexual infantilism and a tendency to obesity are noted. In this case, spermatogenesis is impaired in patients and they are infertile. Their mental development lags behind, however, sometimes the intelligence is normal.

An increase in the number of X chromosomes in the genotype is accompanied by increased mental retardation, mental disorders, antisocial behavior and alcoholism.

Disomy syndrome Y -chromosome (47, XYY) was described in 1961. It occurs with a frequency of 1 in 1000 newborn boys. Men with a set of chromosomes 47 XYY do not differ from the norm in physical and mental development. There is a slight increase in height - about 185 cm. Sometimes there is a slight decrease in intelligence, a tendency to aggressive and antisocial behavior. According to some data, in prison there are 10 times more men with the XYY genotype than men with the normal genotype.

Factors that increase the risk of having children with

chromosomal diseases

In recent decades, many researchers have turned to the causes of chromosomal diseases. There was no doubt that the formation of chromosomal abnormalities (both chromosomal and genomic mutations) occurs spontaneously. The results of experimental genetics were extrapolated and induced mutagenesis in humans was assumed (ionizing radiation, chemical mutagens, viruses). However, the actual reasons for the occurrence of chromosomal and genomic mutations in germ cells or in the early stages of embryo development have not yet been deciphered.

Many hypotheses of chromosome nondisjunction were tested (seasonality, race-ethnicity, maternal and paternal age, delayed fertilization, birth order, family accumulation, drug treatment of mothers, bad habits, non-hormonal and hormonal contraception, viral diseases in women). In most cases, these hypotheses were not confirmed, but a genetic predisposition to the disease cannot be excluded. Although most cases of chromosome nondisjunction in humans are sporadic, it can be assumed that it is genetically determined to a certain extent. This is evidenced by the following facts:

offspring with trisomy appear repeatedly in the same women with a frequency of at least 1%;

relatives of a proband with trisomy 21 or other aneuploidies have a slightly increased risk of having a child with aneuploidy;

consanguinity of parents may increase the risk of trisomy in offspring;

the frequency of conceptions with double aneuploidy may be higher than predicted, consistent with the frequency of individual aneuploidies.

Biological factors that increase the risk of chromosome nondisjunction include maternal age, although the mechanisms of this phenomenon are unclear. The risk of having a child with a chromosomal disease caused by aneuploidy gradually increases with maternal age, but especially sharply after 35 years. In women over 45 years of age, every 5th pregnancy ends in the birth of a child with a chromosomal disease. The age dependence is most clearly manifested for trisomy 21 (Down's disease). For sex chromosome aneuploidies, the age of the parents either does not matter at all or its role is very insignificant.

With age, the frequency of spontaneous abortions also increases, which by 45 years increases by 3 times or more. This situation can be explained by the fact that spontaneous abortions are largely caused (up to 40-45%) by chromosomal abnormalities, the frequency of which is age dependent.

Diseases with hereditary predisposition

(multifactorial)

Diseases with a hereditary predisposition, in contrast to genetic diseases, are caused by both hereditary and, to a large extent, environmental factors. This group of diseases currently accounts for 92% of the total number of hereditary human pathologies. With age, the incidence of diseases increases. In childhood, the percentage of patients is at least 10%, and in the elderly - 25-30%.

The most common multifactorial diseases include: rheumatism, coronary heart disease, hypertension and peptic ulcer, liver cirrhosis, diabetes mellitus, bronchial asthma, psoriasis, schizophrenia, etc.

Diseases with a hereditary predisposition are associated with the action of many genes, which is why they are also called multifactorial.

Being multifactorial systems, they are difficult for genetic analysis. Only recently have advances in the study of the human genome and mapping of its genes opened up the possibility of identifying genetic predisposition and the main causes of the development of multifactorial diseases.

Hereditary predisposition may be mono- or polygenic in nature. In the first case, it is caused by a mutation of one gene, the manifestation of which requires a certain external factor, and in the second case, by a combination of alleles of several genes and a complex of environmental factors.

The clinical picture and severity of multifactorial human diseases are very different depending on gender and age. At the same time, with all their diversity, the following common features are distinguished:

1. High frequency of diseases in the population. Thus, about 1% of the population suffers from schizophrenia, 5% from diabetes mellitus, allergic diseases - more than 10%, hypertension - about 30%.

Clinical polymorphism of diseases varies from hidden subclinical forms to pronounced manifestations.

Features of inheritance of diseases do not correspond to Mendelian patterns.

The degree of manifestation of the disease depends on the gender and age of the patient, the intensity of the work of his endocrine system, unfavorable factors of the external and internal environment, for example, poor nutrition, etc.

Genetic prognosis for multifactorial diseases depends on the following factors:

the lower the frequency of the disease in the population, the higher the risk for the relatives of the proband;

the stronger the severity of the disease in the proband, the greater the risk of developing the disease in his relatives;

the risk to relatives of the proband depends on the degree of relationship with the affected family member;

the risk for relatives will be higher if the proband belongs to the less affected sex;

To assess risk for multifactorial pathology, empirical data are collected on the population and family frequency of each disease or developmental defect.

The polygenic nature of diseases with hereditary predisposition is confirmed using genealogical, twin and population statistical methods. The twin method is quite objective and sensitive. When using it, a comparison is made of the concordance of mono- and dizygotic twins or a comparison of the concordance of monozygotic twins raised together or separately. It has been shown that the concordance of monozygotic twins is higher than that of dizygotic twins for a number of diseases of the cardiovascular system (hypertension, myocardial infarction, stroke, rheumatism). This indicates a genetic predisposition to these diseases. A study of the nature of malignant neoplasms in monozygotic twins showed low concordance (11%), but at the same time, it is 3-4 times higher than that for dizygotic twins. It is obvious that the importance of external factors (especially carcinogenic ones) for the occurrence of cancer is much greater than hereditary ones.

Using the twin method, a hereditary predisposition to some infectious diseases (tuberculosis, polio) and many common diseases (coronary heart disease, rheumatism, diabetes mellitus, peptic ulcer, schizophrenia, etc.) is shown.

The distribution of multifactorial diseases in different human populations can vary significantly, which is associated with differences in genetic and environmental factors. As a result of genetic processes occurring in human populations (selection, mutations, migrations, genetic drift), the frequency of genes that determine hereditary predisposition can increase or decrease until they are completely eliminated.

The successes of the Human Genome program, the isolation and decoding of the molecular organization of genes, and the study of the causes of their pathology will undoubtedly contribute to the development of preventive measures and the identification of groups of people prone to multifactorial diseases.

T E M A No. 8 Medical genetic counseling

Currently, the number of children with severe hereditary diseases in the countries of the former CIS exceeds one million. Enormous amounts of money are spent on their treatment. In this regard, diagnosis, prevention and treatment of hereditary and congenital diseases in children is of great importance.

The most effective method of preventing hereditary pathology is medical genetic counseling, the main goal of which is to determine the prognosis for the birth of sick children in the family, as well as counseling on further family planning.

The first medical genetic consultation was organized in the late 20s. in Moscow, the largest domestic neurologist and geneticist S.N. Davidenkov at the Institute of Neuropsychiatric Prevention.

The first office for medical genetic counseling was organized in 1941 by J. Neal at the University of Michigan (USA). In Russia in 1932 under the leadership of S. G. Levit, a medical genetics institute was created.

Intensive development of medical genetic care in our and other countries began in the 60-70s. XX century, which was associated both with the increase in the proportion of hereditary diseases and with advances in the study of chromosomal pathology and metabolic diseases. According to 1995 data, there were 70 medical genetic institutions on the territory of the Russian Federation, whose services were used by about 80 thousand families.

Main target medical and genetic counseling - preventing the birth of a sick child. Main tasks medical genetic counseling are:

Establishing an accurate diagnosis of hereditary pathology.

Prenatal (prenatal) diagnosis of congenital and hereditary diseases various methods(ultrasonic, cytogenetic, biochemical, molecular genetic).

Determination of the type of inheritance of the disease.

Assessing the risk of having a sick child and providing assistance in decision making.

Promotion of medical and genetic knowledge among doctors and the population.

Occasion for medical genetic counseling may be:

The birth of a child with congenital malformations, mental and physical retardation, blindness and deafness, seizures, etc.

Spontaneous abortions, miscarriages, stillbirths.

Consanguineous marriages.

Unfavorable course of pregnancy.

Spouses work in a hazardous enterprise.

Incompatibility of married couples based on the Rh blood factor.

The woman is over 35 years old, and the man is over 40 years old.

Medical genetic consultation includes 4 stages: diagnosis; forecast; conclusion; advice.

The work begins with clarifying the diagnosis of the disease. An accurate diagnosis is a prerequisite for any consultation. In some cases, the diagnosis of a hereditary pathology can be established by a doctor before referral to a consultation. This applies to well-studied and fairly common hereditary diseases, for example, Down's disease, diabetes mellitus, hemophilia, muscular dystrophy, etc. More often, the diagnosis is unclear.

In medical genetic consultations, the diagnosis is clarified through the use of modern genetic, biochemical, immunogenetic and other methods.

One of the main methods is the genealogical method, i.e. drawing up a pedigree for a married couple who applied for consultation. First of all, this applies to the spouse in whose pedigree there was a hereditary pathology. Careful collection of the pedigree provides certain information for making a diagnosis of the disease.

In more complex cases, for example, when a child is born with multiple developmental defects, the correct diagnosis can only be made using special research methods. During the diagnostic process, there is often a need to examine not only the patient, but also other family members.

After the diagnosis is established, the prognosis for the offspring is determined, i.e. the magnitude of the repeat risk of having a sick child. The basis for solving this problem is theoretical calculations using methods genetic analysis and variation statistics or empirical risk tables. This is the function of a geneticist.

Transmission of hereditary diseases is possible in several ways, depending on the characteristics of the transmission of hereditary pathology. For example, if a child has a disease like one of the parents, this indicates a dominant type of inheritance. In this case, with complete penetrance of the gene, sick family members will pass the disease on to half of their children.

Hereditary pathology in a child of healthy parents indicates a recessive type of inheritance. The risk of having a sick child to parents with a recessive disease is 25%. According to 1976 data, 789 recessively inherited diseases and 944 dominantly inherited diseases were known in humans.

Hereditary pathology can be linked to sex (X-linked type of inheritance). Under these conditions, the risk of disease in boys and carriage in girls is 50%. About 150 such diseases are currently known.

In the case of multifactorial diseases, genetic counseling is quite accurate. These diseases are caused by the interaction of many genes with environmental factors. The number of pathological genes and their relative contribution to the disease are unknown in most cases. To calculate genetic risk, specially developed tables of empirical risk for multifactorial diseases are used.

A genetic risk of up to 5% is considered low and is not a contraindication to having a child again in the family. A risk of 6 to 20% is considered average, and in this case a comprehensive examination is recommended for further family planning. Genetic risk over 20% is generally considered to be high risk. Further childbearing in this family is not recommended.

With chromosomal diseases, the probability of re-birth of a sick child is extremely low and does not exceed 1% (in the absence of other risk factors).

For the translocation form of Down disease, when calculating risk, it is important to determine which parent carries the balanced translocation. For example, with translocation (14/21), the risk is 10% if the carrier is the mother, and 2.5% if the carrier is the father. When the 21st chromosome is translocated to its homologue, the risk of having a sick child is 100%, regardless of which parent is the carrier of the translocation.

To determine the risk of re-birth of a child with pathology, it is important to identify heterozygous carriers of the mutant gene. This is of particular importance in cases of autosomal recessive inheritance, sex-linked inheritance, and consanguineous marriages.

In some cases, heterozygous carriage is established by analyzing the pedigree, as well as by clinical and biochemical tests. So, if a father has a recessive disease linked to the X chromosome (for example, hemophilia), then with a 100% probability his daughter will be heterozygous for this gene. Along with this, a decrease in antihemophilic globulin in the blood serum in the daughters of a hemophilic father can serve as quite convincing evidence of heterozygous carriage of the hemophilia gene.

Currently, some hereditary diseases are identified using DNA diagnostics.

Heterozygous carriers of defective genes should avoid consanguineous marriages, which significantly increase the risk of having children with hereditary pathology.

The conclusion of medical genetic counseling and advice to parents (the last two stages) can be combined. As a result of genetic research, a geneticist gives an opinion about the existing disease, introduces the likelihood of the disease occurring in the future, and gives appropriate recommendations. This takes into account not only the risk of having a sick child, but also the severity of the hereditary or congenital disease, the possibility of prenatal diagnosis and the effectiveness of treatment. At the same time, all decisions on further family planning are made only by the spouses.

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

Modern representations about congenital metabolic diseases 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 of alternative pathways for the “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 weakened with early diagnosis and timely initiation of adequate treatment: restriction of protein and amino acids in the diet, vitamin supplementation. This is why newborns are screened for aminoacidopathies using a variety of chemical and microbiological methods blood or urine test. 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.

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 of dystrophic changes in cartilage, intervertebral discs and other connective tissue formations.

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 to nicotinic acid(vitamin PP), and at this stage a number of intermediate products are formed: kynurenine, xanthurenic acid, hydroxyantranilic 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 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.

A general idea of ​​protein metabolism disorders can be obtained by studying the nitrogen balance of the body and the environment.

Nitrogen imbalance

Violation of nitrogen balance manifests itself in the form of positive or negative nitrogen balance.

Positive nitrogen balance - a condition when less nitrogen is excreted from the body than is supplied with food. It is observed during the growth of the body, during pregnancy, as well as after fasting, with excessive secretion of anabolic hormones (somatotropic hormone, androgens, etc.) and when they are prescribed for therapeutic purposes.

The anabolic effect of hormones is to enhance the processes of protein synthesis compared to its breakdown. The following hormones have this effect.

Somatotropic hormone enhances fat oxidation and mobilization of neutral fat and thus leads to a sufficient release of energy necessary for protein synthesis processes.

Sex hormones enhance protein synthesis processes.

Insulin facilitates the passage of amino acids through cell membranes inside cells and thus promotes protein synthesis and weakens gluconeogenesis. Lack of insulin leads to decreased protein synthesis and increased gluconeogenesis.

Negative nitrogen balance - a condition when more nitrogen is excreted from the body than is taken in with food. Negative nitrogen balance develops during fasting, proteinuria, infectious diseases, injuries, thermal burns, surgical operations, with excessive secretion or prescription of catabolic hormones (cortisol, thyroxine, etc.).

The catabolic effect of hormones is to enhance the processes of protein breakdown compared to the processes of synthesis. The following hormones have this effect.

Thyroxine increases the number of active sulfhydryl groups in the structure of some enzymes - tissue cathepsins are activated and their proteolytic effect is enhanced. Thyroxine increases the activity of amino oxidases - the deamination of some amino acids increases. With hyperthyroidism, patients develop a negative nitrogen balance and creatinuria.

For hormone deficiency thyroid gland, for example, in hypothyroidism, insufficiency of the catabolic effect of the hormone manifests itself in the form of a positive nitrogen balance and accumulation of creatine.

Glucocorticoid hormones (cortisol, etc.) increase the breakdown of proteins. Protein consumption increases for the needs of gluconeogenesis; this also slows down protein synthesis.

Protein metabolism may be disrupted by different stages transformations of protein substances taken with food. The following violations can be distinguished:

• 1) upon receipt, digestion and absorption of proteins in the gastrointestinal tract;
• 2) during the synthesis and breakdown of proteins in the cells and tissues of the body;
• 3) during interstitial amino acid metabolism;
• 4) at the final stages of protein metabolism;
• 5) in the protein composition of blood plasma.

Disturbances in the supply, digestion and absorption of proteins in the gastrointestinal tract

Disorders of the secretion of certain proteolytic enzymes gastric tract, as a rule, do not cause serious disturbances in protein metabolism. Thus, complete cessation of pepsin secretion with gastric juice does not affect the degree of protein breakdown in the intestine, but significantly affects the rate of its breakdown and the appearance of individual free amino acids.

The elimination of individual amino acids in the gastrointestinal tract occurs unevenly. Thus, tyrosine and tryptophan are normally cleaved from proteins already in the stomach, and other amino acids are only cleaved under the action of proteolytic enzymes of intestinal juice. The composition of amino acids in the intestinal contents at the beginning and end of intestinal digestion is different.

Amino acids can enter the system portal vein in different proportions. A relative deficiency of even one essential amino acid complicates the entire process of protein biosynthesis and creates a relative excess of other amino acids with the accumulation of intermediate metabolic products of these amino acids in the body.

Similar metabolic disorders associated with a delay in the elimination of tyrosine and tryptophan occur with achylia and subtotal resection of the stomach.

Malabsorption of amino acids can occur due to pathological changes in the wall of the small intestine, for example, with inflammation and edema.

Disorders of protein synthesis and breakdown

Protein synthesis occurs inside cells. The nature of the synthesis depends on the genetic makeup on the chromosomes in the cell nucleus. Under the influence of genes specific to each type of protein in each organism, enzymes are activated, and messenger ribonucleic acid (RNA) is synthesized in the cell nucleus. mRNA is a mirror copy of deoxyribonucleic acid (DNA) found in the cell nucleus.

Protein synthesis occurs in the cytoplasm of the cell on ribosomes. Under the influence of mRNA, messenger RNA (m-RNA) is synthesized on ribosomes, which is a copy of mRNA and contains encoded information about the type and sequence of amino acids in the molecule of the protein being synthesized.

To incorporate amino acids into a protein molecule in accordance with the matrix (m-RNA), their activation is necessary. The function of activating amino acids is performed by a fraction of RNA called soluble or transport (t-RNA). Activation of amino acids is accompanied by their phosphorylation. The attachment of amino acids by means of t-RNA to certain groups of m-RNA nucleotides occurs when they are dephosphorylated due to the energy of guanine triphosphate. The synthesized protein performs a specific function in the cell or is transported from the cell and performs its function as a blood protein, antibody, hormone, enzyme.

The regulation of protein synthesis in a cell is genetically determined by the presence of not only structural genes that control the sequence of nucleotide bases during mRNA synthesis, but also additional regulatory genes. They also take part in the regulation of protein synthesis in the cell. at least two genes - an operator gene and a regulatory gene.

The regulatory gene is responsible for the synthesis of the repressor, which is an enzyme and ultimately inhibits the activity of structural genes and the formation of mRNA.

The operator gene, or operating gene, is directly subject to the action of a repressor, causing in one case repression, and in the other - derepression: the appearance of the synthesis of a number of enzymes that synthesize mRNA. The operating gene forms a single whole with structural genes, forming a so-called operon.

A repressive substance can be in two states: active and inactive. In the active state, the repressor acts on the operating gene, stops its effects on structural genes, and ultimately stops the synthesis of mRNA and protein synthesis.

Repressor activators are called corepressors. They can be either a certain concentration of the regulated protein or factors formed as a result of the action of this protein.

Protein synthesis is regulated as follows. If there is a lack of protein in the cell, the effect of the repressor on the operon stops. The synthesis of mRNA and m-RNA increases. and the synthesis of protein molecules begins on ribosomes. Protein concentration increases. If the synthesized protein is not metabolized quickly enough, its amount continues to increase. A certain concentration of this protein, or factors formed under its action, can serve as a corepressor of synthesis, activating the repressor. The influence of the operating gene on structural genes stops and protein synthesis ultimately stops. Its concentration decreases, etc.

When the regulation of protein synthesis is disturbed, pathological conditions associated with both excessive synthesis and insufficient protein synthesis can occur.

Protein synthesis can be disrupted under the influence of various external and internal pathogenic factors:

• a) in case of deficiency of the amino acid composition of proteins;
• b) with pathological gene mutations associated with both the appearance of pathogenic structural genes and the absence of normal regulatory and structural genes;
• c) when blocked humoral factors enzymes responsible for the processes of repression and derepression of protein synthesis in cells;
• d) in case of violation of the ratio of anabolic and catabolic factors regulating protein synthesis.

The absence of even one essential amino acid in cells stops protein synthesis.

Protein biosynthesis can be disrupted not only in the absence of individual essential amino acids, but also in the event of a violation of the ratio between the amount of essential amino acids entering the body. Need for separate essential amino acids associated with their participation in the synthesis of hormones, mediators, and biologically active substances.

Insufficient intake of essential amino acids into the body causes not only general disturbances in protein synthesis, but also selectively disrupts the synthesis of individual proteins. A deficiency of an essential amino acid may be accompanied by its characteristic disorders.

Tryptophan . With prolonged exclusion from the diet, rats develop corneal vascularization and cataracts. In children, restriction of tryptophan in food is accompanied by a decrease in the concentration of plasma proteins.

Lysine . Lack of food is accompanied in people by the appearance of nausea, dizziness, headache and increased sensitivity to noise.

Arginine . Lack of food can lead to inhibition of spermatogenesis.

Leucine . A relative excess of it compared to other essential amino acids in rats inhibits growth due to a corresponding impairment in the absorption of isoleucine.

Histidine . Its deficiency is accompanied by a decrease in hemoglobin concentration.

Methionine . Excluding it from food is accompanied by fatty degeneration of the liver, caused by a lack of labile methyl groups for the synthesis of lecithin.

Valin . Its deficiency leads to growth retardation, weight loss, and the development of keratoses.

Nonessential amino acids significantly affect the need for essential amino acids. For example, the need for methionine is determined by the cystine content of the diet. The more cystine in food, the less methionine is consumed for the biological synthesis of cystine. If the body's rate of synthesis of a non-essential amino acid becomes insufficient, an increased need for it appears.

Some non-essential amino acids become essential if they are not supplied with food, as the body cannot cope with their rapid synthesis. Thus, a lack of cystine leads to inhibition of cell growth even in the presence of all other amino acids in the medium.

Dysregulation of protein synthesis - antibodies - may occur with some allergic diseases. Thus, in immunocompetent cells (lymphoid cells) that produce antibodies, the production of autoantibodies is usually repressed. During embryonic development, when phases change (stage of the neural tube, mesenchyme sheets), derepression of the synthesis of autoantibodies occurs. Autoantibodies are detected in tissues, which are involved in the resorption of tissues from previous phases of embryo development. This change in repressor activity occurs several times. In the adult body, the synthesis of autoantibodies is repressed. For example, the synthesis of autoantibodies to antigens of one’s own red blood cells is repressed. If, depending on the blood group, there is agglutininogen A in the erythrocytes, then there are no α-agglutinins in the blood plasma, the production of which is reliably repressed. On this basis, blood transplantation is possible and hematopoietic tissue(bone marrow).

For some tissues (lens of the eye, nervous tissue, testicles), the production of autoantibodies is not repressed, but these tissues, due to their anatomical and functional features are isolated from immunocompetent cells and normally the production of autoantibodies does not occur. When anatomical isolation is disrupted (damage), the production of autoantibodies begins and autoallergic diseases occur.

Amino acid metabolism disorders

Deamination disorders. Oxidative deamination occurs as a result of sequential transformations of amino acids in transamination and deamination reactions:

Amino acids, with the participation of specific transaminases, are first transaminated with α-ketoglutaric acid. A ketoacid and glutamate are formed. Glutamate, under the action of dehydrogenase, undergoes oxidative deamination with the release of ammonia and the formation of α-ketoglutarate. The reactions are reversible. This way new amino acids are formed. The inclusion of α-ketoglutaric acid in the Krebs cycle ensures the inclusion of amino acids in energy metabolism. Oxidative deamination also determines the formation of final products of protein metabolism.

Transamination is associated with the formation of amino sugars, porphyrins, creatine and deamination of amino acids. A violation of transamination occurs with a lack of vitamin B6, since its form - phosphopyridoxal - is an active group of transaminases.

The ratio of transamination substrates determines the direction of the reaction. When urea formation is impaired, transamination accelerates.

Weakening of deamination occurs when the activity of enzymes - amino oxidases - decreases and when oxidative processes are disrupted (hypoxia, hypovitaminosis C, PP, B 2).

If the deamination of amino acids is impaired, the excretion of amino acids in the urine increases (aminoaciduria), and urea formation decreases.

Decarboxylation disorders. Decarboxylation of amino acids is accompanied by the release of CO 2 and the formation of biogenic amines:

In the animal body, only some amino acids undergo decarboxylation to form biogenic amines: histidine (histamine), tyrosine (tyramine), 5-hydroxytryptophan (serotonin), glutamic acid (γ-aminobutyric acid) and the products of further transformations of tyrosine and cystine: 3,4- dioxyphenylalanine (DOPA, hydroxytyramine) and cysteic acid (taurine) (Fig. 47).

Biogenic amines exhibit their effects even at low concentrations. The accumulation of amines in high concentrations poses a serious danger to the body. Under normal conditions, amines are quickly eliminated by amine oxidase, which oxidizes them to aldehydes:

This reaction produces free ammonia. Inactivation of amines is also achieved by binding them to proteins.

The accumulation of biogenic amines in tissues and blood and the manifestation of their toxic effect occurs; when increasing the activity of decarboxylases, inhibiting the activity of oxidases and disrupting their binding to proteins.

In pathological processes accompanied by inhibition of oxidative deamination, the conversion of amino acids into to a greater extent occurs by decarboxylation with the accumulation of biogenic amines.

Metabolism disorders of individual amino acids. There are a number of hereditary human diseases associated with congenital defects in the metabolism of individual amino acids. These disorders of amino acid metabolism are associated with a genetically determined disorder in the synthesis of protein groups of enzymes that carry out the transformation of amino acids (Table 24).

Disorders of phenylalanine metabolism (phenylketonuria) . The cause of the disease is a deficiency of the enzyme phenylalanine hydroxylase in the liver, as a result of which the conversion of phenylalanine to tyrosine is blocked (Fig. 48). The concentration of phenylalanine in the blood reaches 20-60 mg% (normally about 1.5 mg%). Its metabolic products, in particular the ketoacid phenylpyruvate, have a toxic effect on the nervous system. Nerve cells of the cerebral cortex are destroyed and replaced by the proliferation of microglial elements. Phenylpyruvic oligophrenia develops. Phenylpyruvate appears in urine and gives a green color with iron trichloride. This reaction is carried out in newborns and serves to early diagnosis phenylketonuria.

With the development of the disease, already at 6 months of age, the child shows signs of insufficient mental development, clearing of skin and hair color, general agitation, increased reflexes, increased muscle tone and basal metabolism, epilepsy, microcephaly, etc.

Lightening of skin and hair color develops due to insufficient production of melanin, since the accumulation of phenylalanine blocks the metabolism of tyrosine.

Insufficiency of catecholamine synthesis develops, and the level of other free amino acids in the blood plasma decreases. The excretion of ketone bodies in urine increases.

Excluding phenylalanine from the diet leads to a decrease in the content of phenylalanine and its derivatives in the blood and prevents the development of phenylketonuria.

Disorders of homogentisic acid metabolism (a product of tyrosine metabolism) - alkaptonuria - occurs when there is a deficiency of the enzyme - homogentisic acid oxidase (Fig. 49).

In this case, homogentisic acid does not transform into maleylacetoacetic acid (the hydroquinone ring does not break). Under normal conditions, homogentisic acid is not detected in the blood. If the enzyme is deficient, homogentisic acid appears in the blood and is excreted from the body in the urine. There is a characteristic darkening of urine, especially in an alkaline environment.

The deposition of homogentisic acid derivatives in tissues causes pigmentation of connective tissue - ochronosis. The pigment is deposited in articular cartilage, in the cartilage of the nose, ears, endocardium, large blood vessels, kidneys, lungs, and epidermis. Alkaptonuria is often accompanied by kidney stones.

Tyrosine metabolism disorder - albinism . The cause of the disease is a lack of the enzyme tyrosinase in melanocytes - cells that synthesize the pigment melanin (Fig. 50).

In the absence of melanin, the skin acquires a milky white color with whitish hair growth (albinism), photophobia, nystagmus, translucency of the iris, and decreased visual acuity are observed. Sun exposure causes inflammatory changes in the skin - erythema.

Albinism may be accompanied by deafness, muteness, epilepsy, polydactyly and mental retardation. The intelligence of such patients is often normal.

Disorders of histidine metabolism . Mastocytosis - hereditary disease, accompanied by increased proliferation of mast cells. The cause of the disease is considered to be an increase in the activity of histidine decarboxylase, an enzyme that catalyzes the synthesis of histamine. Histamine accumulates in the liver, spleen and other organs. The disease is characterized by skin lesions, disturbances of cardiac activity and gastrointestinal tract function. There is increased urinary excretion of histamine.

Hyperaminaciduria . Occur when the reabsorption of amino acids in the renal tubules is impaired (renal hyperaminoaciduria, for example cystinosis, cystinuria) or when the concentration of amino acids in the blood increases (extrarenal hyperaminoaciduria, for example phenylketonuria, cystathionuria).

Cystinosis . It is observed with a congenital defect in the reabsorption of cystine, cysteine ​​and other non-cyclic amino acids in the renal tubules. Excretion of amino acids in urine can increase 10 times. Excretion of cystine and cysteine ​​increases 20-30 times. Cystine is deposited in the kidneys, spleen, skin, and liver. Cystinosis is accompanied by glucosuria, hyperkaliuria, proteinuria and polyuria.

With cystinuria, cystine excretion can increase up to 50 times compared to normal, accompanied by inhibition of reabsorption of lysine, arginine and ornithine in the renal tubules. The level of cystine in the blood does not exceed the norm. No disturbances were found in the interstitial metabolism of these amino acids. Increased excretion of amino acids can lead to disturbances in protein synthesis and protein malnutrition.

Disorders of the final stages of protein metabolism

Urea formation disorders. The end products of amino acid breakdown are ammonia, urea, CO 2 and H 2 O. Ammonia is formed in all tissues as a result of deamination of amino acids. Ammonia is toxic; when it accumulates, the protoplasm of cells is damaged. There are two mechanisms to bind ammonia and neutralize it: urea is formed in the liver, and in other tissues ammonia joins glutamic acid (amidation) - glutamine is formed. Subsequently, glutamine releases ammonia for the synthesis of new amino acids, the transformations of which are completed by the formation of urea, excreted in the urine. Of the total urine nitrogen, urea accounts for 90% (ammonia about 6%).

Urea synthesis occurs in the liver in the citrulline nargininornithine cycle (Fig. 51). There are diseases associated with hereditary defects in urea formation enzymes.

Arginine succinaturia . It consists of hyperaminoaciduria (argininosuccinic acid) and mental retardation. The cause is a defect in the enzyme argininosuccinate lyase.

Ammoniemia . The concentration of ammonia in the blood is increased. Increased excretion of glutamine in urine. The cause of the disease is blocking of carbamyl phosphate synthetase and ornithine carbamoyltransferase, which catalyze the binding of ammonia and the formation of ornithine in the urea cycle.

Citrullinuria . The concentration of citrulline in the blood can increase above normal by 50 times. Up to 15 g of citrulline per day is excreted in the urine. The cause is a hereditary defect in arginine succinate synthetase.

The activity of urea synthesis enzymes is also impaired in liver diseases (hepatitis, congestive cirrhosis), hypoproteinemia, and inhibition of oxidative phosphorylation. Ammonia accumulates in the blood and tissues - ammonium intoxication develops.

The cells of the nervous system are most sensitive to excess ammonia. In addition to the direct damaging effect of ammonia on nerve cells, ammonia is bound by glutamate, as a result of which it is switched off from metabolism. By accelerating the transamination of amino acids with α-keto-glutaric acid, it is not included in the Krebs cycle, the oxidation of pyruvic and acetic acids is limited and they are converted into ketone bodies. Oxygen consumption decreases. A comatose state develops.

Disorders of uric acid metabolism. Gout. Uric acid is the end product of the metabolism of aminopurines (adenine and guanine) in humans. In reptiles and birds, uric acid is the end product of the metabolism of all nitrogenous compounds. Human blood usually contains 4 mg% uric acid. With excessive consumption of foods rich in purine nucleotides and amino acids, from which purine bases are synthesized in the body (liver, kidneys), the amount of uric acid in the body increases. Its concentration also increases with nephritis and leukemia. Hyperurecemia occurs.

Sometimes hyperurecemia is accompanied by the deposition of uric acid salts in cartilage, tendon sheaths, legs, skin and muscles, since uric acid is poorly soluble. Inflammation occurs around deposits of crystalline urates - a granulation shaft is created surrounding dead tissue, and gouty nodes are formed. Urecemia may be accompanied by the precipitation of uric acid salts in the urinary tract with the formation of stones.

The pathogenesis of gout is not clear. It is believed that the disease is hereditary in nature and is associated with a violation of the factors that maintain uric acid in a soluble state. These factors are associated with the exchange of mucopolysaccharides and mucoproteins, which form the center of crystallization. When liver function is impaired (intoxication), the deposition of urates in tissues and the excretion of urates in the urine increases.

Blood protein disorders

Hypoproteinemia- decrease total number protein in the blood, which occurs mainly due to a decrease in albumin.

In the mechanism of occurrence of hypoproteinemia, the main pathogenetic factors are acquired hereditary disorders in the synthesis of blood proteins, the release of serum proteins from the bloodstream without subsequent return to the vessels and blood thinning.

Disorders of blood protein synthesis depend on the weakening of synthetic processes in the body (fasting, impaired absorption food proteins, vitamin deficiencies, exhaustion of the body due to prolonged infectious intoxication or malignant neoplasms, etc.).

The synthesis of blood proteins can also decrease if the function of the organs and tissues that produce these proteins is impaired. In case of liver diseases (hepatitis, cirrhosis), the content of albumin, fibrinogen, and prothrombin in the blood plasma decreases. There are hereditary defects in the synthesis of certain protein fractions of the blood, for example hereditary forms: afibrinogenemia and agammaglobulinemia. Severe deficiency of gamma globulin synthesis is associated with complete absence in such patients there are plasma cells in all tissues and a significant decrease in the number of lymphocytes in the lymph nodes.

Release of proteins from the bloodstream observed when:

• a) blood loss, wounds, major hemorrhages;
• b) plasma losses, in particular burns;
• c) increasing the permeability of the capillary wall, for example, during inflammation and venous stagnation.

During extensive inflammatory processes, the content of albumin in the blood decreases due to their release from the vessels into the interstitial space (Fig. 52). A large amount of albumin is also found in ascitic fluid in portal hypertension and heart failure.

Hypoalbuminemia can occur when protein reabsorption processes in the kidneys are impaired, for example, with nephrosis.

With hypoproteinemia, due to a decrease in albumin content, the oncotic pressure of the blood decreases, which leads to edema.

With an absolute decrease in the amount of albumin in the blood, the binding and transport of cations (calcium, magnesium), hormones (thyroxine), bilirubin and other substances is disrupted, which is accompanied by a number of functional disorders.

With a deficiency of haptoglobin, a protein from the α 2 -globulin fraction, the binding and transport of hemoglobin, released during physiological hemolysis of erythrocytes, is impaired, and hemoglobin is lost in the urine.

A decrease in the synthesis of antihemophilic globulin from the β 2 -globulin fraction leads to bleeding.

With a lack of transferrin, which belongs to β 1 -globulins, iron transfer is impaired.

The main consequence of hypo- or agammaglobulinemia is a decrease in immunity due to impaired production of antibodies (γ-globulins). At the same time, there is no reaction to homologous transplants (antibodies to foreign tissue are not formed and engraftment is possible).

Hyperproteinemia. More often, relative hyperproteinemia develops with an increase in the concentration of proteins in the blood, although their absolute number does not increase. This condition occurs when the blood thickens due to the body losing water.

Absolute hyperproteinemia is usually associated with hyperglobulinemia. For example, an increase in the content of γ-globulins is characteristic of infectious diseases when intense antibody production occurs. Hypergammaglobulinemia can occur as a compensatory reaction to a lack of albumin in the blood. For example, when chronic diseases liver (cirrhosis) albumin synthesis is impaired; the amount of proteins in the blood does not decrease, but increases due to the intensive synthesis of γ-globulins. In this case, nonspecific γ-globulins can be formed.

The predominance of globulins over albumins changes the albumin-globulin coefficient of blood towards its decrease (normally it is 2-2.5).

In some pathological processes and diseases changes in the blood percentage individual protein fractions, although the total protein content does not change significantly. For example, during inflammation, the concentration of the protective protein properdin increases (from the Latin perdere - to destroy). Properdin, in combination with complement, has bactericidal properties. In its presence, bacteria and some viruses undergo lysis. The content of properdin in the blood decreases with ionizing radiation.

Paraproteinemia . Significant hyperproteinemia (up to 12-15% or more protein in the blood) is noted when large quantity abnormal globulins. A typical example of changes in globulin synthesis is myeloma (plasmacytoma). Myeloma is a type of leukemia (paraproteinemic reticulosis).

In γ-myeloma, abnormal globulins are synthesized by tumor clones of plasma cells that enter the peripheral blood, accounting for 60% or more of the total number of leukocytes. Pathological myeloma protein does not have the properties of antibodies. It has a low molecular weight, passes through the kidney filter, and is deposited in the kidneys, contributing to the development of kidney failure in 80% of cases. In myeloma, ROE sharply accelerates (60-80 mm per hour) due to the predominance of globulins over albumins.

There is a disease called Waldenström's macroglobulinemia, characterized by tumor-like proliferation of lymphoid cells and increased production of macroglobulins with a molecular weight above 1,000,000. Macroglobulins are close to group M globulins (JqM); Normally there are no more than 0.12%. With the disease described, their content reaches 80% of the total amount of protein in the plasma, blood viscosity increases 10-12 times, which makes it difficult for the heart to function.

Metabolic disorders in a variety of diseases can be accompanied by the appearance of completely new proteins in the blood. For example, in the acute phase of rheumatism, with streptococcal, pneumococcal infections, myocardial infarction was found in blood serum C-reactive protein(It is called C-reactive because it gives a precipitation reaction with the C-polysaccharide of pneumococci). C-reactive protein moves between α- and β-globulins during electrophoresis; does not apply to antibodies. Apparently, its appearance reflects the reaction of the reticuloendothelial system to tissue breakdown products.

An unusual blood protein also includes cryoglobulin, which moves with γ-globulins in an electric field. Cryoglobulin can precipitate at temperatures below 37°. It appears in myeloma, nephrosis, liver cirrhosis, leukocytes and other diseases. The presence of cryoglobulin in the blood of patients is dangerous, since with strong local cooling the protein precipitates, which contributes to the formation of blood clots and tissue necrosis.

Leon E. Rosenberg

A number of inborn errors of metabolism are characterized by the deposition or accumulation of excess amounts of individual metabolites in tissues. Most often this reflects a violation of the breakdown processes of the substance, but in some cases the mechanism of the disease remains unknown. In many diseases, large molecules such as glycogen, sphingolipids, mucolipids, cholesteryl esters and mucopolysaccharides accumulate (see Chapters 313, 315 and 316), with others - metals, such as iron and copper (see Chapters 310 and 311). Finally, there is a group of diseases in which relatively small organic molecules accumulate. This group includes gout (see Chapter 309), as well as a number of amino acid metabolism disorders.

Alkaptonuria

Definition. Alkaptonuria is a rare disorder of tyrosine catabolism. Deficiency of the enzyme homogentisic acid oxidase leads to the excretion of large quantities of this acid in the urine and the accumulation of pigment (oxidized homogentisic acid) in the connective tissue (ochronosis). After many years, ochronosis causes the development of a special form of degenerative arthritis.

Etiology and pathogenesis. Homogentisic acid is an intermediate in the conversion of tyrosine to fumarate and acetoacetate. In patients with alkaptonuria, the activity of homogentisic acid oxidase, an enzyme that catalyzes the opening of the phenolic ring to form maleylacetoacetic acid, is reduced in the liver and kidneys. As a result, homogentisic acid accumulates in cells and body fluids. The amount of the latter in the blood of patients increases slightly, since it is very quickly excreted by the kidneys. Up to 3-7 g of homogentisic acid can be excreted in the urine per day, which has virtually no pathophysiological significance. However, homogentisic acid and its oxidized polymers are bound by collagen, resulting in increased accumulation of gray or blue-black pigment. At the same time, the mechanisms of development of dystrophic changes in cartilage, intervertebral discs and other connective tissue formations are unknown, but could consist of simple chemical irritation of the connective tissue or disruption of its metabolism.

Alkaptonuria was the first human disease with established autosomal recessive inheritance. Affected homozygotes occur with a frequency of approximately 1:200,000. Heterozygous carriers are clinically healthy and do not excrete homogentisic acid in the urine even after loading with tyrosine.

Clinical manifestations. Alkaptonuria may remain unrecognized until adulthood, when most patients develop degenerative joint damage. Until then, the ability of patients' urine to darken when standing, as well as slight changes in the color of the sclera and ears, may not attract attention. The last manifestations (discoloration) are usually the earliest external signs of the disease and appear after the age of 20-30 years. Characteristic are foci of gray-brown pigmentation of the sclera and generalized darkening of the auricles, antihelix and, finally, the helix. The ear cartilage may become fragmented and thickened. Ochronous arthritis is characterized by pain, stiffness and some limitation of range of motion in the hip, knee and shoulder joints. Intermittent attacks of acute arthritis appear, which may resemble rheumatoid arthritis, but small joints usually remain intact. Often late manifestations boil down to limited mobility and ankylosis of the lumbosacral spine. Pigmentation of the heart valves, larynx, eardrum and skin. Sometimes patients develop pigmented stones in the kidneys or prostate gland. In older patients, dystrophic changes in the cardiovascular system are more often detected.

Diagnostics. Alkaptonuria should be suspected in persons whose urine darkens to black when standing, but in the conditions of using modern water closets this symptom can be observed infrequently. The diagnosis is usually made on the basis of a triad of symptoms: degenerative arthritis, ochronous pigmentation and blackening of urine after alkalization. The presence of homogentisic acid in the urine can be assumed based on other tests: with the addition of ferric chloride, the urine becomes violet-black, Benedict's reagent turns brown, and a saturated solution of silver nitrate turns black. The results of these screening tests can be confirmed by chromatographic, enzymatic or spectrophotometric determinations of homogentisic acid. Pathognomonic signs are detected using radiography of the lumbar spine. X-rays reveal degeneration and dense calcification of the intervertebral discs, as well as narrowing of the intervertebral spaces.

Treatment. There is no specific treatment for ochronous arthritis. Joint symptoms could be alleviated by reducing the accumulation and deposition of homogentisic acid by limiting dietary intake of phenylalanine and tyrosine, but the duration of the disease precludes such attempts. Since the oxidation and polymerization of homogentisic acid in vitro is prevented by ascorbic acid, the possibility of its use as a means of reducing the formation and deposition of pigment was assumed. The effectiveness of this treatment has not been established. Symptomatic treatment is similar to that for osteoarthritis (Chapter 274).

Cystinosis

Definition. Cystinosis is a rare disease characterized by the accumulation of free cystine in the lysosomes of various tissues of the body. This leads to the appearance of cystine crystals in the cornea, conjunctiva, bone marrow, lymph nodes, white blood cells and internal organs. Three forms of the disease are known: infantile (nephropathic), causing the development of Fanconi syndrome and renal failure during the first 10 years of life, juvenile (intermediate), in which kidney damage manifests itself during the second 10 years of life, and adult (benign), characterized by deposits cystine in the cornea, but not in the kidneys.

Etiology and pathogenesis. Main defect with cystinosis, it is a violation of the “outflow” of cystine from lysosomes, and not a violation of its breakdown. This "efflux" is an active ATP-dependent process. In the infantile form, the content of cystine in tissues can exceed the norm by more than 100 times, and in the adult form - by more than 30 times. Intracellular cystine is localized in lysosomes and does not exchange with other intra- and extracellular amino acid pools. The concentration of cystine in plasma and urine does not increase significantly.

The degree of accumulation of cystine crystals in different patients varies depending on the form of the disease and methods of processing tissue samples. Accumulation of cystine in the kidneys in infantile and juvenile forms of the disease is accompanied by renal failure. The kidneys become pale and wrinkled, their capsule merges with the parenchyma, and the boundary between the cortex and medulla disappears. Microscopy reveals a violation of the integrity of the nephron; the glomeruli are hyalinized, the layer of connective tissue is increased, the normal tubular epithelium is replaced by cuboid cells. The narrowing and shortening of the proximal tubules causes their deformation in the form of a swan neck, which is characteristic, but not pathognomonic for cystinosis. In infantile and juvenile forms of the disease, focal depigmentation and degeneration of the peripheral parts of the retina are sometimes noted. Cystine crystals can also be deposited in the conjunctiva and choroid eye.

Any form of cystinosis is inherited, apparently, as an autosomal recessive trait. Obligate heterozygotes in intracellular cystine content occupy an intermediate position between healthy and sick ones, but clinical symptoms they don't have.

Clinical manifestations. In the infantile form of the disease, disorders usually appear at the age of 4-6 months. The child's growth is delayed, he develops vomiting, fever, vitamin D-resistant rickets, polyuria, dehydration and metabolic acidosis. Generalized proximal tubular dysfunction (Fanconi syndrome) leads to hyperphosphaturia and hypophosphatemia, renal glycosuria, general aminoaciduria, hypouricemia and often hypokalemia. The progression of glomerular insufficiency may be influenced by pyelonephritis and interstitial fibrosis. Death from uremia or accidental infection usually occurs before the age of 10 years. During the first few years of life, photophobia is noted due to cystine deposits in the cornea, and retinal degeneration may appear even earlier.

In contrast, in the adult form of the disease, only ocular pathology develops. The main symptoms include photophobia, headache and a burning or itching sensation in the eyes. The function of the glomeruli and tubules of the kidneys, as well as the integrity of the retina, are preserved. The signs of the juvenile form of the disease occupy an intermediate position between these extreme forms. In these patients, both the eyes and the kidneys are involved in the process, but the latter are only slightly affected until the second 10 years of life. However, although the kidneys suffer less than in the infantile form of the disease, patients ultimately die from renal failure.

Diagnostics. Cystinosis should be suspected in any child with vitamin D-resistant rickets, Fanconi syndrome, or glomerular insufficiency. Hexagonal or rectangular cystine crystals can be found in the cornea (when examined with a slit lamp), in peripheral blood or bone marrow white blood cells, or in biopsies of the rectal mucosa. The diagnosis is confirmed by quantitative determination of cystine in peripheral blood leukocytes or in cultured fibroblasts. The infantile form of the disease is diagnosed prenatally by elevated levels of cystine in amniotic fluid cell culture.

Treatment. The adult form is benign and does not require treatment. Symptomatic treatment for kidney disease in infantile or juvenile cystinosis is no different from that for other types of chronic renal failure: ensuring adequate fluid intake to avoid dehydration, correcting metabolic acidosis and consuming additional amounts of calcium, phosphate and vitamin D, which is aimed at combating rickets . These activities can support growth, development and wellness sick children. Two more specific treatments have been attempted, but with little success. A cystine-depleted diet did not prevent progression renal pathology. Similarly, the use of sulfhydryl reagents (penicillamine, dimercaprol) and reducing agents (vitamin C) was not accompanied by a long-term effect.

The most promising treatment for nephropathic cystinosis is kidney transplantation. This method was used in the treatment of more than 20 children with last stage renal failure. In patients who underwent surgery and avoided immunological problems, kidney function returned to normal. The transplanted kidneys did not develop functional disorders typical for cystinosis (for example, Fanconi syndrome or glomerular insufficiency). However, they sometimes reaccumulated some cystine, probably due to the migration of interstitial or mesangial cells of the host.

Primary hyperoxaluria

Definition. Primary hyperoxaluria is common name two rare disorders characterized by chronic urinary excretion of excess oxalic acid, calcium oxalate kidney stones, and nephrocalcinosis. As a rule, with both forms of the disease, renal failure develops already in the early years of life and patients die from uremia. At autopsy, widespread foci of calcium oxalate deposits are found in both the kidneys and extrarenal tissues. This condition is called oxalosis.

Etiology and pathogenesis. The metabolic basis of primary hyperoxaluria lies in disruption of glyoxylate metabolic pathways. In type I hyperoxaluria, urinary excretion of oxalate, as well as oxidized and reduced forms of glyoxylate, is increased. The accelerated synthesis of these substances is explained by the blockade alternative path glyoxylate metabolism. In the liver, kidneys and spleen, the activity of β-ketoglutarate glyoxylate carboligase, which catalyzes the formation of β-hydroxy-β-ketoadipic acid, is reduced. The resulting increase in the glyoxylate pool leads to an increase in both the oxidation of glyoxylate to oxalate and its reduction to glycolate. Both of these two-carbon acids are excreted in excess amounts in the urine. With hyperoxaluria type II, urinary excretion of not only oxalate, but also L-glyceric acid is increased. At the same time, in leukocytes (and, probably, in other cells), there is no activity of D-glyceric acid dehydrogenase, an enzyme that catalyzes the reduction of hydroxypyruvate to D-glyceric acid in the catabolic reactions of serine metabolism. The accumulated hydroxypyruvate is instead reduced by lactate dehydrogenase to the L-isomer of glycerate, which is excreted in the urine. The reduction of hydroxypyruvate is somehow associated with the oxidation of glyoxylate to oxalate, i.e., with the formation of increased amounts of the latter. Both disorders appear to be inherited as autosomal recessive traits. Heterozygotes have no clinical symptoms.

The pathogenesis of kidney stone formation, nephrocalcinosis and oxalosis is directly related to the insolubility of calcium oxalate. Outside the kidneys, large accumulations of oxalate are found in the heart, artery and vein walls, genitourinary tract in men and in bones.

Clinical manifestations. Nephrolithiasis and oxalosis can appear already in the first year of life. In most patients, renal colic or hematuria occurs between the ages of 2 and 10 years, and uremia develops before the age of 20 years. With the onset of uremia, patients may experience sharp spasms of peripheral arteries and necrosis of their walls, which leads to vascular insufficiency. As kidney function declines, oxalate excretion decreases. With late onset of symptoms, patients can reach the age of 50-60 years, despite recurrent nephrolithiasis.

Diagnostics. In healthy children or adults, daily oxalate excretion does not reach 60 mg per 1.73 m2 of body surface. In patients with hyperoxaluria type I or II, this figure exceeds the norm by 2-4 times. It is possible to differentiate two types of primary hyperoxaluria based on the results of determining other organic acids: type I is characterized by the excretion of glycolic acid, and type II is characterized by the excretion of L-glyceric acid. It is necessary to exclude pyridoxine deficiency or a chronic process in ileum, since these conditions may also be accompanied by the excretion of excess amounts of oxalate.

Treatment. There is no satisfactory treatment. The level of oxalate in urine can be temporarily reduced by increasing the rate of urination. It may decrease after the administration of large doses of pyridoxine (100 mg/day), but its long-term effect is weak. The frequency of attacks of renal colic decreases, apparently, when following a diet with high content phosphate, but oxalate excretion does not change. A kidney transplant does not help either, since the deposition of calcium oxalate impairs the function of the transplanted organ.