Amino acid metabolism disorders in children. Protein metabolism disorders
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 insufficiency of one or another enzyme responsible for the synthesis of amino acids. Diseases are accompanied by vomiting and dehydration, a lethargic state or agitation and convulsions. At a later age, the extinction of mental and physical development is manifested.
Hereditary diseases with impaired amino acid metabolism include phenylketonuria, albinism, etc.
Phenylketonuria (PKU) was first described by A. Feling in 1934. In patients, the conversion of the amino acid phenylalanine to 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. Further, phenylalanine is converted to 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 an average global scale with a frequency of 1 per 1000 newborns. However, there are significant differences between populations in this indicator: 1:2600 in Turkey, 1:4500 in Ireland, 1:30000 in Sweden, 1:119000 in Japan. The frequency of heterozygous carriage in most European populations is 1:100.
Locus (phenylhydroxylase) is located in the long arm of the 12th chromosome. At present, molecular genetic diagnosis and detection of heterozygous carriage are possible for most families. The disease is inherited in an autosomal dominant manner. Several forms of phenylketonuria are known, which differ in the severity of the course 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 first weeks, due to the intake of phenylalanine in the body with mother's milk, irritability, convulsions, a tendency to dermatitis develop, urine and sweat of patients have a characteristic "mouse" smell, but the main symptoms of PKU are convulsive seizures and oligophrenia.
Most patients are blondes with fair skin and blue eyes, which is determined by insufficient synthesis of 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 content of phenylalanine is determined. Sometimes a Felling test is used - 10 drops of a 5% solution of iron trichloride and acetic acid are added to 2.5 ml of the child's fresh urine. The appearance of a blue-green color indicates the presence of the disease.
The method of treatment for phenylketonuria is currently well developed. It consists in prescribing a diet to the patient (vegetables, fruits, jam, honey) and specially processed protein hydrolysates with a low content of phenylalanine (lofelac, ketonil, minafen, etc.). Currently, methods of prenatal diagnosis have been developed. Early diagnosis and preventive treatment prevent the development of the disease.
Albinism (oculocutaneous) described in 1959. The disease is due to the lack of tyrosinase enzyme synthesis. It is characterized by discoloration of the skin, hair, eyes, regardless of race and age. The skin of patients is pink-red, does not sunbathe at all. Has a predisposition to malignant neoplasms. Hair is white or yellowish. The iris is gray-blue, but may also be pinkish due to the reflection of light from the fundus. Patients are characterized by severe photophobia, their vision is reduced and does not improve with age.
Albinism occurs at a frequency of 1 in 39,000 and is inherited in an autosomal recessive manner. The gene is located on the long arm of the 11th chromosome.
hereditary diseases,related to violation
carbohydrate metabolism
It is known that carbohydrates are part of a number of biologically active substances - hormones, enzymes, mucopolysaccharides that perform energy and structural functions. As a result of a violation of carbohydrate metabolism, glycogen disease, galactosemia, etc.
Glycogen 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. If these processes are violated, a person develops severe diseases - various types of glycogenoses. These include Gierke's disease, Pompe's disease, etc.
Glycogenosis (I type - Gierke's disease). Patients in the liver, kidneys and intestinal mucosa accumulate a large amount of glycogen. Its transformation into glucose does not occur, because. there is no enzyme gluco-6-phosphatase, which regulates blood glucose levels. As a result, the patient develops hypoglycemia, 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 glycogemic seizures and hepatomegaly (liver enlargement). Growth retardation is noted from the 1st year of life. The appearance of the patient is characteristic: a large head, a "doll face", a short neck, a protruding belly. In addition, nosebleeds, delayed physical and sexual development, and muscle hypotension are noted. Intelligence is normal. Uric acid levels rise in the blood, so gout can develop with age.
Diet therapy is used as a treatment: frequent meals, high carbohydrate content and restriction of fats in the diet.
Glycogenosis (II type - Pompe disease) is more severe. Glycogen accumulates both in the liver and in skeletal muscles, myocardium, lungs, spleen, adrenal glands, vascular walls, and neurons.
After 1-2 months, newborns develop muscle weakness, a deficiency of 1,4-glucosidase in the liver and muscles. In the same period, cardiomegaly (enlargement of the heart) and macroglossia (abnormal enlargement of the tongue) occur. Often, patients develop a severe form of pneumonia due to the accumulation of secretions in the airways. Children die in the first year of life.
The disease is inherited in an autosomal recessive manner. The gene is located on the long arm of the 17th chromosome. 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 blood of the patient, which leads to damage to many organs: the liver, nervous system, eyes, etc. Symptoms of the disease appear in newborns after taking milk, since galactose is an integral part of lactose milk sugar. Hydrolysis of lactose produces glucose and galactose. The latter is necessary for the myelination of nerve fibers. With an excess of galactose in the body, it is normally converted to glucose using the enzyme galactose-1-phosphate uridyltransferase. With a decrease in the activity of this enzyme, galactose-1-phosphate accumulates, which is toxic to the liver, brain, and lens of the eye.
The disease is manifested from the first days of life by digestive disorders, intoxication (diarrhea, vomiting, dehydration). In patients, the liver enlarges, liver failure and jaundice develop. A cataract (clouding of the lens of the eye), mental retardation is detected. At autopsy, children who died in the first year of life are found to have cirrhosis of the liver.
The most accurate methods for diagnosing galactosemia are to determine the activity of the enzyme galactose-1-phosphate-uridyltransferase in erythrocytes, as well as galactose in the blood and urine, where its levels are increased. With the exclusion of milk (a source of galactose) from food and an early diet, sick children can develop normally.
The type of inheritance of galactosemia is autosomal recessive. The gene is located on the short arm of the 9th chromosome. The disease occurs with a frequency of 1 in 16,000 newborns.
Hereditary diseases associated with the violation
lipid metabolism
Hereditary lipid metabolism diseases (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.
Gaucher disease, Niemann-Pick disease, and amaurotic idiocy (Tay-Sachs disease) are among the most studied hereditary diseases of lipid metabolism of the first type.
Gaucher disease characterized by the accumulation of cerebrosides in the cells of the nervous and reticuloendothelial system, due to 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.
Allocate childhood and juvenile forms of the disease. Children's manifests itself in the first months of life with a delay in mental and physical development, an increase in the abdomen, liver and spleen, difficulty in swallowing, spasm of the larynx. Possible respiratory failure, infiltration (compaction of the lungs with Gaucher cells) and convulsions. Death occurs in the first year of life.
The juvenile form of Gaucher disease is the most common. It affects children of all ages and is chronic. The disease usually manifests itself in the first year of life. Skin pigmentation (brown spots), osteoporosis (decrease in bone density), fractures, bone deformities occur. The tissues of the brain, liver, spleen, bone marrow contain a large amount of glucocerebrosides. In leukocytes, cells of the liver and spleen, the activity of glucosidase is reduced. The type of inheritance is autosomal recessive. The gene is located on the long arm of the 1st chromosome.
Niemann-Pick disease due to a decrease in the activity of the enzyme sphingomyelinase. As a result, sphingomyelin accumulates in the cells of the liver, 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 common symptoms for all forms.
The disease often manifests itself at an early age. The child has enlarged lymph nodes, the size of the abdomen, liver and spleen; vomiting, refusal of food, muscle weakness, hearing loss and vision loss are noted. In 20-30% of children, a cherry-colored spot is found on the retina of the eye (the “cherry stone” symptom). The defeat of the nervous system leads to a lag in neuropsychic development, deafness, blindness. Resistance to infectious diseases is sharply reduced. Children die at an early age. The inheritance of the disease is autosomal recessive.
Diagnosis of Niemann-Pick disease is based on the detection of elevated levels of sphingomyelin in the blood plasma and cerebrospinal fluid. In the peripheral blood, large, granular, foamy Pick cells are detected. Treatment is symptomatic.
Amavrotic idiocy (disease Thea-Saxa) also refers to diseases associated with impaired lipid metabolism. 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, indifferent to others. The delay in mental development leads to a decrease in intelligence to the degree of idiocy. There is muscle hypotension, convulsions, a characteristic symptom of "cherry pit" on the retina. By the end of the first year of life comes blindness. The reason is atrophy of the optic nerves. Later, complete immobility develops. Death occurs at 3-4 years of age. The type of inheritance of the disease is autosomal recessive. The gene is located on the long arm of the 15th chromosome.
hereditary diseasesconnective tissue
Connective tissue in the body performs supporting, trophic and protective functions. The complex structure of connective tissue is genetically determined. Pathology in its system is the cause of various hereditary diseases and is caused to some extent by violations of the structure of structural proteins - collagens.
Most connective tissue diseases are associated with defects in the musculoskeletal system and skin. These include Marfan's syndrome, mucopolysaccharidoses.
Marfan syndrome belongs to the number of hereditary metabolic diseases and is characterized by a systemic lesion of the 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 connective tissue fiber protein fibrillin. Blocking its synthesis leads to increased extensibility of the connective tissue.
Patients with Marfan syndrome are distinguished by high growth, long fingers, chest deformity (funnel-shaped, keeled, flattened), flat feet. Often there are femoral and inguinal hernias, hypoplasia (underdevelopment) of muscles, muscle hypotension, blurred vision, changes in the shape and size of the lens, myopia (up to retinal detachment), heterochromia (different staining of the iris); subluxation of the lens, cataract, strabismus.
In addition to the above, Marfan syndrome is characterized by congenital heart defects, aortic expansion with the development of an aneurysm. Often there are disorders of the respiratory system, lesions of the gastrointestinal tract and urinary system.
Treatment is mainly symptomatic. Massage, physiotherapy exercises, and in some cases surgery 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, the great Italian violinist and composer Nicolo Paganini suffered from Marfan's syndrome.
Mucopolysaccharidoses represented by a whole group of hereditary connective tissue diseases. They are characterized by a violation in the body of the metabolism of acidic glycosaminoglycans, which is associated with a deficiency of lysosomal enzymes. As a result, pathological metabolic products are deposited in the connective tissue, in the liver, spleen, cornea and in the cells of the central nervous system. The first information about mucopolysaccharidoses appeared in 1900, and then in 1917-1919.
With mucopolysaccharidoses, the musculoskeletal system, internal organs, eyes, and nervous system are affected. Clinical signs of the disease are: growth retardation, short neck and torso, bone deformity, decreased intelligence, coarse facial features with large lips and tongue, umbilical and inguinal hernias, heart defects, impaired mental development lagging behind the norm.
The type of inheritance of the disease is autosomal recessive. The gene is mapped on the short arm of the 4th chromosome.
In total, 8 main types of mucopolysaccharidoses are distinguished, 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, physiotherapy, etc.), hormonal and cardiovascular agents.
hereditary disordersexchange in erythrocytes
Hemolytic anemia include diseases caused by a decrease in hemoglobin levels and a shortening of the life of erythrocytes. In addition, the cause of the disease can be:
Disruption of the erythrocyte 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. - Minkow's hemolytic anemia sky-chauffard. The disease was described in 1900. In about half of the cases, it occurs in newborns. The diagnosis is made at the age of 3-10 years. The disease is caused by genetic abnormalities of erythrocytes 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. Erythrocytes take a spherical shape. 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), skeletal changes are noted. The disease can occur in two forms - chronic and acute, in which hemolysis increases, causing anemia.
In children in the first months of life, "nuclear jaundice" often occurs. The reason is the defeat of the nuclei of the brain due to the high content of bilirubin. At an older age, a high level of bilirubin leads to the formation of stones and the development of cholelithiasis.
Patients are characterized by an increase in the spleen and liver, deformation of the skeleton, and a violation of the location of the teeth.
The mode of inheritance is autosomal dominant with incomplete penetrance. The gene is mapped on the short arm of the 8th chromosome.
Hereditary anomaliescirculating proteins.Hemoglobinopathies- These are diseases associated with a hereditary violation of hemoglobin synthesis. There are quantitative (structural) and qualitative forms. The former are characterized by a change in the primary structure of hemoglobin proteins, which can lead to a violation of its stability and function. With qualitative 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" - the Mediterranean Sea. It is believed that the origin of most carriers of the thalassemia gene 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 stop at one of them.
Homozygous (large) thalasse mia, aka cooley 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 by the end of the first year of a child's life. It is characterized by a Mongoloid face, a towering type of skull, and a lag in physical development. With this pathology, target-shaped erythrocytes with a low content of Hb, shortened life expectancy and increased osmotic stability are found in the patient's blood. Patients have an enlarged spleen and, less commonly, the liver.
According to the severity of the disease, several forms of thalassemia are distinguished. Severe thalassemia ends with a quick death in the first months of a child's life. In chronic - sick children live up to 5-8 years, and in mild forms, patients live to adulthood.
sickle cell anemia - the most common hereditary disease caused by a change in the structure of the hemoglobin molecule. People with sickle cell anemia in most cases die before reaching adulthood. Under conditions of low partial pressure of oxygen, their red blood cells take on the shape of a sickle. In the patient's parents, the erythrocytes 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 a severe form of anemia. In the patient's blood, he detected red blood cells of an unusual crescent shape.
In 1946, Nobel laureate L. Pauling and colleagues conducted a biochemical and genetic analysis of the hemoglobin of sick and healthy people and showed that the hemoglobins of normal and sickle cell erythrocytes differ in mobility in an electric field and solubility. It turned out that hemoglobin in people with signs of sickle cell is a mixture of equal amounts of both normal and mutant hemoglobin. It became clear that the mutation causing sickle cell anemia is associated with a change in the chemical structure of hemoglobin. Further studies have shown that in the case of sickle cell anemia, glutamic acid is replaced by valine in the sixth pair of nucleotides 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, pallor of the skin and mucous membranes, yellowness are noted. In 60% of children, the liver is enlarged. There are also noises in the region of the heart, etc. The disease proceeds in the form of alternating crises and remissions.
There are no special methods of treatment. 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 a large group of congenital hereditary diseases with multiple congenital malformations. They are based on chromosomal or genomic mutations. These two different types of mutations are collectively referred to as "chromosomal abnormalities" for brevity.
Isolation of at least three chromosomal diseases as clinical syndromes of congenital developmental disorders was done before establishing their chromosomal nature.
The most common disease, trisomy 21, was clinically described in 1866 by the English pediatrician L. Down and was called "Down's syndrome". In the future, the cause of the syndrome was repeatedly subjected to genetic analysis. Suggestions were made about a dominant mutation, about a congenital infection, about a chromosomal nature.
The first clinical description of the 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. By the name of these scientists, monosomy on the X chromosome is called Shereshevsky-Turner syndrome.
Anomalies in the system of sex chromosomes in men (trisomy XXY) as a clinical syndrome was first described by G. Klinefelter in 1942. The listed diseases became the object of the first clinical and cytogenetic studies conducted in 1959.
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 have been 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 only monosomy X occurs from monosomy.
As for chromosomal mutations, all their types (deletions, duplications, inversions, translocations) have been found in humans. 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 allow you to accurately characterize the form of chromosomal pathology.
The first principle - etiological - characterization 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 consists of (lack or excess of chromosomal material). Differentiation of chromosomal pathology on the basis of the clinical picture is not significant, since different chromosomal anomalies are characterized by a large commonality of developmental disorders.
The second principle is determining the type of cells in which 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 anomaly occurs in the zygote or in the early stages of cleavage (such mutations are called somatic, in contrast 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, which coincide with the full forms in the clinical picture, at least 10% of cells with an abnormal set are needed.
The third principle is identification of the generation in which la mutation : it arose anew in the gametes of healthy parents (sporadic cases) or the parents already had such an anomaly (inherited, or family, forms). No more than 3-5 are passed from generation to generation. % of them. Chromosomal abnormalities are responsible for approximately 50% of spontaneous abortions and 7% of all stillbirths.
All chromosomal diseases are usually divided into two groups.
Diseases associated with anomaliesnumber of chromosomes
This group includes three subgroups:
Diseases caused by a violation of the number
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 segment of a chromosome.
Inversions are 180 degree rotations of a segment of a chromosome.
Duplications - duplication of a section of a chromosome
Isochromosomy - chromosomes with repeated genetic material in both arms.
The emergence of ring chromosomes (connection of two terminal deletions in both arms of the 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% - to the pathology of the sex chromosomes. Structural adjustments account for 10.4%. The most common chromosomal rearrangements are translocations and deletions.
Diseases associated with chromosome aberrations
Down syndrome (trisomy 21st chromosome). The most common disease with a quantitative disorder of chromosomes 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 with the same age of the parents. This disease is one of the most common and studied human pathologies. The frequency of having children with Down's disease 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, it is about 3%. A high frequency of children with Down syndrome (about 2%) is observed in women who give birth early (up to 18 years of age). Therefore, for population comparisons of the birth rate of children with Down's 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 of age 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). An increase in the frequency of Down syndrome with increasing maternal age is known, but most children with Down syndrome are still born to mothers younger than 30 years old. This is due to the higher number of pregnancies in this age group compared to older women.
The literature describes the "bunching" of the birth of children with Down syndrome at certain intervals 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's syndrome was described in 1866. Its genetic nature was deciphered much later - in 1959, when Lejeune and colleagues discovered an extra chromosome 21 in the karyotype of these patients. More rare cytogenetic variants of Down's disease, 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.
The ratio of boys and girls with Down syndrome is 1:1.
The clinical symptoms of Down's syndrome are varied: these are congenital malformations, and disorders of the postnatal development of the nervous system, and secondary immunodeficiency, etc. Children with Down syndrome are born at term, but with moderately severe prenatal hypoplasia (8-10% below average). Many of the symptoms of Down syndrome are already noticeable at birth and become more pronounced later on. A qualified pediatrician establishes the correct diagnosis of Down syndrome in the maternity hospital in at least 90% of cases. Of the craniofacial dysmorphias, a Mongoloid incision of the eyes is noted (for this reason, Down syndrome has long been called Mongoloidism), brachycephaly, a round flattened face, a flat back of the nose, epicanthus, a large (usually protruding) tongue, and deformed auricles. Muscular hypotension is combined with looseness of the joints. Often there are congenital heart defects, typical changes in dermatoglyphics (four-finger, or "monkey", fold on the palm, two skin folds instead of three on the little finger). Gastrointestinal disorders are rare.
Down syndrome is diagnosed based on a combination of several symptoms. The presence of 4-5 of them reliably indicates Down's syndrome: 1) flattening of the face profile (90%); 2) no sucking reflex (85%); 3) muscular hypotension (80%); 4) Mongoloid incision of the palpebral fissures (80%); 5) excess skin on the neck (80%); 6) loose joints (80%); 7) dysplastic pelvis (70%); 8) dysplastic (deformed) auricles (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's syndrome often suffer from pneumonia and are difficult to tolerate childhood infections. They have a lack of body weight, hypovitaminosis is expressed.
Congenital malformations of internal organs, 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) is leukemia, which often occurs 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 training methods. The IQ for different children can range from 25 to 75. Children with Down syndrome are affectionate, attentive, obedient, patient in 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.
Medical care for children with Down syndrome is multifaceted and non-specific. Congenital heart defects are eliminated promptly. General strengthening treatment is constantly carried out. Food must be complete. Careful care is needed for a sick child, protection from the action of harmful environmental factors (colds, infections). Great successes in saving the lives of children with Down syndrome and their development are provided by special methods of education, strengthening physical health from early childhood, 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, create families.
Patau syndrome (trisomy 13th chromosome) described in 1960. in children with multiple congenital malformations. It occurs in newborns with a frequency of 1:5000 - 1:7000. The disease is caused by trisomy on the 13th chromosome in 80-85% of patients with Patau syndrome. Nondisjunction of chromosomes during meiosis occurs most often in the mother. Boys and girls with Patau syndrome are born with the same frequency.
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 congenital malformations of the brain and face. This is a pathogenetically single group of early (and therefore severe) disorders in the formation of the brain, eyeballs, bones of the brain and facial parts of the skull. The circumference of the skull is usually reduced. Forehead sloping, low; the palpebral fissures are narrow, the nose bridge is sunken, the auricles are low and deformed. A typical symptom of Patau's syndrome is cleft lip and palate (usually bilateral). Defects of several internal organs are always found in different combinations: defects in the septa of the heart, incomplete rotation of the intestine, kidney cysts, anomalies of the internal genital organs (in girls it is a doubling of the uterus and vagina, in boys it is cryptorchidism - testicular retention during descent into the scrotum), pancreatic defects glands. As a rule, polydactyly is observed (more often bilateral and on the hands). Deafness is detected in 80-85% of patients. At birth, sick children are distinguished 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). 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 up to 5 years (about 15% of patients) and even up to 10 years (2-3% of patients).
Medical care for children with Patau syndrome is non-specific: operations for congenital malformations (for health reasons), restorative treatment, careful care, prevention of colds and infectious diseases. Children with Patau syndrome are almost always deep 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 and 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. Skull dolichocephalic (elongated) shape; lower jaw and mouth opening small; palpebral fissures narrow and short; auricles deformed and low located. 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. Spinal hernia and cleft lip are rare (5% of cases of Edwards syndrome).
Children with Edwards syndrome die at an early age (90% before 1 year) from complications caused by congenital malformations (asphyxia, pneumonia, intestinal obstruction, cardiovascular insufficiency).
Syndromes due tointrachromosomal
restructuring
This type of chromosome rearrangement (along with deletions, duplications and inversions) includes partial trisomy and monosomy of autosomes.
Syndrome "cat's cry" associated with a deletion of the short arm of the 5th chromosome. First described by J. Lejeune in 1963. Its sign is the unusual cry of children, reminiscent of a meow or a cat's cry. This is due to the pathology of the larynx or vocal cords. However, this cry disappears with age.
The clinical picture of the syndrome varies greatly. The most typical, in addition to the "cat's cry", is mental and physical underdevelopment, microcephaly (an abnormally reduced head).
The appearance of patients is peculiar: a moon-shaped face, microgenia (small sizes of the upper jaw), epicanthus (vertical fold of skin at the inner corner of the palpebral fissure), high palate, flat back of the nose, strabismus. The auricles are located low and deformed. There are also congenital heart defects, pathology of the musculoskeletal system, syndactyly of the feet (complete or partial fusion of neighboring fingers), flat feet, clubfoot, etc., muscle hypotension.
Most children die at an early age. At the same time, descriptions of patients older than 50 years are known. The population frequency of the "cat's cry" syndrome is 1:40,000 - 1:50,000 newborns. The size of the deletion in different cases is different.
Wolff-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 the 4th chromosome. It is noted that most deletions occur again, about 13% occur as a result of translocations in parents. Less commonly, in the genome of patients, in addition to translocation, there are also ring chromosomes. Along with divisions of chromosomes, pathology in newborns can be caused by inversions, duplications, isochromosomes.
The disease is characterized by numerous congenital malformations, mental retardation and psychomotor development.
Newborns have a small weight with a normal duration of pregnancy. Among the external signs are noted: microcephaly, coracoid nose, epicanthus, anti-Mongoloid incision of the eyes (omission of the outer corners of the palpebral fissures), abnormal auricles, cleft lip and palate, small mouth, deformity of the feet, etc.
The frequency of this syndrome is low - 1:100,000 births.
The viability of children is sharply reduced, most die before the age of 1 year. Only 1 patient aged 25 years has been described.
Syndromes with numericsex chromosome abnormalities
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 the sex chromosomes. Only women are ill, they lack one X chromosome (45 XO).
The frequency of occurrence of the syndrome is 1:3000 newborn girls. It is noted that only in 20% of women the pregnancy with a sick fetus is preserved to 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. In children, already in the first year of life, there is a lag in growth, which becomes most clearly visible by the age of 9-10. The average height of sick adult women is on average 135 cm. They have anomalies in the development of the skeleton: a short neck with lateral skin folds, a short and wide chest, excessive mobility of the elbow and knee joints, shortening of the 4-5th fingers on the hands. 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 is no menstruation, the patients are infertile. However, in the literature there are 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 psychoses.
Life expectancy is close to normal. Treatment is aimed at stimulating growth and reducing sexual infantilism (long courses of sex hormones, etc.).
X chromosome polysomy syndrome me in women. The syndrome includes trisomy (karyotype 47, XXX), tetrasomy (48, XXXX), pentasomy (49, XXXXX). The most common trisomy is 1 per 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, underdevelopment of the genitals are noted. Diagnosis of polysomy X syndrome includes the determination of sex chromatin and the study 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 was found that patients have an extra X chromosome (karyotype 47, XXY, instead of 46, XY). Along with this, there are variants of polysomy with a large number of X- and Y-chromosomes, which are also referred to as Klinefelter's syndrome.
Before birth, the disease is not clinically diagnosed. Genetic anomalies appear 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 (the development of the mammary glands is greater than normal), weak hair growth on the face, in the armpits and on the pubis. The testicles are reduced in size, there is sexual infantilism, a tendency to obesity. At the same time, spermatogenesis is impaired in patients and they are infertile. Their mental development lags behind, however, sometimes the intellect is normal.
An increase in the number of X chromosomes in the genotype is accompanied by an increase in mental retardation, mental disorders, antisocial behavior and alcoholism.
Syndrome of disomia Y -chromosome (47, XYY) was described in 1961. It occurs with a frequency of 1 per 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 acts. According to some data, in places of detention there are 10 times more men with the XYY genotype than men with a 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 anomalies (both chromosomal and genomic mutations) occurs spontaneously. The results of experimental genetics were extrapolated and induced mutagenesis was assumed in humans (ionizing radiation, chemical mutagens, viruses). However, the real reasons for the occurrence of chromosomal and genomic mutations in germ cells or at the early stages of embryo development have not yet been deciphered.
Many hypotheses of non-disjunction of chromosomes were tested (seasonality, racial and ethnic origin, age of mother and father, 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 is not excluded. Although in most cases the nondisjunction of chromosomes in humans is sporadic, it can be assumed that it is genetically determined to some extent. The following facts testify to this:
offspring with trisomy appear again in the same women with a frequency of at least 1%;
relatives of a proband with trisomy 21 or other aneuploidy 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, in accordance with the frequency of individual aneuploidy.
Maternal age is one of the biological factors that increase the risk of chromosome nondisjunction, although the mechanisms of this phenomenon are unclear. The risk of having a child with a chromosomal disease due to aneuploidy gradually increases with the age of the mother, but especially sharply after 35 years. In women over 45, every 5th pregnancy ends with the birth of a child with a chromosomal disease. The age dependence is most clearly manifested for trisomy 21 (Down's disease). For aneuploidies on sex chromosomes, 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 the age of 45 increases by 3 times or more. This situation can be explained by the fact that spontaneous abortions are largely due (up to 40-45%) to chromosomal abnormalities, the frequency of which is age-dependent.
Diseases with hereditary predisposition
(multifactorial)
Diseases with a hereditary predisposition, unlike gene 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 human hereditary pathologies. With age, the frequency 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, so they are also called multifactorial.
Being multifactorial systems, they are difficult for genetic analysis. Only recently, advances in the study of the human genome and mapping of its genes open up the possibility of identifying the genetic predisposition and the main causes of the development of multifactorial diseases.
Hereditary predisposition can be mono- or polygenic in nature. In the first case, it is caused by a mutation of one gene, for the manifestation of which a certain external factor is required, and in the second case, by a combination of alleles of several genes and a complex of environmental factors.
The clinical picture and the severity of the course of multifactorial human diseases depending on gender and age are very different. However, 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, allergic diseases - more than 10%, hypertension - about 30%.
Clinical polymorphism of diseases varies from latent subclinical forms to pronounced manifestations.
Features of the 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, adverse factors of the external and internal environment, for example, poor nutrition, etc.
Genetic prognosis in 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 for 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 in multifactorial pathology, empirical data are collected on the population and family frequency of each disease or malformation.
The polygenic nature of diseases with a hereditary predisposition is confirmed using genealogical, twin and population-statistical methods. Quite objective and sensitive twin method. When using it, a comparison is made of the concordance of mono- and dizygotic twins or a comparison of the concordance of monozygotic twins grown 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. The study of the nature of malignant neoplasms in monozygotic twins showed a low concordance (11%), but at the same time, it is 3-4 times higher than that for dizygotic twins. Obviously, the importance of external factors (especially carcinogenic) for the occurrence of cancer is much greater than hereditary ones.
Using the twin method, hereditary predisposition to certain infectious diseases (tuberculosis, poliomyelitis) and many common diseases (ischemic heart disease, rheumatism, diabetes mellitus, peptic ulcer, schizophrenia, etc.) are shown.
The spread of multifactorial diseases in different human populations can vary significantly due to 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 up to their complete elimination.
The successes of the "Human Genome" program, the isolation and decoding of the molecular organization of genes, 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. Huge amounts of money are spent on their treatment. In this regard, the 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 purpose 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 1920s. in Moscow, the largest domestic neurologist and geneticist S.N. Davidenkov at the Institute of Neuro-Psychiatric Prevention.
The first cabinet for medical genetic counseling was organized in 1941 by J. Neil at the University of Michigan (USA). in Russia in 1932. under the leadership of S. G. Levit, a medical genetic institute was created.
The intensive development of medical genetic care in our and other countries began in the 60-70s. XX century, which was associated both with an 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, the services of which were used by about 80 thousand families.
Main target medical genetic counseling - prevention of the birth of a sick child. Main tasks medical genetic counseling are:
Establishing an accurate diagnosis of hereditary pathology.
Prenatal (antenatal) diagnosis of congenital and hereditary diseases by various methods (ultrasound, cytogenetic, biochemical, molecular genetic).
Determination of the type of inheritance of the disease.
Assessing the risk of having a sick child and assisting in making a decision.
Propaganda of medical genetic knowledge among physicians and the population.
occasion for medical genetic counseling can be:
The birth of a child with congenital malformations, mental and physical retardation, blindness and deafness, convulsions, etc.
Spontaneous abortions, miscarriages, stillbirths.
consanguineous marriages.
Unfavorable course of pregnancy.
The work of spouses in a harmful enterprise.
Incompatibility of married couples on the Rh factor of blood.
The age of a woman is over 35 years old, and men - 40 years old.
Medical genetic consultation includes 4 stages: diagnosis; forecast; conclusion; advice.
The work begins with the clarification of 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 even before referral to a consultation. This applies to well-studied and fairly common hereditary diseases, such as 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. compilation of a pedigree for a married couple who applied for a consultation. First of all, this applies to that of the spouses, in whose pedigree there was a hereditary pathology. Careful collection of the pedigree provides certain information for the diagnosis of the disease.
In more complex cases, for example, when a child is born with multiple malformations, the correct diagnosis can only be made using special research methods. In the process of diagnosis, it often becomes necessary 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 recurrent risk of having a sick child. The basis for solving this problem is theoretical calculations using the methods of genetic analysis and variation statistics or empirical risk tables. This is the role of a geneticist.
The 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, affected family members will pass on the disease 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 in parents with a recessive disease is 25%. According to 1976 data, 789 recessively inherited diseases and 944 inherited according to the dominant type were known in humans.
Hereditary pathology can be sex-linked (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 is unknown in most cases. To calculate the genetic risk, specially designed empirical risk tables for multifactorial diseases are used.
A genetic risk of up to 5% is considered low and is not a contraindication to re-birth of a child in the family. The risk of 6 to 20% is considered to be average, and in this case, a comprehensive examination is recommended for further family planning. Genetic risk over 20% is considered high risk. Further childbearing in this family is not recommended.
In 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's disease, it is important to determine which parent carries a balanced translocation when calculating risk. For example, with a translocation (14/21), the risk value is 10% if the mother is the carrier, and 2.5% if the father is the carrier. 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 rebirth of a child with a pathology, it is important to establish heterozygous carriers of the mutant gene. This is of particular importance in autosomal recessive inheritance, in sex-linked inheritance, and in closely related marriages.
In some cases, heterozygous carriage is established by analyzing the pedigree, as well as by clinical and biochemical analyzes. So, if the father has a recessive disease linked to the X chromosome (for example, hemophilia), then with a probability of 100% his daughter will be heterozygous for this gene. Along with this, a decrease in antihemophilic globulin in the blood serum of the daughters of a hemophilic father can serve as quite convincing evidence of heterozygous carriage of the hemophilia gene.
Currently, some hereditary diseases are established using DNA diagnostics.
Heterozygous carriers of defective genes should avoid closely related marriages, which significantly increase the risk of having children with a hereditary pathology.
The conclusion of medical genetic counseling and advice to parents (the last two stages) can be combined. As a result of the genetic studies carried out, the geneticist gives a conclusion about the existing disease, introduces the likelihood of the disease in the future, and gives appropriate recommendations. This takes into account not only the magnitude of the risk of a sick child, but also the severity of a 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 spouses.
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MOSCOW STATE TECHNICAL UNIVERSITY
named after N.E. BAUMAN
Faculty of Biomedical Engineering
Department of Medical and Technical Information Technologies
Independent work
Diseases associated with disorders of amino acid metabolism and their biochemical nature
Student: Pirozhkova A.A. Group:BMT2-32
Head: Yershov Yu.A.
Moscow 2014
Amino acid concept
Amino acid metabolism
Diseases associated with impaired metabolism of amino acids
Conclusion
Bibliography
Amino acid concept
amino acid metabolism deamination
Amino acids are the most important, and some of them vital organic compounds, the molecule of which simultaneously contains carboxyl and amine groups.
Amino acids perform many functions in living organisms. They are structural elements of peptides and proteins, as well as other natural compounds. To build all proteins, whether they are proteins from the most ancient lines of bacteria or from higher organisms, the same set of 20 different amino acids is used, covalently linked to each other in a specific sequence characteristic only for a given protein. A truly remarkable property of cells is their ability to connect 20 amino acids in various combinations and sequences, resulting in the formation of peptides and proteins with completely different properties and biological activity. From the same building blocks, different organisms are able to produce such diverse products as enzymes, hormones, the protein of the lens of the eye, feathers, cobwebs, milk proteins, antibiotics, fungal poisons, and many other compounds endowed with specific activity. Also, some of the amino acids are neurotransmitters or precursors of neurotransmitters, neurotransmitters, or hormones.
Amino acid metabolism
The most important and irreplaceable role in the life of organisms is played by the metabolism of amino acids. Non-proteinogenic amino acids are formed as intermediate products during the biosynthesis and degradation of proteinogenic amino acids or in the urea cycle. In addition, for animals and humans, amino acids - the building blocks of protein molecules - are the main sources of organic nitrogen, which is used primarily for the synthesis of body-specific proteins and peptides, and of them - nitrogen-containing substances of non-protein nature (purine and pyrimidine bases, porphyrins , hormones, etc.).
If necessary, amino acids can serve as a source of energy for the body, mainly due to the oxidation of their carbon skeleton.
The main directions of amino acid metabolism
The apparent constancy of the chemical composition of a living organism is maintained due to the balance between the processes of synthesis and destruction of its constituent components, i.e. balance between catabolism and anabolism. In a growing organism, this balance is shifted towards protein synthesis, i.e. anabolic function prevails over catabolic. In the body of an adult, as a result of biosynthesis, up to 400 g of protein is updated daily. Moreover, different proteins are updated at different rates - from several minutes to 10 or more days, and such a protein as collagen is practically not updated during the entire life of the body. In general, the half-life of all proteins in the human body is about 80 days. Of these, about a quarter of the proteinogenic amino acids (about 100 g) are irreversibly decomposed, which must be renewed at the expense of food proteins, the rest of the amino acids are partially synthesized by the body.
With insufficient intake of proteins from food, the body uses the proteins of some tissues (liver, muscles, plasma, etc.) for the directed synthesis of proteins of other vital organs and tissues: the heart muscle, etc. Protein biosynthesis is carried out only if all 20 natural amino acids are present as initial monomers, each in the right amount. Prolonged absence and insufficient intake of even one of the 20 amino acids leads to irreversible changes in the body.
Proteins and amino acids are the most important nitrogen-containing compounds of animal organisms - they account for more than 95% of biogenic nitrogen. The concept of nitrogen balance (AB) is inextricably linked with the metabolism of proteins and amino acids, which is understood as the difference between the amount of nitrogen introduced into the body with food (Nin) and the amount of nitrogen excreted from the body (Nout) in the form of end products of nitrogen metabolism, mainly urea:
AB \u003d N input - N output, [g day -1]
With a positive nitrogen balance, the biosynthesis of proteins prevails over the processes of their decay, i.e. less nitrogen is excreted from the body than it enters. A positive nitrogen balance is observed during the period of growth of the body, as well as during recovery from debilitating diseases. With a negative nitrogen balance, the breakdown of proteins prevails over their synthesis, and more nitrogen is excreted from the body than it enters. This condition is possible with aging of the body, starvation and various debilitating diseases. Normally, a practically healthy adult has a nitrogen balance, i.e. the amount of nitrogen introduced into the body is equal to the amount excreted. The norms of protein in the diet when nitrogen balance is reached are on average 100-120 g·day -1.
The absorption of free amino acids resulting from the hydrolysis of proteins occurs mainly in the small intestine. This process is an active transport of amino acid molecules, which requires energy and depends on the concentration of Na+ ions. More than five specific transport systems have been found, each of which transports the amino acids closest in chemical structure. Different amino acids can compete with each other for binding sites on transport proteins built into the membrane (see Chapter 15 of this Section). Thus, absorbed amino acids in the intestines enter the liver through the portal system, and then enter the blood.
Further catabolism of amino acids to final products is a combination of deamination, transamination and decarboxylation reactions. At the same time, each individual amino acid has its own specific metabolic pathway.
Deamination / Transdeamination / Decarboxylation
Deamination is the removal of amino groups from amino acids to form ammonia. It is with deamination reactions that amino acid catabolism most often begins. In living organisms, four types of deamination of amino acids are possible.
The common product of all four types of deamination is ammonia, a compound that is quite toxic to cells and tissues, so it is detoxified in the body (see below). As a result of deamination due to the amino groups "lost" in the form of ammonia, the total number of amino acids decreases. Most living organisms, including humans, are characterized by oxidative deamination of amino acids, while other types of deamination are found only in some microorganisms.
Oxidative deamination of L-amino acids is carried out by oxidases present in the liver and kidneys. A common coenzyme of L-amino acid oxidase is FMN, which acts as a hydrogen carrier from an amino acid to oxygen. The overall reaction of oxidative deamination is as follows:
R-CH(NH 2) -COOH + FMN + H 2 O >
> R-CO-COOH + FMNN 2 + NH 3 + H 2 O 2
During the reaction, an intermediate compound is formed - an imino acid, which is then hydrated to form a keto acid. In addition to ketoacid and ammonia, as the main products of deamination, hydrogen peroxide is also formed in this reaction, which then decomposes into water and oxygen with the participation of catalase:
H 2 O 2 > H 2 O + SO 2
Oxidative deamination, as an independent process, plays an insignificant role in the conversion of amino groups of amino acids; only glutamic acid is deaminated at a high rate. This reaction is catalyzed by the enzyme glutamate dehydrogenase, the coenzyme of which is NAD or NADH. The activity of glutamate dehydrogenase is regulated by allosteric modifiers, GTP and ATP act as inhibitors, and GDP and ADP act as activators. Oxidative deamination of glutamic acid can be represented by the following scheme:
HOOS-CH 2 -CH 2 -CH (NH 2) -COOH + NAD>
> HOOS-CH 2 -CH 2 -CO-COOH + NH3 + (NADH + H +)
This reaction is reversible, but under the conditions of a living cell, the equilibrium of the reaction is shifted towards the formation of ammonia. Other, non-oxidative types of deamination are characteristic of serine, cysteine, threonine, and histidine. The remaining amino acids undergo transdeamination.
Transdeamination is the main pathway for the catabolic breakdown of amino acids. By the name of the process, it is easy to guess that it proceeds in two stages. The first is transamination, and the second is the actual oxidative deamination of the amino acid. Transamination is catalyzed by the enzyme aminotransferases, also known simply as transaminases. Pyridoxal phosphate (vitamin B6) acts as an aminotransferase coenzyme. The essence of transamination is the transfer of an amino group from a b-amino acid to a b-keto acid. Thus, the transamination reaction is an intermolecular redox process, in which not only the carbon atoms of the interacting amino acids, but also pyridoxal phosphate participate.
Decarboxylation is the process of removing a carboxyl group from an amino acid in the form of CO2. Some amino acids and their derivatives can undergo decarboxylation under the conditions of a living organism. Decarboxylation is catalyzed by special enzymes - decarboxylases, the coenzyme of which (with the exception of histidine decarboxylase) is pyridoxal phosphate. Decarboxylation products are amines with biological activity - biogenic amines. Most of the neurotransmitters and regulatory factors of local action (tissue mediators that regulate metabolism) belong to this group of compounds. The decarboxylation reaction of an arbitrary amino acid can be represented as follows:
DecarboxylaseBiogenic amine
Formation of biologically active amines
GABA is a nervous system mediator (gamma-aminobutyric acid).
Glutamate
Histamine is a mediator of inflammation and allergic reactions.
HistidineHistamine
Tab. Precursors, chemical structure, biological role of biogenic amines
Diseases associated with disorders of amino acid metabolism
Metabolism in the body is a very important process. Any deviation from the norm can lead to a deterioration in human health. There are hereditary and acquired disorders of amino acid metabolism. The highest rate of amino acid metabolism is observed in the nervous tissue. For this reason, in neuropsychiatric practice, various hereditary aminoacidopathy is considered one of the causes of dementia.
Violation of the metabolism of tyrosine.
Tyrosine, in addition to being involved in the synthesis of proteins, is a precursor of the adrenal hormones adrenaline, norepinephrine, dopamine mediator, thyroid hormones thyroxine triiodothyronine, pigments. Tyrosine metabolism disorders are numerous and are called tyrosinemias.
Tyrosinemia type I.
Etiology.
The disease occurs when there is a deficiency of fumarylacetoacetate hydrolase. At the same time, fumarylacetoacetate and its metabolites accumulate, affecting the liver and kidneys.
Fumarylaceto hydrolase
clinical picture.
The acute form makes up the majority of cases with onset between 2 and 7 months of age. and death in 90% of patients aged 1-2 years due to liver failure.
In the chronic form, the disease develops later, progresses more slowly. Life expectancy is about 10 years.
Fundamentals of treatment.
Treatment is ineffective. A diet with a decrease in the amount of protein, phenylalanine and tyrosine, injections of glutathione is used. Liver transplant needed.
Tyrosinemia type 2.
Much rarer disease.
Etiology.
The disease occurs when there is a deficiency of tyrosine aminotransferase.
clinical picture.
Mental and physical retardation, microcephaly, cataracts and corneal keratosis (pseudoherpetic keratitis), skin hyperkeratosis, self-mutilation, impaired fine coordination of movements.
A diet low in tyrosine is effective and skin and cornea lesions disappear quickly.
Tyrosinemia in newborns.
Etiology.
Neonatal tyrosinemia (type 3) is the result of hydroxyphenylpyruvate hydroxylase deficiency. More commonly seen in premature babies.
clinical picture.
Decreased activity and lethargy. The anomaly is considered harmless. Ascorbic acid deficiency enhances the clinical picture.
Fundamentals of treatment.
A diet with a decrease in the amount of protein, phenylalanine, tyrosine and high doses of ascorbic acid.
Alkaptonuria.
Etiology.
Genetic autosomal recessive enzymopathy. The disease is based on a decrease in the activity of the liver enzyme homogentisate oxidase, as a result, homogentisic acid accumulates in the body.
clinical picture.
Since the homogenizate polymerizes in air into a melanin-like compound, the most frequent and constant symptom is dark urine, dark brown spots remain on the diaper and underwear. Otherwise, the disease does not manifest itself in childhood.
With age, homogentisin acid accumulates in connective tissue formations, sclera and skin, causes a slate-deep shade of the ear and nasal cartilage, staining of clothing areas, sweating areas of the body (armpits).
At the same time, homogentisic acid inhibits lysyl hydroxylase, preventing the synthesis of collagen, which makes cartilage formations fragile. By old age, degenerative arthrosis of the spine and large joints sets in, the intervertebral spaces are narrowed.
Fundamentals of treatment.
Although effective methods are not known, similar to other amino acid disorders, it is recommended to limit the intake of phenylalanine and tyrosine from an early age, which should prevent the development of ochronosis and joint disorders. Assign large doses of ascorbic acid to protect the activity of lysyl oxidase.
Albinism.
Etiology. The disease is caused by a complete or partial defect in the synthesis of the tyrosinase enzyme (frequency 1:20,000), which is necessary for the synthesis of dihydroxyphenylalanine in pigment cells.
clinical picture. In the complete absence of the enzyme, total deligmentation of the skin, hair, eyes, and the color is the same for all racial groups and does not change with age. The skin does not tan, nevi, age spots are completely absent, photodermatitis develops. Strongly expressed nystagmus, photophobia, day blindness, red pupillary reflex. With partial insufficiency, light yellow hair, slightly pigmented moles, and very fair skin are noted.
Parkinsonism.
Etiology. The cause of parkinsonism (frequency after 60 years 1:200) is the low activity of tyrosine hydroxylase or DOPA decaboxylase in the nervous tissue, while developing a deficiency of the neurotransmitter dopamine and the accumulation of tyramine.
clinical picture.
The most common symptoms are muscle stiffness, stiffness, tremors, and spontaneous movements.
Fundamentals of treatment.
Systematic administration of medicinal dopamine analogues and the use of monoamine oxidase inhibitors are required.
Fumarate Acetoacetate
Fumarate acetoacetate
Phenylketonuria
Etiology. Phenylalanine hydroxylase deficiency. Phenylalanine is converted to phenylpyruvate.
clinical picture.
§ Violation of myelination of nerves
§ Brain mass is below normal.
§ Mental and physical retardation.
Diagnostic criteria:
§ the level of phenylalanine in the blood.
§ FeCl3 test.
§ DNA samples (prenatally).
Conclusion
The value of amino acids for the body is primarily determined by the fact that they are used for the synthesis of proteins, the metabolism of which occupies a special place in the processes of metabolism between the body and the environment. Protein hormones play an important role in coordinating the work of all cell systems. The metabolism of proteins and amino acids plays an important and indispensable role in the life of organisms.
Bibliography
1. Ershov YuA, Zaitseva NI. Fundamentals of biochemistry for engineers. MSTU 2010
2. Ershov YuA..etc. General chemistry. M. 2011.
3. Belousova E.D., Nikanorova M.Yu. , Nikolaeva E.A. Hereditary metabolic diseases that manifest themselves in the neonatal period // Russian Bulletin of Perinatology and Pediatrics, N6-2000, pp. 12-19
4. Lehninger A. Fundamentals of biochemistry. M. Mir. 1985. 1055 p.
5. Blau N, Duran M, Blascovich ME, Gibson KM (eds) Physician`s Guide to the Laboratory Diagnosis of Metabolic Diseases (second edition). New York: Springer, 1996
6. Nikolaev A. Ya., Biological chemistry, M. "Medical Information Agency", 2004
7. Florentiev V. L., Biochemistry. - M., 2004. - 464 p.
8. Berezov T.T., Korovkin B.F., Biological chemistry. M, Medicine, 1998
9. Ershov Yu.A. etc. General chemistry. 8th ed. M. VS. 2009. 560 p.
10. Ershov Yu.A. and other Kinetics and thermodynamics of biochemical and physiological processes. M. Medicine. 1990. 208 p.
11. Kolman Ya., Rem K.-G. Visual biochemistry. M., Mir, 2004. 269 p.
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The largest group of hereditary metabolic diseases. Almost all of them are inherited in an autosomal recessive manner. The cause of diseases is the insufficiency of one or another enzyme responsible for the synthesis of amino acids. These include:
- phenylketonuria - a violation of the conversion of phenylalanine to tyrosine due to a sharp decrease in the activity of phenylalanine hydroxylase;
- alkaptonuria - a violation of the metabolism of tyrosine due to reduced activity of the homogentisinase enzyme and the accumulation of homotentisic acid in the tissues of the body;
- oculocutaneous albinism - due to the lack of tyrosinase enzyme synthesis.
Phenylketonuria (PKU) is a severe hereditary disease characterized mainly by damage to the nervous system. As a result of the mutation of the gene that controls the synthesis of phenylalanine hydroxylase, a metabolic block develops at the stage of conversion of phenylalanine to tyrosine, as a result of which the main pathway for the conversion of phenylalanine becomes deamination and the synthesis of toxic derivatives - phenylpyruvic, phenyl-lactic and phenylacetic acids. In the blood and tissues, the content of fvnylalanine significantly increases (up to 0.2 g / l or more at a rate of 0.01-0.02 g / l). An essential role in the pathogenesis of the disease is played by insufficient synthesis of tyrosine, which is a precursor of catecholamines and melanin. The disease is inherited in an autosomal recessive manner.
DISORDERS OF AMINO ACID METABOLISM. The most common diseases associated with impaired amino acid metabolism are phenylketonuria and albinism.
Normally, the amino acid phenylalanine (FA) is converted by the enzyme phenylalanine hydroxylase into the amino acid tyrosine, which in turn, by the action of the enzyme tyrosinase, can be converted into the pigment melanin. In violation of the activity of these enzymes, human hereditary diseases phenylketonuria and albinism develop.
Phenylketonuria (PKU) occurs in various human populations with a frequency of 1:6000-1:10,000, in Belarus - 1:6000. It is inherited in an autosomal recessive manner; patients are recessive homozygotes (aa). The mutant gene responsible for the synthesis of the enzyme phenylalanine hydroxylase has been mapped (12q22-q24), identified and sequenced (the nucleotide sequence has been determined).
Phenylalanine is one of the essential amino acids. Only part of FA is used for protein synthesis; the main amount of this amino acid is oxidized to tyrosine. If the enzyme phenylalanine hydroxylase is not active, then FA does not turn into tyrosine, but accumulates in the blood serum in large quantities in the form of phenylpyruvic acid (PPVA), which is excreted in the urine and sweat, as a result of which a "mouse" smell comes from patients. A high concentration of PPVC leads to disruption of the formation of the myelin sheath around axons in the CNS. Children with phenylketonuria are born healthy, but in the first weeks of life they develop clinical manifestations of the disease. FPVC is a neurotropic poison, resulting in increased excitability, muscle tone, hyperreflexia, tremor, and convulsive epileptiform seizures. Later, violations of higher nervous activity, mental retardation, microcephaly join. Patients have weak pigmentation due to impaired melanin synthesis.
There are three forms of this disease. Phenylketonuria I has an autosomal recessive type of inheritance, caused by mutations in the PAH gene located on the long arm of the 12th chromosome (12q24.1).
Phenylketonuria //is also inherited in an autosomal recessive manner, the gene defect is localized in the short arm of the 4th chromosome, section 4p15.3. The frequency of the disease is 1:100,000. Due to the deficiency of dihydropteridine reductase, the restoration of the active form of tetrahydrobiopterin, which is involved as a cofactor in the hydroxylation of phenylalanine, tyrosine and tryptophan, is disrupted, which leads to the accumulation of metabolites, disruption of the formation of catecholamine and serotonin neurotransmitter precursors. In the pathogenesis of the disease, a decrease in the level of folates in the blood serum, erythrocytes, and cerebrospinal fluid is also important.
Phenylketonuria III is inherited in an autosomal recessive manner and is associated with a deficiency of 6-pyruvoyl-tetrahydropterin synthase, which is involved in the synthesis of tetrahydrobiopterin from dihydroneopterin triphosphate. The frequency of the disease is 1:30,000. The main role in the genesis of the disease is played by the deficiency of tetrahydrobiopterin.
Diagnosis of the disease is carried out by biochemical methods: even before the development of the clinical picture, PPVC is determined in the urine, and a high content of phenylalanine is found in the blood. In maternity hospitals, a screening test for phenylketonuria is mandatory.
Albinism occurs in different populations with different frequencies - from 1:5,000 to 1:25,000. Its most common form, oculocutaneous tyrosinase-negative albinism, is inherited in an autosomal recessive manner.
The main clinical manifestations of albinism at any age are the absence of melanin in skin cells (its milky white color), very fair hair, light gray or light blue iris, red pupil, increased sensitivity to UV radiation (causes inflammatory skin diseases). ). In patients, there are no pigment spots on the skin, visual acuity is reduced. Diagnosis of the disease is not difficult.
61. Hereditary diseases of carbohydrate metabolism (galactosemia)
Hereditary diseases associated with impaired carbohydrate metabolism include, for example, galactosemia, in which the process of enzymatic conversion of galactose to glucose is disrupted. As a result, galactose and its metabolic products accumulate in cells and have a damaging effect on the liver, central nervous system, and others. ), delayed mental and physical development.
Hereditary disorders of carbohydrate metabolism include diabetes(see Diabetes diabetes) and a number of other diseases.
Pathology of carbohydrate metabolism. An increase in blood glucose - hyperglycemia can occur due to excessively intense gluconeogenesis or as a result of a decrease in the ability of glucose utilization by tissues, for example, in violation of the processes of its transport through cell membranes. A decrease in blood glucose - hypoglycemia - can be a symptom of various diseases and pathological conditions, and the brain is especially vulnerable in this regard: irreversible impairment of its functions can be a consequence of hypoglycemia.
Genetically caused defects of U.'s enzymes. are the cause of many hereditary diseases. An example of a genetically determined hereditary disorder of monosaccharide metabolism is galactosemia, developing as a result of a defect in the synthesis of the enzyme galactose-1-phosphate uridyltransferase. Signs of galactosemia are also noted with a genetic defect in UDP-glucose-4-epimerase. The characteristic signs of galactosemia are hypoglycemia, galactosuria, the appearance and accumulation in the blood along with galactose of galactose-1-phosphate, as well as weight loss, fatty degeneration and cirrhosis of the liver, jaundice, cataracts that develop at an early age, and psychomotor retardation. In severe galactosemia, children often die in the first year of life due to impaired liver function or reduced resistance to infections.
An example of hereditary monosaccharide intolerance is fructose intolerance, which is caused by a genetic defect in fructose phosphate aldolase and, in some cases, by a decrease in fructose-1,6-diphosphate aldolase activity. The disease is characterized by damage to the liver and kidneys. The clinical picture is characterized by convulsions, frequent vomiting, and sometimes a coma. Symptoms of the disease appear in the first months of life when children are transferred to mixed or artificial nutrition. Fructose loading causes severe hypoglycemia.
Diseases caused by defects in the metabolism of oligosaccharides mainly consist in a violation of the breakdown and absorption of dietary carbohydrates, which occurs mainly in the small intestine. Maltose and low molecular weight dextrins formed from starch and food glycogen under the action of a-amylase of saliva and pancreatic juice, milk lactose and sucrose are broken down by disaccharidases (maltase, lactase and sucrase) to the corresponding monosaccharides mainly in the microvilli of the small intestine mucosa, and then, if the process of transport of monosaccharides is not disturbed, their absorption occurs. The absence or decrease in the activity of disaccharidases to the mucous membrane of the small intestine is the main cause of intolerance to the corresponding disaccharides, which often leads to damage to the liver and kidneys, is the cause of diarrhea, flatulence (see. Malabsorption syndrome ). Particularly severe symptoms are characterized by hereditary lactose intolerance, which is usually found from the very birth of the child. For the diagnosis of sugar intolerance, exercise tests are usually used with the introduction of a carbohydrate per os on an empty stomach, the intolerance of which is suspected. A more accurate diagnosis can be made by biopsy of the intestinal mucosa and determination of the activity of disaccharidases in the obtained material. Treatment consists in the exclusion from food of foods containing the corresponding disaccharide. A greater effect is observed, however, with the appointment of enzyme preparations, which allows such patients to eat ordinary food. For example, in the case of lactase deficiency, it is desirable to add an enzyme preparation containing lactase to milk before eating it. The correct diagnosis of diseases caused by disaccharidase deficiency is extremely important. The most common diagnostic error in these cases is the establishment of a false diagnosis of dysentery, other intestinal infections, and antibiotic treatment, which leads to a rapid deterioration in the condition of sick children and serious consequences.
Diseases caused by impaired glycogen metabolism constitute a group of hereditary enzymopathies, united under the name glycogenoses. Glycogenoses are characterized by excessive accumulation of glycogen in cells, which may also be accompanied by a change in the structure of the molecules of this polysaccharide. Glycogenoses are referred to as so-called storage diseases. Glycogenoses (glycogenic disease) are inherited in an autosomal recessive or sex-linked manner. An almost complete absence of glycogen in cells is noted with aglycogenosis, the cause of which is the complete absence or reduced activity of liver glycogen synthetase.
Diseases caused by a violation of the metabolism of various glycoconjugates, in most cases, are the result of congenital disorders of the breakdown of glycolipids, glycoproteins or glycosaminoglycans (mucopolysaccharides) in various organs. They are also storage diseases. Depending on which compound accumulates abnormally in the body, glycolipidoses, glycoproteinodes, and mucopolysaccharidoses are distinguished. Many lysosomal glycosidases, the defect of which underlies hereditary disorders of carbohydrate metabolism, exist in various forms, the so-called multiple forms, or isoenzymes. The disease can be caused by a defect in any one isoenzyme. For example. Tay-Sachs disease is a consequence of a defect in the form of AN-acetylhexosaminidase (hexosaminidase A), while a defect in the forms A and B of this enzyme leads to Sandhoff's disease.
Most accumulation diseases are extremely difficult, many of them are still incurable. The clinical picture in various storage diseases may be similar, and, on the contrary, the same disease may manifest itself differently in different patients. Therefore, it is necessary in each case to establish an enzyme defect, which is detected mostly in leukocytes and fibroblasts of the skin of patients. Glycoconjugates or various synthetic glycosides are used as substrates. With various mucopolysaccharidoses, as well as in some other storage diseases (for example, with mannosidosis), significant amounts of oligosaccharides differing in structure are excreted in the urine. The isolation of these compounds from the urine and their identification is carried out in order to diagnose storage diseases. Determination of enzyme activity in cultured cells isolated from amniotic fluid obtained by amniocentesis in case of suspected storage disease allows prenatal diagnosis.
At some diseases serious disturbances At. occur secondarily. An example of such a disease is diabetes mellitus, caused either by damage to b-cells of the pancreatic islets, or defects in the structure of insulin itself or its receptors on the cell membranes of insulin-sensitive tissues. Nutritional hyperglycemia and hyperinsulinemia lead to the development of obesity, which increases lipolysis and the use of non-esterified fatty acids (NEFA) as an energy substrate. This impairs the utilization of glucose in muscle tissue and stimulates gluconeogenesis. In turn, an excess of NEFA and insulin in the blood leads to an increase in the synthesis of triglycerides in the liver (see. Fats ) And cholesterol and, consequently, to an increase in the concentration in the blood lipoproteins very low and low density. One of the reasons contributing to the development of such severe complications in diabetes as cataracts, nephropathy, anglopathy and tissue hypoxia is non-enzymatic glycosylation of proteins.
62. Hereditary connective tissue diseases (mucopolysaccharidoses)
Mucopolysaccharidoses, or MPS for short, or MPS (from (mucopolysaccharides + -ōsis)) is a group of metabolic connective tissue diseases associated with impaired metabolism of acid glycosaminoglycans (GAGs, mucopolysaccharides) caused by a deficiency of lysosomal enzymes of glycosaminoglycan metabolism. The diseases are associated with hereditary metabolic anomalies, manifest themselves in the form of "accumulation disease" and lead to various defects in bone, cartilage, and connective tissues.
Types of diseases
Depending on the nature of the enzymatic defect, several main types of mucopolysaccharidoses are distinguished:
- Type I - Hurler syndrome (mucompolysaccharidosis I H - Hurler), Hurler-Scheie syndrome (mucopolysaccharidosis I H / S - Hurler-Scheie), Scheie syndrome (mucopolysaccharidosis I S - Scheie). It is caused by a deficiency of alpha-L-iduronidase (an enzyme for catabolism of mucopolysaccharides). The disease gradually leads to the accumulation of heparan sulfate and dermatan sulfate in the tissues. There are three phenotypes: Hurler syndrome, Scheye syndrome and Hurler-Scheie syndrome.
- Type II - Hunter's syndrome
- Type III - Sanfilippo syndrome
- IV type - Morquio's syndrome
- Type V - Scheye's syndrome
- Type VI - Maroteau-Lami syndrome
- Type VII - Sly's syndrome p-glucuronidase deficiency
63. Mendelizing signs in humans
Mendelian traits are those whose inheritance occurs according to the laws established by G. Mendel. Mendelian traits are determined by one gene monogenously (from Greek monos-one), that is, when the manifestation of a trait is determined by the interaction of allelic genes, one of which dominates (suppresses) the other. Mendelian laws are valid for autosomal genes with full penetrance (from lat.penetrans - penetrating, reaching) and constant expressivity (degree of expression of the trait).
If the genes are localized on the sex chromosomes (with the exception of the homologous region on the X and Y chromosomes), or are linked on the same chromosome, or in the DNA of organelles, then the results of crossing will not follow Mendel's laws.
The general laws of heredity are the same for all eukaryotes. A person also has Mendelian traits, and all types of their inheritance are characteristic of him: autosomal dominant, autosomal recessive, linked to sex chromosomes (with a homologous section of X- and Y-chromosomes).
Types of inheritance of Mendelian traits:
I. Autosomal dominant type of inheritance. According to the autosomal dominant type, some normal and pathological signs are inherited:
1) a white curl above the forehead;
2) hair is hard, straight (hedgehog);
3) woolly hair - short, easily split, curly, lush;
4) the skin is thick;
5) the ability to roll the tongue into a tube;
6) Habsburg lip - the lower jaw is narrow, protruding forward, the lower lip is drooping and the mouth is half open;
7) polydactyly (from Greek polus - numerous, daktylos - finger) - polydactylism, when there are six or more fingers;
8) syndactyly (from Greek syn - together) - fusion of soft or bone tissues of the phalanges of two or more fingers;
9) brachydactyly (short-fingered) - underdevelopment of the distal phalanges of the fingers;
10) arachnodactyly (from the Greek agahna - spider) - strongly elongated "spider" fingers
II. Autosomal recessive type of inheritance.
If recessive genes are localized in autosomes, then they can appear when two heterozygotes or homozygotes for the recessive allele are married.
The following traits are inherited in an autosomal recessive manner:
1) the hair is soft, straight;
2) the skin is thin;
3) blood group Rh-;
4) not feeling the bitter taste of phenylcarbamide;
5) inability to fold the tongue into a tube;
6) phenylketonuria - the conversion of phenylalanine to tyrosine is blocked, which turns into phenylpyruvic acid, which is a neurotropic poison (signs - convulsive syndromes, mental retardation, impulsivity, excitability, aggression);
7) galactosemia - the accumulation of galactose in the blood, which inhibits the absorption of glucose and has a toxic effect on the function of the liver, brain, lens of the eye;
8) albinism.
The frequency of recessive hereditary diseases is especially increased in isolates and among populations with a high percentage of consanguineous marriages.
Some traits have long been thought to be Mendelian, but their inheritance mechanism is likely based on a more complex genetic model and may involve more than one gene. These include:
hair color
eye color
Morton's finger
twisting the tongue
64. Hereditary diseases of circulating proteins (thalassemias)
Thalassemia (Cooley's anemia) - inherited by a recessive type (two-hallel system), which is based on a decrease in the synthesis of polypeptide chains that are part of the structure of normal hemoglobin. Normally, the main variant of hemoglobin (97%) in an adult is hemoglobin A. It is a tetramer consisting of two α-chain monomers and two β-chain monomers. 3% of adult hemoglobin is represented by hemoglobin A2, consisting of two alpha and two delta chains. There are two genes HBA1 and HBA2 encoding the alpha monomer and one HBB gene encoding the beta monomer. The presence of a mutation in the hemoglobin genes can lead to disruption of the synthesis of chains of a certain type.
65. Human kareotype. The structure and types of chromosomes. See question. 12 and 22
66. . Hereditary diseases of circulating proteins (sickle cell anemia)
sickle cell anemia- this is a hereditary hemoglobinopathy associated with such a violation of the structure of the hemoglobin protein, in which it acquires a special crystalline structure - the so-called hemoglobin S. Red blood cells that carry hemoglobin S instead of normal hemoglobin A under a microscope have a characteristic crescent shape (sickle shape), for which this form of hemoglobinopathies and is called sickle cell anemia.
Erythrocytes carrying hemoglobin S have reduced resistance and reduced oxygen-transporting capacity, therefore, in patients with sickle cell anemia, the destruction of erythrocytes in the spleen is increased, their life span is shortened, hemolysis is increased, and there are often signs of chronic hypoxia (oxygen deficiency) or chronic "over-irritation" erythrocyte bone marrow.
Sickle cell anemia is inherited in an autosomal recessive manner (with incomplete dominance). In carriers heterozygous for the sickle cell anemia gene, hemoglobin S and hemoglobin A are present in approximately equal amounts of hemoglobin S and hemoglobin A in erythrocytes. At the same time, under normal conditions, symptoms almost never occur in carriers, and sickle-shaped erythrocytes are detected by chance in a laboratory blood test. Symptoms in carriers may appear during hypoxia (for example, when climbing mountains) or severe dehydration of the body. Homozygotes for the sickle cell anemia gene have only sickle-shaped red blood cells carrying hemoglobin S in the blood, and the disease is severe.
Sickle cell anemia is very common in malaria-endemic regions of the world, and patients with sickle cell anemia have an increased (though not absolute) innate resistance to infection with various strains of malarial plasmodium. The sickle-shaped erythrocytes of these patients also do not lend themselves to infection with malarial plasmodium in vitro. Heterozygotes-carriers who do not suffer from anemia also have increased resistance to malaria (advantage of heterozygotes), which explains the high frequency of this harmful allele in African
Hyperaminoaciduria. Hyperaminoaciduria is said to be when the excretion of one or more amino acids in the urine exceeds physiological values.
Depending on the origin, one can distinguish: 1. metabolic or prerenal and 2. renal aminoaciduria.
In metabolic aminoaciduria, one or more amino acids are produced more than normal, or a smaller amount is metabolized. The excess exceeds the reabsorption capacity of the tubules, so the 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 found.
Symptomatic forms of metabolic aminoaciduria can be encountered with severe liver damage.
However, in most cases, metabolic aminoaciduria are hereditary enzymopathies: the interstitial metabolism of any amino acid is disturbed 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 anomalies are described in more detail in the chapter on kidney disease. Here, attention will be paid only to congenital metabolic aminoaciduria.
Phenylketonuria. Phenylpyruvic oligophrenia (Fölling's disease). Enzymopathy inherited in an autosomal recessive manner. Its biochemical essence is the impossibility of converting phenylalanine to tyrosine due to the absence of the enzyme phenylalanine oxidase. The clinical manifestations of this anomaly are associated with severe brain damage, accompanied by mental retardation. This common disease is one of the most common causes of oligophrenia. Among the population it occurs with a frequency of 1:10,000-1:20,000.
Pathogenesis. Due to the absence of an enzyme involved in the metabolism of phenylalanine - phenylalanine oxidase, phenylalanine and its metabolic product, phenylpyruvic acid, accumulate in the blood. The accumulation of these substances is the cause of the leading clinical symptom - brain damage, caused, apparently, by the inhibitory effect of these metabolites on other enzymatic processes in the brain. In addition, a violation of the normal synthesis of tyrosine, which is the main material for the production of adrenaline, norepinephrine and diiodothyrosine, also plays a certain role in the formation of the disease.
Clinical picture. The leading symptom of phenylketonuria is oligophrenia, which manifests itself already in early infancy and rapidly progresses. Often there is hypertension of the muscles, in some cases epileptiform convulsions are observed.
Among other changes associated with a metabolic defect, insufficient pigmentation of patients should be mentioned. Many of them are blue-eyed, have light skin and blond hair. Brachycephaly and hypertaylorism are common. Blood pressure is usually low. Sweat of patients has an unpleasant ("mouse") smell.
Diagnosis. In connection with the possibility of treating the disease, early recognition of carriers of the anomaly is of great importance. Phenylalanine and its metabolic products can be found in the blood and urine. The concentration of phenylalanine in the blood is many times higher than the upper limit of normal (1.5 mg%). In the urine, the presence of phenylpyruvic acid can be qualitatively shown using the Volling test: 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 already at the end of the first week are given by the Guthrie test: a microbiological method based on the effect that phenylalanine has on the growth of hay bacillus. Certainly, this method is most suitable for surveying the population of infants. Its disadvantage is the need to take blood, which is still difficult to carry out on a large scale. Until this analysis becomes universal, it is necessary to produce a ferrochloride test at 3-4 weeks of age and, in suspicious cases, confirm the diagnosis by examining the amino acid spectrum of blood and urine using paper chromatography. With aggravated heredity, a blood test should be performed already in the first week of life.
Treatment . When therapy is started early, possibly as early as the neonatal period, success can be achieved by minimizing dietary phenylalanine. However, the use of casein hydrolysate, which forms the basis of the diet, providing restriction of phenylalanine, is difficult and expensive. Currently, special preparations for the treatment of phenylketonuria - berlofen, lofenalak, minafen, hypofenate - are proposed, which are satisfactorily tolerated by patients. With treatment begun in late infancy, only a cessation of the further progression of idiocy can be achieved.
Alkaptonuria. The disease is characterized by dark brown urine, which appears when standing in the air. Hereditary enzymopathy, patients lack the enzyme homogentisinase. Homogentisic acid, released in large quantities, oxidizes in air, turning brown. The baby's diapers and underwear are also stained, making it easier to diagnose.
In addition to the features of urine described above, with this anomaly there are only two other symptoms: arthropathy that appears at a later age and a bluish coloration of the cartilage, easily detected on the auricle. There is no cure.
Albinism is also a hereditary anomaly in the metabolism of aromatic amino acids. At the same time, there is no enzyme tyrosinase, which catalyzes the conversion of tyrosine into DOPA - dihydroxyphenylalanine. Since DOPA is the basis for the synthesis of melanin, the carriers of the anomaly are light-skinned, fair-haired people, in whom a reddish vascular network shines through the iris devoid of pigmentation.
Albinism is incurable. Patients should avoid direct sunlight.
maple syrup disease. Recessively inherited rare enzymopathy. In this disease, there is no 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 amounts 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 convulsions, developing already in the first weeks of life and ending in death in early infancy.
When making a diagnosis, the Felling test matters, because if it is positive, it indicates the direction of further research; an accurate diagnosis is established by examining blood and urine amino acids by paper chromatography.
For treatment attempts are being made to improve metabolism with a synthetic diet.
Hartnap's disease. A very rare hereditary disease that is accompanied by renal hyperaminoaciduria. A large amount of indican found in the urine indicates a violation of tryptophan metabolism. Clinically characterized by cerebellar ataxia and pellagra-like skin changes.
oxalosis. Rare hereditary disease. Due to the enzymatic block in the metabolism of glycocol, 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 based on the detection of hyperoxaluria and oxalate crystals in the bone marrow and lymph nodes.
In treatment- along with symptomatic therapy, it seems promising to take sodium benzoate continuously, which together with glycocol forms hippuric acid and reduces the production of oxalic acid.
cystinosis. Hereditary, autosomal recessive disease, which is based on the accumulation of cystine crystals in the reticuloendothelium and individual organs and developing in connection with this severe nephropathy.
Pathogenesis 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. Decisive fate of the patient nephropathy manifests itself in the second half of life. There are signs indicating initial tubular damage: hyperaminoaciduria, glucosuria, proteinuria. Later, the situation is aggravated by polyuria, renal tubular acidosis, as well as hypokalemia and hypophosphatemia of renal origin. Polyuria causes exsicosis and hyperthermia, phosphate-diabetes causes rickets and dwarf growth, potassium deficiency is manifested by paralysis. In the final stage of the disease, glomerular insufficiency joins tubular insufficiency, and uremia develops.
Diagnosis. Tubal insufficiency, glucosuria, acidosis, hyperaminoaciduria, hyperphosphaturia, accompanied by osteopathy and dwarf growth, in the advanced phase of the disease, together give a characteristic picture. These shifts correspond to the picture of the De Toni-Debre-Fanconi syndrome, which, however, may have a different origin.
In differential diagnosis, the detection of cystine crystals in the cornea using a slit lamp or in a biooptical preparation of the lymph glands is of decisive importance.
For treatment prescribe a diet with restriction of methionine and cystine. For the purpose of symptomatic therapy, high doses of vitamin D, the introduction of alkaline solutions and compensation for the lack of potassium, an increased amount of water in the child's diet, and finally penicillamine are used.
Forecast bad.
Homocystinuria. The clinical symptoms of the anomaly are characterized by oligophrenia of varying degrees, ectopia of the lenses, blond hair attracts attention. In the blood, the content of methionine and homocystin is increased, with the help of special methods, homocystin is detected in the urine.
Treatment- poor methionine diet, but it is not very effective.
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This is a special, very large group of diseases, the detection and treatment of which is currently a very urgent problem due to their wide prevalence and severe impairment of the physical and intellectual development of sick children. Studies that allow a correct diagnosis are usually very complex and expensive. Carrying out them is possible only in the conditions of large specialized centers. Therefore, a special contingent of children has been identified for which these studies must be performed. These children include:
- children who have a combination of mental retardation and visual impairment;
- children who have mental retardation and periodically experience seizures;
- children who, from birth, have a change in the color and smell of urine;
- children in whom mental retardation is combined with various skin lesions.
Below are the main diseases caused by disorders of amino acid metabolism in the body.
Phenylketonuria in children
Phenylketonuria is associated with a violation of the metabolism of amino acids, which are part of the hormones of the thyroid gland and adrenal glands. As a result, the substance phenylalanine is formed in excess, which accumulates in the body and causes disorders, mainly associated with damage to the brain and spinal cord. Despite the fact that the disease is very common, it almost never occurs among blacks and Jews. Girls and boys get sick equally often.
Very often, a sick child is born to completely healthy parents. This is due to the fact that the mother and father of the child, without suspecting it, are carriers of the affected gene. The probability of the appearance of a sick child in a family where marriages between relatives are made very sharply increases.
Signs of phenylketonuria
They do not appear immediately after birth. Until 2-6 months of age, the child gives the impression of being quite healthy. Upon reaching the above age, when foods containing a “forbidden” amino acid appear in the diet, the child’s parents begin to notice that he has become lethargic, his physical activity has decreased, and interest in toys and people around him has begun to disappear. In some cases, the child, on the contrary, becomes restless, aggressive, he is often sick and vomits, the skin is affected. In the future, convulsive seizures join. After the sixth month of life, his lag in physical and mental development becomes noticeable, later on there is a decrease in intelligence up to deep mental retardation, which is observed in more than half of all patients. However, cases of the course of the disease with the preservation of normal intelligence are known. This fact is interpreted by experts as a consequence of the fact that disorders in several different genes are responsible for the development of the disease, and therefore the severity of its symptoms can be very diverse. The picture of various neurological disorders is very rich in the disease.
The physical development of the child also suffers, but not so much, the body length is slightly reduced or normal. A slight decrease in the size of the head due to a violation of the growth of the bones of the skull is very characteristic; the teeth in such children begin to erupt at a very late age. Often there are malformations of the skeleton and internal organs. Very late, the child learns basic motor skills: crawling, sitting, standing. In the future, the sick child has a very peculiar position of the body and gait. When walking, his legs are widely spaced and somewhat bent at the knee joints, while his head and shoulders are lowered. The steps are very small, the child sways from side to side. The position of a sick child when sitting is called the "tailor's position" - his legs are tucked up to the body as a result of increased muscle tension.
The appearance of a sick child is also very characteristic. His hair and skin are very light in color, as the body contains practically no pigments. The eyes are light blue. Together with urine, harmful metabolic products are excreted, as a result of which a peculiar, so-called "mouse" smell emanates from the child. Some patients develop seizures resembling those of epilepsy. However, at a later age they completely disappear. In general, the spectrum of neurological disorders in phenylketonuria is very wide.
The most frequently observed violation of coordination of movements, involuntary obsessive movements, shaking of the fingers, convulsions in various muscle groups, their twitching. Reflexes on the arms and legs are significantly increased, sometimes there are reflexes that are not observed normally. When the skin is irritated, a bright, long-lasting red or white color appears on it. The child often sweats, the tips of his fingers and toes are bluish in color. Very typical for phenylketonuria are neurological disorders, known in the clinic under the name "Salaam's seizures". They manifest themselves in the form of periodic nods and bows, during which the child spreads his arms to the sides. During the occurrence of such attacks, the likelihood of injury is very high.
Numerous lesions are noted on the skin of the child, since, as a result of the lack of pigments, it is very vulnerable to the action of sunlight. Lesions occur in the form of eczema, dermatitis, and various rashes often appear. Violations of the internal organs are detected only in cases where there are congenital malformations of their development. Blood pressure in most cases is at very low values. The function of the gastrointestinal tract is often disturbed, constipation appears.
The severity of these manifestations is directly related to the degree of metabolic disturbance. All together, these signs are detected only when the corresponding enzymes are generally absent in the body. With a partial disruption of the work of enzymes, the manifestations of the disease are very diverse. As a rule, in varying degrees, a violation of the mental and physical development of the child, neurological disorders and the development of characteristic manifestations after ingestion of food containing large amounts of phenylalanine are combined. There may not be any manifestations at all, while the results of biochemical analyzes indicate that the child has a disease.
These are the main manifestations of the form of the disease known as type 1 phenylketonuria. In the second type of the disease, the lag in the intellectual development of the child is much more pronounced, convulsive seizures often occur, the child is constantly restless, very excitable, aggressive. Reflexes on the arms and legs are greatly increased, muscle tension is disturbed, complete paralysis of the muscles of the arms and legs occurs. The disease develops very quickly, and, having reached the age of 2-3 years, the child dies.
There is also a variety of the disease and the third type, which in its characteristics is very much like the second type, only a much more severe mental retardation is detected, a significant decrease in the size of the skull, movements in the muscles of the arms and legs are more impaired.
In the diagnosis of the disease, various laboratory tests are very important, especially the determination of the content of phenylalanine in the blood. Various methods of genetic research are being used more and more widely.
Treatment of phenylketonuria in children
It consists in preventing complications associated with the disease. Full compensation of disturbed metabolic processes is possible only when the correct diagnosis is made and adequate treatment is started as soon as possible, preferably even before the birth of the child. From the very first days of life, all foods containing the "forbidden" amino acid are excluded from the child's diet.
Only this event can achieve a positive result and further normal development of the child. The diet must be followed for a very long time, usually at least 10 years.
All protein-rich foods are completely excluded from the child’s daily diet: meat, fish, sausages, eggs, cottage cheese, bakery products, cereals, legumes, nuts, chocolate, etc. Dairy products, vegetables and fruits are allowed, but only in small amounts and taking into account the phenylalanine contained in them.
It should be borne in mind that this amino acid is still indispensable in the body and the minimum requirements for it must be fully satisfied, otherwise this will lead to even more profound developmental disorders of the child than the disease itself. Since most food products are contraindicated for a child, for a very long time he is doomed to eat only special products produced both abroad and in Russia. From the first days of a child's life, it is forbidden to breastfeed, he should receive only mixtures specially designed for these patients.
Diet for older children should only be prepared by a medical specialist. This takes into account not only the amount of phenylalanine in the product, but also the age of the child, his height, weight, individual needs for nutrients and energy.
Proteins in the child's body come almost exclusively as part of the above specialized foods. The need for fats is met mainly by butter and vegetable oils. It is easier to provide the required amount of carbohydrates. For this purpose, the child is allowed to eat various fruits, vegetables, juices, sugar, foods containing starch. Minerals and trace elements enter the body almost exclusively through specialized products.
It should be remembered that their taste and smell can lead to a decrease in the child's appetite. Some children develop nausea, vomiting after eating such food, and then the child becomes naughty and refuses to feed. In these cases, it is allowed to exclude the mixture from the diet for a short period of time. The child's diet becomes much more varied after reaching three months of age, when it is allowed to give fruit juices, fruit puree is introduced after half a month. A month later, the timing of the introduction of the first complementary foods in the form of vegetable puree or canned food, but without the content of dairy products, is suitable. At six months, a child can already eat porridge, but made from mashed sago or protein-free cereals, jelly. Then the diet is expanded by the introduction of mousses.
In sick children who are in the second year of life, nutrition is very different from that of healthy ones. In the daily diet, the main place belongs to various vegetables and fruits. Special protein-free diets are used, which include protein-free pasta, sago, protein-free cereals, cornstarch, vegetable margarine, sour cream. Of the products containing sugar, the use of honey, jam, jam is allowed.
With an appropriate diet, a necessary condition is the constant monitoring of the content of phenylalanine in the blood. With its increase, dietary recommendations need to be revised. When a disease is detected, when its therapy has just begun, such studies should be carried out at least once a week, and later, when the child's condition is normalized, at least once a month. When the child reaches an older age and stable normalization of his condition, laboratory tests can be performed less frequently.
You can gradually cancel the diet only when the child reaches the age of ten. In the future, all these children are under the supervision of relevant specialists in the clinic. Periodic evaluation of their mental and physical development is carried out.
In addition to dietary recommendations, the child is prescribed medication, which includes calcium, phosphorus, iron, vitamins, especially group B, drugs that improve the transmission of impulses in the nervous system, improve metabolic processes. A complex of physiotherapy exercises is prescribed. With a child with signs of mental retardation, work is carried out with the participation of experienced teachers.
For girls who plan to have a pregnancy in the future, dieting is necessary up to and during pregnancy. These activities greatly increase the likelihood of having a healthy baby.
Forecast. It is completely determined by the timeliness of the diagnosis and the start of treatment. The second and third types of the disease proceed most unfavorably, since with them the diet is practically ineffective.
Histidinemia
It was first isolated as an independent disease in 1961. The metabolism of the amino acid histidine is disturbed, which mainly occurs in the skin and liver. The disease can be spread among different groups of children with different frequency.
Causes and mechanism of development of histidinemia
As a result of impaired cleavage of histidine, it accumulates in organs and tissues, mainly causing brain damage. There are several varieties of the disease, the main of which are:
1) the most common form in which the amino acid metabolism is disturbed both in the skin and in the liver;
2) violation of metabolism only in the liver while it is preserved in the skin. The disease in this case proceeds in a milder form, since the exchange is partially preserved;
3) incomplete violation of metabolism in the liver and skin. The disease is also relatively mild.
Signs of histidinemia
The first signs of the disease may appear at different ages. They can occur both in a newborn child and during puberty. The disease is very diverse in its manifestations. The child may have a very profound mental retardation, but there may be no manifestations and in the future never occur during later life. Mental developmental disorders are detected in a child at a very early age. They manifest themselves in the form of emerging convulsions, loss of motor skills, the child ceases to show interest in toys and people around him. In the future, mental retardation is always observed. It can be expressed to a small extent, and can reach almost extreme values. Mental disorders are manifested in the fact that the child very often has a change in mood, most often he is excited and aggressive, behavior is disturbed, the ability to concentrate on any subject. Most patients have speech impairment, often even with normal mental development.
It is characteristic that among sick children fair-haired with blue eyes are more common than dark ones with brown eyes. Therefore, doctors have difficulty in differentiating the disease from phenylketonuria.
The main additional methods that help in the diagnosis are biochemical laboratory tests. Diagnosis is possible even before the birth of the child.
Treatment of histidinemia
As with other metabolic diseases, diet therapy is the most important treatment for histidinemia. From birth, all foods containing the amino acid histidine are excluded from the diet. But since this substance is indispensable for the child's body, the minimum need for it must still be met.
Fortunately, the product containing small amounts of histidine and recommended for infants in the nursing period is mother's milk. In the absence of such, special formulas for feeding, mare and soy milk can be given. Fruits and vegetables contain mostly carbohydrates, so they are "safe" foods and can be given in the same way as healthy children. Vegetables are preferred as the first additional meal for a child. In the second half of life, when the child begins to be given meat products, sick children should receive them in very limited quantities. The correctness of the diet is assessed by the well-being of the child and the indicators of laboratory tests.
Particularly undesirable in the diet of a child are products such as beef, chicken, eggs, cow's milk, cottage cheese, cheese, peas, barley, rye, wheat flour, rice.
Under the influence of diet therapy, convulsions very quickly cease to disturb the child. But speech disorders and mental retardation are not corrected in this way.
Treatment with medications is also possible, but it does not eliminate the cause of the disease, affecting only one or another of its manifestations.
The prognosis in most cases is favorable and is determined by the timeliness of diagnosis and treatment.
Hartnup disease
Opened in 1956. Associated with impaired absorption of the amino acid tryptophan in the intestine. It is quite widespread, but it does not manifest itself in all patients.
Symptoms of Hartnup's disease
First of all, attention is drawn to lesions of the skin, similar to those with a deficiency of B vitamins. Often there are allergic skin lesions to the action of sunlight. Disturbances from a nervous system are very various. Twitching of the eyeballs, trembling of the fingers when working with small objects, disturbances in the normal tension of the muscles of the arms and legs, movements in them, and coordination of movements associated with damage to the cerebellum are noted.
When making a diagnosis, they are guided by the data of laboratory studies: a biochemical analysis of blood, urine.
Treatment of Hartnup's disease
Treatment consists mainly of a therapeutic diet. In the diet of a child, the amount of protein-containing foods should be limited. Increase the amount of fruits consumed. Of the drug methods, the administration of vitamin preparations of various groups is prescribed. It is necessary to protect the child's skin from direct sunlight.
