Pediatric Medical Genetics - S.I. Smiyan 2003

Inborn errors of metabolism (enzymopathies)

Relevance of the problem. This group of diseases is characterized by high prevalence. At least 5% of children are born with congenital pathology. Yu.I. Barashnev and Yu.E. Veltishchev (1984) emphasize that the total number of Metabolic Disorders with a hereditary defect exceeded 2,000, with an identified primary defect present in 10% of them. Diagnosing this pathology presents significant difficulties because these diseases have a low individual incidence (less than 1:10,000), making it hard for clinicians to gain substantial personal experience in studying their Clinical presentation and Treatment. Furthermore, a child with a hereditary enzymopathy is born looking normal, and the initial clinical manifestations are non-specific. Many hereditary enzymopathies result in death or severe mental and physical disability, primarily due to diagnostic challenges and inadequate Methods of Prevention and treatment. In 50% of cases, deafness and blindness are hereditary. Hereditary pathology accounts for a significant proportion of childhood mortality: it is the primary cause in 11% of cases, and in 31% of cases, it is a fatal outcome of another disease occurring against the Background of hereditary disorders. Genetic Disorders lead to Spontaneous Abortion, Miscarriage, and stillbirth, as some types of hereditary pathology are incompatible with fetal life. The total global economic cost of caring for children with Down syndrome exceeds the cost of combating Influenza.

In our opinion, there is no more urgent problem in the medical and social spheres than the prevention, detection, and Treatment of Hereditary pathology in children, and the progressive degradation of The environmental situation in our country and worldwide places this challenge at the very limit of human civilization's capabilities in the near future.

The Classification largely reflects Modern achievements in this field. The most successful classification of human diseases seems to be the one by H. Harris: 1) hereditary (chromosomal, Gene-related); 2) caused by harmful environmental factors (trauma, Burns); 3) caused by hereditary predisposition and the action of provoking environmental factors (Diabetes Mellitus, PEPTIC ULCER DISEASE). With new scientific advances in molecular biology, the first and third groups of diseases are drawing closer and closer and may eventually form a single group. This is why, when considering hereditary metabolic anomalies, attention must also be paid to Multifactorial Diseases. Significant difficulties arise when considering the Classification of Congenital Malformations and Hereditary diseases. Indeed, why is hereditary pathology not considered congenital? From a clinician's point of view, it is congenital. Therefore, such a classification is justified (Scheme 2).

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Scheme 2. Classification of congenital diseases.

In this report, we are interested in gene diseases (enzymopathies), in The Study of which great progress has been made. Today, we can speak of the feasibility of preventing, diagnosing, and even successfully treating many of these diseases.

Pathogenesis. Hereditary metabolic abnormalities of various substances in a child's body are based on genetically determined enzyme disorders resulting from Gene Mutations. Consequently, there is either an absence of synthesis of a specific enzyme, or its Structure and function are altered. Schematically, this is represented as follows. Normally, a gene activates (synthesizes) an enzyme, under METABOLISM/18.html">The Influence of which substance A is converted into substance B, etc. (Scheme 3).

Scheme 3. Hereditary metabolic distortion.

Therefore, the following metabolic and clinical consequences of an enzymatic block are possible in the body: a) accumulation of toxic metabolic products that adversely affect primarily the Central Nervous system (e.g., phenylketonuria); b) absence of physiologically essential substances in the body due to an enzymatic block of further metabolism (e.g., Glycogen Storage Diseases).

For clarity, we present the pathogenesis scheme of a well-studied enzymopathy — phenylketonuria (Scheme 4).

Scheme 4. Pathogenesis of phenylketonuria.

Enzymopathies (enzyme-protein) reflect damage to one type of Cell/13.html">Protein Structure — Enzymes, meaning we are talking about defects in the protein substrate. However, considering that enzymes control all Types of Metabolism, it is fair to call this group of hereditary pathology enzymopathy. True, today we can also speak of acquired enzymopathies that occur in both acute and chronic diseases.

Amino acid (AA) metabolic abnormalities are represented by a large group of diseases based on a hereditary defect in The activity of enzymes that catalyze the metabolic reactions of various Amino Acids.

The development and improvement of mass and selective screening methods for newborns and high-risk children for AA metabolic diseases have allowed the identification of AA metabolism alterations of various genetic origins.

Based on the analysis of fundamental research, 4 types of AA metabolic abnormalities can be distinguished:

1. Hereditary disorders of AA metabolism accompanied by an increase in their concentration in Blood and urine. To date, there are 23 forms of such disorders. The most well-known pathologies in this group are phenylketonuria, histidinemia, tryptophanuria, "maple syrup urine disease", and "hops-drying disease". All these diseases are caused by a metabolic block associated with impaired synthesis or structure of certain enzymes: phenylalanine 4-hydroxylase in phenylketonuria, and histidase in histidinemia. A significant portion of these diseases is inherited in an autosomal recessive manner. Laboratory evaluation of affected children reveals elevated AA levels in both blood serum and urine.

2. Hereditary disorders of AA metabolism accompanied by increased urinary excretion without changes in blood levels. This group, like the previous one, belongs to hereditary enzymopathies. In these conditions, due to impaired renal reabsorption, there is no significant increase in serum levels of the blocked amino acids. Insufficient renal reabsorption of amino acids leads to their increased excretion in urine. This group includes homocystinuria, hypophosphatasia, and other diseases.

3. Hereditary Disorders of the AA transport system. This group includes diseases whose development is caused by reduced reabsorption of certain AAs in the Kidneys and intestines. Impairments of active AA transport are multifaceted, yet their true specific mechanisms at THE CELLULAR LEVEL remain unexplained to this day. This group includes cystinuria, Methionine malabsorption, etc. (approximately 12 forms in total).

4. Secondary hyperaminoacidurias. This is a known group of aminoacidurias that occur due to the action of various factors on the renal transport system. In these conditions, normal AA levels are detected in blood serum, while generalized hyperaminoaciduria is observed in urine As a result of secondary tubular disorders. To date, the true mechanism of Renal Involvement in the pathological process remains unknown. Secondary generalized hyperaminoaciduria occurs in diseases such as Fanconi Syndrome, fructosemia, galactosemia, cystinosis, lactose intolerance, etc.

The Clinical presentation of amino acid metabolic abnormalities is diverse, but it is typically characterized by central nervous system damage and elevated levels of specific amino acids in urine and blood serum.

Congenital amino acid metabolic disorders that cause clinical manifestations in the neonatal period usually become quite pronounced and often lead to a fatal outcome. There are several clinical signs that may lead to suspicion of an amino acid metabolic pathology in a newborn:

- Newborns appear healthy, but the first signs, such as lethargy, feeding difficulties, seizures, and vomiting, manifest within a few hours after birth. This timeline of symptom onset typically contrasts with other genetic diseases or perinatal injuries, where manifestations appear immediately.

- Severe vomiting, once surgical pathology (pylorospasm, pyloric stenosis) has been ruled out, also points to a congenital disorder of Amino acid metabolism.

- In most newborns, metabolic disorders are inherited in an autosomal recessive pattern; therefore, the family history must be evaluated for consanguinity or unexplained neonatal deaths.

- Physical examination usually reveals nonspecific findings indicating central nervous system involvement, hepatomegaly, or an unusual body odor (Table 6).

Table 6 Changes in body and excreta odor in children with amino acid metabolism disorders

In the postnatal period, clinical manifestations such as mental and motor developmental delay are the most consistent signs of amino acid metabolism disorders.

The course of the disease can be episodic or intermittent, with acute flare-ups alternating with periods of well-being. These episodes are typically triggered by stress or nonspecific insults (such as infection). A child may die during such an attack.

Inborn errors of metabolism, and amino acid disorders in particular, should be considered as a potential Diagnosis in any child presenting with any of the following:

- Unexplained mental and motor developmental delay, or seizures.

- An unusual odor, especially during acute illness.

- Intermittent episodes of unexplained vomiting, acidosis, mental status changes, or coma.

- Hepatomegaly.

- Renal calculi.

Among all types of amino acid metabolism disorders, hyperphenylalaninemia (phenylketonuria) is the most thoroughly studied, with its various aspects detailed below. First described by Følling in 1934, this disease is inherited in an autosomal recessive manner and occurs with an incidence of 1 in 20,000 births, making it the most common disorder in this group of metabolic anomalies.

The pathogenesis of phenylketonuria (PKU) is driven by a significant disruption in the metabolism of The amino acid phenylalanine. In a healthy child, phenylalanine is converted into Tyrosine by the enzyme phenylalanine hydroxylase, and tyrosine is subsequently converted through several intermediates into thyroxine, melanin, and epinephrine.

Clinical symptoms are absent During the first weeks and months of life. Affected infants are born outwardly healthy, with normal birth weight and length. Furthermore, psychomotor and physical development is unimpaired in the first months; however, the child subsequently loses 5% of their intelligence quotient (IQ) every 10 weeks. Symptoms typically manifest at the beginning of the second half of the first year of life. Infants become lethargic, listless, fail to fixate their gaze on objects, and show no interest in interacting with family members. They exhibit poor attention span, inappropriate crying or laughter, and stereotypic movements. Motor development is severely delayed, and previously acquired skills are lost (for example, by the end of the second year, the child may stop sitting and walking). Typically, patients have fair Hair, blue eyes, and fair, sensitive Skin, which frequently leads to dermatitis. A characteristic mousy odor (from sweat) is present, and about half of the patients experience seizures. Untreated PKU is characterized by severe intellectual disability that progresses until the age of four, resulting in profound cognitive impairment (70%) and moderate-to-severe cognitive impairment (30%). Blood pressure is usually low. Microcephaly is common, and Congenital Heart defects are occasionally diagnosed.

Diagnosis during the first days and weeks of life, when treatment is most effective, is only possible through specialized screening tests. Phenylalanine and its abnormal metabolites are present in the blood and urine. Qualitative biochemical tests include: 1. Følling's test (ferric chloride test) — 10 drops of a 10% ferric chloride solution are added to 2-5 mL of fresh urine; in the presence of phenylpyruvic acid, the urine turns dark green. 2. Indicator paper tests (Biophan P, etc.) — a strip of indicator paper is dipped first into a buffered ferric chloride solution and then into urine; in the presence of phenylpyruvic acid, the paper turns green.

These tests become positive by the 4th to 6th week of life (requiring a tenfold increase in blood phenylalanine levels) and can also be positive in other hereditary diseases or after the administration of salicylates or chlorpromazine (aminazine). Therefore, more accurate diagnostic methods have been developed. Semiquantitative microbiological assay for blood phenylalanine concentration: 1. The Guthrie test allows diagnosis in newborns after five days of life. It utilizes a culture of B. subtilis, whose growth is inhibited by The addition of an inhibitor, 2-thienylalanine. Elevated concentrations of phenylalanine (PA) in the patient's blood overcome this inhibition. The bacterial growth zones are measured and compared with a standard. The test is positive at PA concentrations above 40 mg/L. 2. The auxotrophic E. coli K-12 strain method. The patient's blood is applied as discs onto paper cards. If the growth zone corresponds to a PA concentration above 40 mg/L, the test is considered positive. Semiquantitative Biochemical Methods for PA determination include paper Chromatography and fluorometric assays. Quantitative biochemical determination of blood PA concentration is performed using Ion-exchange chromatography (automatic amino acid analyzer). In PKU, blood PA levels rise to 15-100 mg % (normal: 0.8-2 mg %), CEREBROSPINAL FLUID levels rise to 3-10 mg % (normal: 0.2 mg %), and urinary excretion reaches 0.3-1.2 g daily.

Treatment initiated during the neonatal period prevents damage to the central nervous system. The cornerstone of therapy is replacing phenylalanine-containing foods (milk, meat, eggs) with protein hydrolysates containing minimal phenylalanine and normal amounts of Other Amino Acids (such as Berlofen, Lofenelac, Gymogen, Hypophenat, etc.), while allowing unrestricted consumption of vegetables, fruits, and Vitamins. This diet is recommended until five years of age. In older children, the Toxic Effect of phenylalanine and its abnormal metabolites on The Nervous System is absent. Initiating medical dietary therapy after Clinical symptoms of PKU have already developed does not reverse existing damage but does prevent further injury to the central nervous system.

The flowchart structure of hyperphenylalaninemia (phenylketonuria) can be represented as follows:

Inborn errors of Carbohydrate Metabolism are common pediatric disorders that can trigger other acquired conditions and may be fatal. Inherited enzyme defects occur at the level of carbohydrate Hydrolysis and Absorption in the intestines, as well as the Interconversion of CARBOHYDRATES.

Galactosemia, first described in 1908 by von Reuss, is inherited in an autosomal recessive pattern and occurs with a variable incidence (ranging from 1:1,800 to 1:187,000).

The Etiology AND PATHOGENESIS are due to the deficiency of the enzyme galactose-1-phosphate uridyltransferase, which is responsible for converting galactose to glucose. Consequently, galactose-1-phosphate, the upstream metabolite prior to the metabolic block, accumulates in erythrocytes, the Liver, Muscles, heart, lens, and Cerebral Cortex. This leads to varying degrees of dysfunction in these Organs. Additionally, the activity of enzymes such as phosphoglucomutase and glucose-6-phosphate dehydrogenase is inhibited, resulting in hypoglycemia and cataract development.

Pathomorphological changes are most characteristic in the liver, manifesting as fatty degeneration, perilobular necrosis, and cirrhosis. Dystrophic changes are also observed in the Brain, kidneys, and lens.

In severe cases, clinical manifestations appear shortly after birth. An infant who initially appeared healthy loses appetite, develops diarrhea, abdominal distension, and hypoglycemic episodes, and becomes lethargic with diminishing Reflexes. Initially, the jaundice resembles physiological jaundice, but it subsequently worsens, leading to liver cirrhosis and portal Hypertension (Splenomegaly, ascites). Hemorrhagic diathesis occurs due to prothrombin deficiency secondary to hepatic impairment. Cataracts typically develop by the third week of life. The child falls behind in weight gain, growth, and psychomotor development. Ingestion of large amounts of galactose during breastfeeding leads to severe hypoglycemia. Galactosuria, proteinuria, cylindruria, and Aminoaciduria are observed. Blood glucose levels are decreased, while galactose levels are elevated. Liver function tests are abnormal, showing elevated bilirubin, increased transaminase activity, and a positive thymol turbidity test. The most reliable diagnostic criterion for galactosemia is reduced galactose-1-phosphate uridyltransferase activity in erythrocytes.

However, our experience shows that measuring blood glucose levels using different methods is a highly reliable diagnostic criterion for this disease. Specifically, determining blood sugar levels using the glucose oxidase method 30 and 60 minutes after a fasting galactose tolerance test reveals a flat curve because only glucose is measured. Conversely, simultaneous determination of blood sugar using the Hagedorn-Jensen method shows a sharp increase in glycemia because it measures all reducing sugars, although a galactose tolerance test is unwarranted if galactosemia is suspected. Given the availability of these testing methods in any healthcare facility and the rapid turnaround time of the results, they should be utilized for early diagnosis and timely treatment.

Treatment is aimed at eliminating galactose, which is found in milk sugar. From the moment of diagnosis, the infant is not given milk, replacing it with protein hydrolysates and lactose-free protein formulas (Enfamil Soy, Nutramigen, Similac Isomil, Nutrisoy, Prosoyal). Later (after two months of age), eggs, vegetable fats, almond or soy milk, rice flour porridge, and vegetable and meat dishes are introduced. Symptomatic therapy and high doses of vitamins are also used. Late-onset treatment in severe cases leads to a poor prognosis.

The Cytology/cytology/92.html">SCHEMATIC STRUCTURE OF galactosemia is as follows:

Glycogenoses (glycogenosis, glycogen storage disease) comprise a group of Autosomal Recessive Disorders with a prevalence of 1:40000. Only a few hundred cases have been described in the global literature.

The etiology and pathogenesis are determined by an enzymatic defect. Since The breakdown of glycogen to glucose is a multi-step process, 12 types of glycogen storage diseases are distinguished depending on the level of the metabolic block. They are characterized by impaired glycogen Synthesis and Breakdown, leading to its accumulation (with normal or altered structure) in the liver, kidneys, myocardium, muscles, Spleen, Lungs, central nervous system, and Lymph Nodes.

Type I glycogenosis (von Gierke's disease, hepatorenal type) is the most common, caused by a defect in the enzyme glucose-6-phosphatase. Consequently, glycogen accumulates in The Liver and cannot be converted into glucose. This leads to hypoglycemia, even after relatively short fasting periods, as well as increased lipolysis, lipemia, acetonemia, and acetonuria.

Clinical manifestations appear as early as the neonatal period with hepatomegaly and abdominal distension. Subsequently, the liver reaches an unusual size, the spleen and kidneys enlarge, and anorexia, vomiting, hypoglycemia, convulsions, and a tendency to Hemorrhage and bleeding develop, with children falling behind in growth. For diagnosis, the occurrence of fasting hypoglycemia accompanied by lipemia, elevated plasma levels of free Fatty acids and Ketone Bodies, and acetonuria is crucial. Glucagon and epinephrine do not cause an increase in blood glucose levels, whereas in healthy children, it rises by 50-60 %. Liver biopsy reveals high glycogen content and the absence or significant reduction of glucose-6-phosphatase.

Treatment is symptomatic and aimed at preventing hypoglycemic crises (frequent, evenly spaced carbohydrate intake, fat restriction) and acidosis, especially during intercurrent illnesses (sodium bicarbonate). Attempts have been made to use anabolic Hormones and glucagon.

The prognosis is poor in most cases, with children dying within the first 2 years of life, though some patients survive into adulthood.

Type II glycogenosis (generalized glycogenosis, glycogen cardiomegaly, Pompe disease) is characterized by the absence of the lysosomal enzyme alpha-glucosidase, leading to glycogen accumulation in Muscle Cells, myocardium, liver, kidneys, and the central nervous system. Therefore, hypoglycemia does not develop.

The clinical presentation of this pathology appears in early infancy with cardiomegaly, cyanosis (especially after feeding), respiratory distress, signs of Heart Failure, macroglossia, and Skeletal Muscle weakness. The glucose tolerance test is normal, and leukocytes show a high glycogen content.

Treatment is symptomatic but ineffective. Children die before one year of age from heart failure or Pneumonia.

Type III glycogenosis (liver and muscle glycogenosis, Forbes disease) is caused by a deficiency in the activity of amylo-1,6-glucosidase or oligo-1,4-glucantransferase enzymes, leading to glycogen accumulation in the liver, skeletal muscles, and heart.

The clinical presentation is similar to von Gierke's disease, but the manifestations are milder. The absence of the specific enzyme can be determined in liver and muscle biopsies. The course of the disease is favorable.

Treatment is dietary and aimed at preventing hypoglycemia and ketoacidosis.

Other types of glycogen storage diseases are extremely rare.

Hereditary fructose intolerance (fructosemia) is very rare, inherited in an autosomal recessive manner, and was first described in 1956.

The etiology and pathogenesis are explained by a deficiency in fructose-1-phosphate aldolase activity, leading to a metabolic block at the stage of fructose-1-phosphate conversion. This results in hypoglycemia, which is the primary cause of the clinical symptoms.

Clinical manifestations appear when the child ingests food containing fructose (sucrose, fruit juices). The main symptom is hypoglycemia (sweating, tremors, somnolence, convulsions). In addition, poor appetite, growth retardation, psychomotor delay, hepatomegaly, and jaundice are observed. In mild cases, only intestinal disorders may occur. Serum glucose levels are low, while fructose levels are high. Fructose is detected in the urine.

Treatment is effective and consists of eliminating sugar, fruits, and vegetables containing fructose from the diet. During a hypoglycemic attack, intravenous glucose administration brings improvement. At an older age, patients tolerate fructose-containing foods better.

Intolerance or malabsorption of glucose, galactose, and fructose is rare. In these patients, dietary Disaccharides and those formed during polysaccharide hydrolysis are cleaved normally. However, the resulting glucose, galactose, and fructose cannot be absorbed due to impaired Active Transport of these Monosaccharides.

Clinically, it manifests as frequent watery stools and abdominal distension from the moment these carbohydrates enter the body (glucose and galactose after birth; fructose after the Introduction of sucrose, fructose, or vegetables). The diagnosis is established by determining glycemic curves after loading with the respective sugars and is confirmed by the absence of an increase in serum glucose levels.

Treatment is effective when foods containing the non-absorbable carbohydrate are excluded: for glucose malabsorption — milk, sugar, maltose; for galactose — milk; for fructose — fruits and vegetables containing fructose.

Hereditary lactose intolerance is caused by a deficiency of the enzyme lactase, which breaks down milk sugar into glucose and galactose. Therefore, lactose accumulates in the intestinal lumen, leading to Fermentation with The production of large amounts of lactic acid, a decrease in stool pH, abdominal distension, and increased peristalsis. The disease manifests from the first days of life with diarrhea, vomiting, poor weight gain, malnutrition, and frequent, low-volume acidic stools. The diagnosis is confirmed by the absence of a glycemic rise after lactose loading.

Treatment is aimed at strictly limiting the intake of sweet dairy products and introducing acidified formulas and low-lactose formulas. The prognosis with treatment is always favorable.

Hereditary sucrose intolerance is explained by the absence of the enzyme sucrase, which cleaves this disaccharide into glucose and fructose. The MAIN CLINICAL MANIFESTATIONS are chronic watery diarrhea, regurgitation, abdominal distension, and The Development of malnutrition. All of these develop after the child is transitioned to foods containing sugar. The glycemic curve after sucrose loading is flat.

Treatment is effective and consists of eliminating sucrose (sugar) and replacing it with glucose, maltose, etc.

Hereditary maltose intolerance develops in the absence of maltase, when the undigested disaccharide—maltose—accumulates in the intestines and undergoes fermentation. Consequently, the child develops diarrhea, malnutrition, anemia, and highly acidic stools. The disease manifests after transitioning the child to mixed or formula feeding. Following a maltose tolerance test, there is no glycemic rise.

Treatment is effective and is achieved by eliminating foods high in starch and limiting fruits and vegetables.

The clinical presentation of hereditary disorders of hydrolysis and absorption is similar to that of acquired dyspeptic syndrome. Differential diagnostic features are presented below (Table 7).

Table 7 Differential diagnosis OF malabsorption syndrome and dyspeptic syndrome

Renal diabetes (diabetes renalis, syn. - renal glucosuria) is caused by decreased activity of the phosphatase that dephosphorylates glucose-6-phosphate during glucose reabsorption. In this disease, glucosuria is observed ranging from traces to 3%, less commonly 6-7%. High glucosuria is accompanied by polyuria, polydipsia, and rarely hypoglycemia. Unlike diabetes mellitus, the glycemic level remains within the normal range fasting and after a sugar loading test.

Treatment is aimed at providing the body with the necessary amount of sugar to prevent depletion of glycogen stores. The disease is incurable, although working capacity is not impaired.

Oxalosis (oxalosis) is inherited in an autosomal recessive manner, caused by defects in various enzymes that lead to several types of hyperoxaluria. The Metabolism of Glycine and glyoxylic acid is impaired, causing the development of interstitial nephritis, urolithiasis, and nephrocalcinosis.

Clinical manifestations appear by the age of 5 years with attacks of Renal Colic, proteinuria, erythrocyturia, periodic leukocyturia, bacteriuria, and hyperoxaluria. With a long-term and unfavorable course, symptoms of renal failure of varying severity are observed. Radiologically, Nephrolithiasis, nephrocalcinosis, and osteochondrosis are observed. A reliable sign of oxalosis is the presence of calcium oxalates in the Bone Marrow aspirate.

Treatment is aimed at limiting or eliminating the consumption of foods containing large amounts of oxalic acid (cocoa, chocolate, beets, meat jelly, rhubarb, sorrel), prescribing large doses of pyridoxine (up to 400 mg), thiamine, magnesium oxide (0.1-0.3 g per day), phytin, and aluminum hydroxide. Fluid intake is increased in the afternoon. The development of renal failure indicates an unfavorable prognosis.

Hereditary Disorders of Lipid Metabolism are uncommon and are characterized by Impairment of Vital, chemically diverse structures (glycerides, Cholesterol and its esters, non-esterified fatty acids, Phospholipids, Glycolipids).

The largest group of disorders is hyperlipoproteinemias. A differential diagnostic table, convenient for clinicians, is presented below (Table 8).

Thus, the prevention, early diagnosis, and treatment of hyperlipoproteinemia is a broad social issue, as it can help reduce the incidence of atherosclerosis and cardiovascular disease in both children and adults.

Progressive segmental lipodystrophy (lipodystrophia) (Barraquer-Simons disease) is a rare form of adipose tissue disorder.

Clinically, it manifests during school age with adipose tissue atrophy in localized areas of the face and upper torso, intellectual disability, cystic bone changes, and otosclerosis.

Table 8 Characteristics of Hyperlipoproteinemias (according to A.N. Klimov and N.G. Nikulcheva)

Treatment is symptomatic (massage, physical therapy, sedatives). The prognosis for life is favorable.

Lipidoses (lipidosis) comprise a group of rare disorders characterized by an enzyme defect that leads to the accumulation of elevated amounts of abnormal complex lipid substances in the Cells and Tissues of the central nervous system and Internal Organs. They are inherited in an autosomal recessive pattern. These are typically severe diseases that manifest in the first years of life with intellectual disability, neurological symptoms, visceromegaly, and pulmonary and bone changes.

Treatment is largely ineffective. Mortality is high at an early age, or patients experience severe intellectual disability and long-term disability.

Gaucher disease (Laeneher) is characterized by the deposition of cerebroside in the liver, spleen, and bones, which differs from normal cerebroside by containing glucose instead of galactose.

Clinically, three forms are distinguished. The infantile form manifests within the first months of life with neuropsychomotor and physical developmental delay, hepatosplenomegaly, dysphagia, stridor, opisthotonus, and, less frequently, convulsions. Bone marrow involvement leads to anemia, leukopenia, and thrombocytopenia, the latter causing hemorrhagic syndrome. Death typically occurs by the end of the first year of life.

Treatment is ineffective. In the juvenile form, the disease manifests later, typically during the second year of life, with intellectual disability, hepatosplenomegaly, anemia, leukopenia, hyperreflexia, choreoathetosis, convulsions, etc. Despite treatment (hormone therapy, splenic irradiation, splenectomy), children usually die between 6 and 12 years of age.

The chronic visceral form typically occurs without central nervous system involvement or intellectual disability, manifesting in adolescence or adulthood. The prognosis is relatively favorable.

In addition to the described clinical presentation, a characteristic hallmark for the diagnosis of Gaucher's disease is the presence of Gaucher cells (cerebroside-laden histiocytes), which are found in large numbers in the red pulp of the spleen, lymph nodes, hepatic sinusoids, and bone marrow. Acid phosphatase activity in the blood is increased by 5 to 50 times compared to normal levels.

Niemann-Pick disease is recessively inherited and is rare. The disease is caused by a sphingomyelinase deficiency, which leads to the accumulation of sphingomyelin in the Cells of the liver, spleen, skin, bone marrow, lymph nodes, blood mononuclear cells, and the nervous system. Up to six forms of the disease have been described.

Clinical manifestations are observed in infancy: feeding refusal, vomiting, regurgitation, hepatosplenomegaly, severe developmental delay, altered muscle tone (muscle hyper- or hypotonia), and convulsions. A cherry-red spot is found on the retina of one in four such patients. Subsequently, blindness, deafness, and profound intellectual disability develop. The child dies from secondary complications. The diagnosis is confirmed by finding Niemann-Pick cells in bone marrow or spleen aspirates, as well as by sphingomyelinase deficiency in Blood Leukocytes, internal organ biopsies, and skin. Treatment is of limited efficacy. Lipotropic agents and multivitamins are prescribed.

Diseases with Hereditary predisposition. The prevention, detection, and treatment of chronic pathology in both children and adults are linked to understanding the combined influence of genetic and exogenous factors. These highly prevalent, so-called multifactorial diseases include atherosclerosis, CORONARY HEART DISEASE, Collagen diseases, hypertension, diabetes mellitus, Bronchial Asthma, obesity, peptic ulcer disease, urolithiasis, Schizophrenia, hepatobiliary system diseases, and others. For instance, it has been established that about 60% of the predisposition to coronary heart disease is determined by genetic factors, approximately 20% by familial environmental factors, and about 20% by random environmental factors (I.K. Shkhvatsabaya et al., 1980). Today, Specific characteristics of multifactorial diseases have been identified (C.O. Carter, 1969; Yu.E. Veltishchev et al., 1985):

1) a relatively high prevalence of the disease in the general population, combined with a significant familial predisposition to the illness;

2) the presence of pathogenetic and associated markers of susceptibility;

3) a chronic course and the existence of forms that constitute a continuous spectrum of manifestations, ranging from severe to subclinical, the so-called clinical continuum;

4) distinct differences in manifestations depending on sex and age;

5) an earlier onset and worsening of clinical symptoms in successive generations of the family;

6) a relatively high concordance (agreement) of the disease in monozygotic twins (within 60%), which is lower than the concordance of Monogenic Diseases;

7) an increased risk of recurrence in children predisposed to the disease with each subsequent affected child;

8) similarity of disease manifestations between the affected child and first-degree relatives, reflecting a heritability coefficient exceeding 50-60%;

9) non-conformity of inheritance patterns to simple Mendelian models (dominant, recessive, etc.).

The Practical Application of scientific achievements in studying hereditary predisposition is presented in Table 9, THE PRINCIPLE OF which can also be applied to other diseases.

Table 9 Prevention of atopic diseases (after R.N. Hamburger et al.)

Review Questions

1. Provide the classification of congenital disorders in humans.

2. Outline The Mechanism of development of a hereditary gene disease.

3. Outline the pathogenesis of phenylketonuria.

4. List the primary clinical manifestations of phenylketonuria.

5. List the specific tests used for the diagnosis of phenylketonuria.

6. State the Basic principles of therapy for phenylketonuria.

7. Describe the main etiopathogenetic links and clinical manifestations of galactosemia.

8. What does the pathogenetic therapy of galactosemia consist of?

9. What types of glycogenosis are you familiar with?

10. Outline the main etiopathogenetic links of alactasia (hypolactasia).

11. List the clinical and laboratory manifestations of alactasia.

12. List all the lactose-free and low-lactose formulas for feeding infants in their 1st year of life that you are familiar with.