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Genetic diseases. Klassifikatsiya, clinical features, diagnosis, principles of diagnosis of hereditary tretment. Multifaktoris diseases .Prenatal diagnosiz. The classification of monogenic diseases • Autosomal dominant: • Marfan's syndrome, • Huntington's chorea, • myopia Minkowski Chauffard • Autosomal recessive: • phenylketonuria, • galactosemia, • glycogenosis, • sindromTeya-Sachs, • Niemann-Pick syndrome The classification of monogenic diseases • Linked to the X chromosome, • dominant: • phosphate diabetes, • hematuric chronic nephritis. • X-linked, recessive: • DMD Phenylketonuria •It is an inherited disorder of amino acid metabolism caused by mutations in the gene for the hepatic enzyme phenylalanine hydroxylase, phenylalanine hydroxylation reaction was carried out, ie its conversion into tyrosine. •The disease is common in populations where the spread of kinship marriage. •The disease is transmitted in an autosomal recessive manner. •Phenylpyruvic mental retardation was opened in 1934, Felling. Phenylketonuria • Diagnosis is based on clinical and biochemical data of molecular genetic studies. • Because of the clinical polymorphism of PKU should be excluded from each of the retarded child. • The most affordable and easy sample is Felling. By 2-3 ml of acidified urine was added hydrogen chloride reagent Felling (10% solution of ferric chloride of iron - FeCl3) in an amount of 0.5 - 1 ml. The sample is considered positive when a green coloring. Phenylketonuria • Increasing the concentration of phenylalanine in the plasma and urine can be detected by TLC. • When determining phenylalanine in the blood plasma sample is used Guthrie based V.subtil good growth in medium containing a phenylalanine Phenylketonuria • TREATMENT. Phenylalanine is an essential amino acid and a minimum dietary administration is absolutely necessary. For the treatment of PKU amino acid mixture used or protein hydrolysates with a low content of phenylalanine. • This basic diet supplemented with protein-free and low-protein foods, vitamins and trace elements. Phenylketonuria • Limited to products containing a large amount of phenylalanine (breast milk, animals). • Such a diet should be administered no later than 2-3 weeks of age and continue until 5 years of age. At older ages, decreasing the sensitivity of the central nervous system to the damaging effects of phenylalanine and products of metabolism, and the main stages of brain development had already been completed. Phenylketonuria • Protein hydrolysates or amino acid mixtures "Gipofenat'''''' Berlafen etc. • By reducing blood phenylalanine administered to normal animal proteins under the control of biochemical studies (daily phenylalanine content not more than 25 mg per 1 kg of the child. • From the diet excludes meat, fish, liver, kidney, eggs, cheese, products made from wheat and rye flour, cottage cheese, nuts, beans, etc., milk and potatoes are considering their content of phenylalanine in limited quantities. Patients brother and sister with PKU Chondrodystrophy, the patient 7 months. (macrocephaly, high forehead, "saddle nose" micromelia, isodactylism) Mucopolysaccharidosis syndrome (Gunther) Marfan Syndrome Cystinosis (Fanconi syndrome) • The hereditary disease associated with metabolic disorders of cystine due to the enzymatic block (biochemical mechanism has not been fully elucidated.) • Due to the poor solubility of cystine in biological fluids in the excessive accumulation of it in the cells, it is easily precipitated as crystals, causing various operational disturbances in the internal organs, primarily the kidneys. Cystinosis (Fanconi syndrome) • Frequency - 1 600 000. • The disease is inherited in an autosomal recessive manner. • CLINIC. The disease manifests itself in the late first or early in the second half of life. • Dyspeptic syndrome (loss of appetite, constant thirst, constipation, vomiting) • Immunosuppression. • The defeat of the eye (conjunctivitis, convergent strabismus, deposits of cystine crystals in the cornea, photophobia). Cystinosis (Fanconi syndrome) • Gepatosplenomealiya • renal dysfunction (dysuria). • The progressive growth retardation up to severe forms of dwarfism. • Rahitopodobnyh changes in the skeletal system. However, many children die before deployed rahitopodobnyh changes from hyperthermia, coma, collapse. • Some of the children changes of the skeletal system, on the contrary, it is the main sign of the disease. Cystinosis (Fanconi syndrome) • Children are stunted. They are marked curvature of the long bones, the parietal bumps, deformities of the chest, spine, muscle hypotonia, "beads" on the edges, "rachitic bracelets", etc. Clinical and radiological manifestations of these phenomena are similar to rickets associated with a deficiency of vitamin D. • From the disease de Toni-Debre-Fanconi cystinosis different development at an earlier age and more unfavorable course. Cystinosis (Fanconi syndrome) • Diagnosis is based on characteristic clinical picture, laboratory data: giperaminoatsiduriya, phosphaturia, glycosuria, kaltsiyuriya. • Cystine crystals may be found in the cornea with a slit lamp examination. • With conjunctival biopsy, kidney or lymph node puncture can establish the presence of crystals in it. Cystinosis (Fanconi syndrome) • Treatment of cystinosis is not fully developed. • Apply large doses of vitamin D (100 000 IU per day), which prevents the progression of rahitopodobnyh changes in the bones and reduces the aminoaciduria, glucosuria, phosphate - and kaltsiyuriyu. • Displaying treatment of anabolic hormones. Cystinosis (Fanconi syndrome) • In the fight against acidosis shows the assignment of citrate mixture of 4% solution of soda. • Application of the penicillin compound promotes formation of cystine, readily soluble in water. • FORECAST usually unfavorable, in 2-3 years from the onset of illness comes death. Tyrosinosis • Progression of the disease is due to the lack of парагидроксифенилпировиноградной acid oxidase. In healthy individuals, this enzyme converts the said acid gomogentenzinovuyu. In the presence of the enzymatic defect exchange disrupted tyrosine, which leads to the development of tyrosinemia and tirozinurii. • In the early pathological process involved the liver, kidney, skeletal system (rahitopodobnyh change). Tyrosinosis • The disease is transmitted in an autosomal recessive manner. • CLINIC. The disease begins to manifest itself in the first months of life vomiting, retarded physical development, enlargement of the liver. • In connection with the development of cirrhosis, jaundice, ascites, bleeding into the skin. • As a consequence of renal disease develops glyukoamino phosphate diabetes, which causes changes rahitopodobnyh bone: osteoporosis, osteomalacia, bending bones, etc. • In many cases, delayed mental development. Tyrosinosis • Diagnosis is based on clinical symptoms, early signs of hepatic insufficiency, as well as the biochemical examination data (positive sample Millon excretion, increased plasma tyrosine to 10 mg% or more, the presence paragidroksifenilpyruvic acid in the urine). The absence of the enzyme can be installed in histochemically punctates liver. Tyrosinosis • Treatment aims to control phenylalanine and tyrosine in the diet and in many ways is similar to the treatment of PKU. • FORECAST unfavorable. In the absence of appropriate treatment children die before the age of 10 years from liver failure. ALAKAPTOURIA • The disease is known for more than 100 years. A urine of patients allocated gomogentenzinovaya acid, which is absent in normal. In liver and kidneys of patients no enzyme gomogentenzinovoy acid oxidase, which results in an accumulation and enhanced urinary excretion. • The frequency of the disease - 1:1,000,000 population. • The disease is inherited in an autosomal recessive way. • Pathogenetic mechanism of the disease is not fully understood. ALAKAPTOURIA • CLINIC. The disease is clinically 3 symptoms: dark urine (birth - red diaper), blue-gray pigmentation of cartilage and connective tissue (after 20-30 years ochronosis), arthropathy (after 30-40 years Ankylosing "rheumatism" are most often affected vertebral post, at least the larger joints, calcification and osteophytes). • The disease does not shorten life expectancy. ALAKAPTOURIA • ДИАГНОЗ устанавливается при обнаружении гомогентензиновой кислоты в моче. Ее почернение при добавлении раствора NаС03 достаточно специфично для заболевания. Достоверный диагноз ставится после хроматографического исследования мочи. • ДИФФЕРЕНЦИАЛЬНЫЙ ДИАГНОЗ проводится с порфирией, аргирией, меланомой. • ЛЕЧЕНИЕ преимущественно симптоматическое. Histidinemia • Histidinemia refers to the exchange of hereditary disorders caused by the absence of histidine or insufficient activity of an enzyme gistidazy. • The incidence rate is similar to PKU (1: 7000, 1: 10000). • Inherited Disease differently depending on the genetic variants of the disease. • The result is an accumulation of metabolic blocking blood histidine and its derivatives, and reducing the concentration of urocanic, glutamic acid and other Histidinemia • CLINIC. For children in the first year of life is an essential amino acid histidine. With a lack of histidine cited poor weight gain, the manifestations of skin exfoliation, eczematous rashes, etc. • With a lack of histidine in adult erythropoiesis violation of manifestations, negative nitrogen balance, decreased serum albumin, anorexia, peeling and dry skin, fatigue, rash erythematous, etc. Histidinemia • Signs of anemia with erythropoiesis violation explains the reduction in the formation of hemoglobin, which includes a large number of histidine. • For patients with histidinemia typical blond hair and blue eyes. The clinical picture in the foreground of the nervous system in the form of reduced intelligence, impaired speech, seizures, hydrocephalus, hypo-or hypertonic muscles, cerebellar ataxia. In some cases histidinemia combined with iron deficiency anemia, kidney disease, bone system. Ребенок 9 лет, д-з наследственная гидроцефалия Histidinemia • DIAGNOSIS. A high concentration of histidine in biological fluids (blood, urine, cerebrospinal fluid). • Increased excretion imidazolpirovinogradnoy, imidazole-lactic acid and imidazoluksusnoy that is a hallmark of the disease. These acids like phenylpyruvic acid react with a reagent Felling, but the reaction is strongly positive. Histidinemia • An important specific feature of the disease is the absence of the main metabolite pathway of histidine (urocanic, glutamic acid, etc.). • Confirms the diagnosis of a direct determination of the activity gistidazy in the horny layer of the skin and liver. • An important feature of the disease is an abnormal response to an oral load of histidine. Homocystinuria • Disease is based on the absence or inactivation of the enzyme tsistationinsintetazy that causes a violation of the exchange of methionine. Patients found to increase blood concentrations of methionine and homocysteine (not in the norm) and a decrease of cystine, the appearance in the urine of homocysteine and cysteine. • The disease is inherited in an autosomal recessive way. • The disease manifests itself marfanopodobnym syndrome. Homocystinuria • Symptom-complex of homocystinuria: • 1) The skeletal anomalies: the disparity physique as shortening the torso, limb lengthening, chonechondrosternon, incorrect posture, "winged" scapula, "tower" skull, malocclusion of the teeth and growth, high palate, valgus deformity of the knee, limiting the mobility of the joints, flat feet, osteoporosis, susceptibility to fractures; Homocystinuria • 2) изменения нервной системы: снижение интеллекта, обедненная речь, дизлалия, спастическая походка, эписиндром; • 3) нарушение зрения: подвывих хрусталика, вторичная глаукома, изменение глазного дна; • 4) со стороны сердечно-сосудистой системы: нарушение обменных процессов в миокарде, склонность к артериальным и венозным тромбозам; • 5) внешние признаки: светлые, мягкие, вьющиеся крупными завитками волосы, голубой цвет радужной оболочки. Homocystinuria • Diagnosis is based on the determination of cystine and methionine in serum and urine tsistationinsintetazy determining activity in the liver. • Differential diagnosis of the disease should be done with Marfan. • Treatment consists in the appointment of a diet enriched with cystine and methionine lacking. The effect of treatment depends upon the destination therapy. • Therapeutic effect of vitamin B6 is associated with increased enzyme activity. albinism • A group of diseases which are based on hereditary defect of melanin metabolism, leading to a decrease or absence of pigment in the skin, mucous membranes, hair and eyes. Melanin is formed primarily of tyrosine. This multi-step process catalyzed by the next series of enzymes: tyrosinase, peroxidase, and others. • The frequency of albinism varies from 1: 5000 to 1: 40 000 albinism • There are the following clinical forms of albinism: Ophthalmic, skin, eye, and skin. • Of Eye-cutaneous albinism is inherited in an autosomal recessive manner. • There are several forms of this type: of ocular albinism, skin part, Chediak-Higashi syndrome, albinism complete perfect, albinism type I, type II albinism, albinism with hemorrhagic diathesis pigmented reticuloendothelial cells, the GermanPudlak syndrome. albinism • CLINIC. Skin color and hair milky white. The iris in the oblique incident light is transparent gray or blue. Characterized by photophobia, and nystagmus. In the direct light of the pronounced red pupillary reflex. The pigment in the fundus is missing. The complete absence of pigment in the skin determines its sensitivity to sunlight. MUCOVISIDOSIS • "If a child feels when a kiss salt, which means he will die soon" - so wrote in the old German books on medicine about children with cystic fibrosis. • Currently live patients over 20 years, i.e. 10 years longer than before. • Cystic fibrosis - this is the most restrictive paradigm inherited disease. The carrier of cystic fibrosis is one of the 25th European. MUCOVISIDOSIS • The disease belongs to a hereditary metabolic diseases. In this disease disrupted the activities of all the body's exocrine glands (sweat, lacrimal, salivary, gland respiratory system and digestive tract). • The frequency of the disease in different populations. On average, occurs with a frequency of 1:2500, 1:5000. Okolo96% of cystic fibrosis patients die from lung disease. • Inheritance - autosomal recessive Disorders of carbohydrate metabolism disorders galactosemia • Galactosemia refers to a group of abnormalities of carbohydrate metabolism, characterized by lesions of the central nervous system, muscular system, liver problems, abnormal red blood cells, hypoglycemic state. • A typical variant of galactosemia inherited as an autosomal recessive. • The incidence is approximately 1: 30 000 live births, but according to different authors, it ranges from 1:8000 to 1: 187,000 population. Galactosemia • The basis of the primary biochemical defect is galactosemia enzyme deficiency of galactose-1-fosfaturidiltransferazy (HA-1BOP), resulting in the tissues of the body accumulates excess galactose-1-phosphate and other products of incomplete decomposition of lactose causing clinical manifestations galactosemia Galactosemia • ЛЕЧЕНИЕ. С первых дней жизни ребёнок должен быть переведён на безмолочную диету. В качестве заменителей молока можно использовать смеси, приготовленные на миндальном и соевом молоке GLICOGENOSIS • Under this general title brings together a group of diseases for which the characteristic accumulation of glycogen in tissues and organs associated with the violation of the activity of an enzyme involved in the metabolism of glycogen. • Disease are inherited in an autosomal recessive way. • Frequency of glycogen storage of all types of 1: 40,000 people. • The most well-described 6 types of glycogen storage disease, although they are at much greater GLICOGENOSIS • CLINIC. Common clinical symptoms are: onset in childhood, symptoms of hypoglycemia (vomiting, convulsions, loss of consciousness, coma). Glycogen is the most intensively accumulated in those organs in which it is synthesized, ie in the liver, kidney and muscle. Depending on which organ is most involved in the pathological process, distinguish three main forms of the disease: • 1.Pechenochnaya • 2.Myshechnaya • 3.Generalizovannaya • Biochemical types of glycogen storage disease: • 1.Bolezn Gierke (I type) - deficiency of the enzyme glucose-6-phosphatase. • 2.Bolezn Pompe (II type) - deficiency of the enzyme acid glucosidase. • 3.Bolezn Corey (W type) - deficiency of the enzyme 1,6-glucosidase. • 4.Bolezn Andersen (IY type) - branching enzyme deficiency. • 5.Bolezn McArdl (Y type) - deficiency of the enzyme phosphorylase muscles. • 6.Bolezn Hers (YI type) - deficiency of the enzyme phosphorylase liver. GLICOGENOSIS • ЛЕЧЕНИЕ гликогенозов недостаточно разработано. • Применение адреналина, гидрокортизона, способных в норме повышать сахар в крови за счет распада гликогена оказалось неэффективным. • Некоторыми авторами рекомендуется использование глюкагона и малых доз тиреоидина. • Большое значение уделяют диетотерапии, которая заключается в увеличении в рационе больных легкоусвояемых углеводов и в учащении приема пищи Disorders of lipid metabolism disorders • Lipid disorders are a frequent companion of pathological processes in children. In its genesis, they can be divided into 2 groups: • hereditary • acquired diseases. Болезни нарушения обмена липидов • Наследственные дефекты обмена липидов делят на 2 группы: • 1). Липидозы или сфинголипидозы – болезни нарушения катоболизма структурных липидов, приводящих к накоплению сфинголипидов в клетках разных тканей; • 2). Болезни, обусловленные с нарушением обмена липидов, содержащихся в крови. АМАВРОТИЧЕСКАЯ ИДИОТИЯ ТЕЯ – САКСА • Амавротическая идиотия Тея - Сакса преимущественно встречается среди евреев-ашкенази. • Частота заболевания составляет 1: 6000 среди евреев-ашкенази и 1: 500000 среди других национальностей. Частота гетерозиготных носителей рецессивного гена среди евреев-ашкенази составляет 1: 40, среди других национальностей – 1: 380. AMAVROTICHESKAYA idiot Tay SACHS • Heterozygous carriers of the abnormal gene reduced the activity of the enzyme hexosaminidase A and the contents of sphingomyelin and kephaline in red blood cells. • The disease is inherited in an autosomal recessive manner. AMAVROTICHESKAYA idiot Tay SACHS • DIAGNOSIS. In the blood plasma of patients with elevated cholesterol levels, and reduced the number of glycolipids. In patients erythrocytes also increases cholesterol and the amount of phospholipids is reduced. Patients glutaminschavelevouksusnoy transaminase enzyme activity increased 3-4 times the activity of the enzyme fructose-I-phosphate aldolase reduced. Niemann-Pick disease • This form sfingolipidoza is a relatively frequent and severe lipidosis, which occurs in 50% of cases among Ashkenazi Jews. • The disease is associated with a congenital deficiency of the enzyme sfingomielinidazy that leads to the accumulation of sphingomyelin in tissues. When this sphingomyelin and cholesterol accumulated in all organs and tissues from a primary lesion of the CNS, spleen, liver, bone marrow, lung, etc. • The disease is inherited in an autosomal recessive manner. Gaucher disease • CLINIC. Known 3 clinical forms of the disease. With early dominated by neurological disorders. From birth, a marked malnutrition, bulbar disorders, soundless scream (Athos), impaired swallowing (dysphagia), lockjaw, sagging of the lower jaw. Death occurs from aspiration of food masses, pneumonia. • In older children and adults, the clinical picture is dominated by an enlarged spleen, hemorrhagic syndrome, anemia. THANK YOU!