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MINISTRY OF HEALTH OF THE REPUBLIC OF
UZBEKISTAN
TASHKENT MEDICAL ACADEMY
Department of Infectious Diseases and Pediatrics
Lecture on
Number of students Form of educational occupation
Genetic Disease
TECHNOLOGY OF TRAINING
Time – 2 hours
Lecture - visualization
Lecture plan
1.
2.
3.
4.
5.
6.
To give definition to gene diseases
To discuss Classification of gene diseases the
development mechanism.
The factors influencing development of gene
diseases, them patogenezis
To discuss the methods used for diagnostics of gene
diseases at children.
To show the principles of diagnostics and differential
diagnostics.
To discuss the principles of prevention, medical
examination and the social importance of gene diseases in
families.
Purpose of educational occupation: To acquaint students with an etiology, patogenezy, criteria of
diagnostics and differential diagnostics, the modern principles of prevention of gene diseases.
Tasks of the teacher:
1 .To fix and deepen knowledge of
students of features monogenic diseases
and the factors causing their
development.
Results of educational activity:
The student has to have:
1. Concept about monogenic diseases and the factors
causing their development.
2 . Idea of modern methods
diagnostics of monogenic diseases.
3 . Features of carrying out differential diagnostics.
2 . To explain the principles of carrying
4 . Principles of their treatment, prevention.
out differential diagnostics
3. To develop at students skills of
independent adoption of reasonable
decisions at definition of tactics of VOP
in relation to patients with monogenic
diseases
4 . To acquaint students the principles of
carrying out preventive actions
Stages, time
TECHNOLOGICAL CARD OF LECTURE
Occupation singular occupation
Plural occupations
Teacher
students
1 stage
Introduction
(5 min.)
2 stage
Updating of
knowledge
(20 min.)
1 . Reports the subject name, the purpose,
planned results of lecture and the plan of
its carrying out
11.With the purpose to staticize
knowledge of students asks focusing
questions:
1 . Call Mendel's 3 laws
2 . What you know inheritance types?
3.What is the heterozygote and
homozygote?
4 . what is the genotype and a phenotype?
Carries out a blitz poll.
2.2 . Displays and offers to examine the
lecture purpose. Makes comments on the
maintenance of a slide. Slide No. 1
2.3 . Displays a slide No. 2
1 . Listen
2.1 . Answer questions
2.2 . Study the maintenance of
a slide No. 1
2.3 . Study the contents
3 stage
Informatsion
ny (55 min.)
4 stage
Final (10 min.)
3.1 . Consistently states a material of
lecture on plan questions, uses visual
materials and system of focusing
questions:
On 1 question of the plan: Give definition
to gene diseases at children?
On the 2nd question of the plan: list the
main symptoms of gene diseases
On the 3rd question of the plan: what
mechanisms underlie development of
gene diseases?
On the 6th question of the plan: What
prevention of gene diseases?
Focuses attention on the key moments of
a subject, suggests them to write down.
3.1 . Discuss the maintenance
of the offered materials,
specify, ask questions.
Write down the main thing
4.1 . Asks a question:
4.1 . Answer a question
1 . List signs characteristic for gene
diseases characteristic for FKU.
2 . Than differs hereditary diseases from
not hereditary?
4.2 . Gives a task for independent work:
Albinism.
4.2 . Listen, write down
Genetic disease
- is different in clinical group of diseases caused by mutations in single genes.
The number of currently known monogenic hereditary disease of more than 4,000 clinical
entities. These diseases occur with a frequency of 1: 500 to 1: 100,000 and less.
In one and the same variety of gene mutations occur. It is known that one and the same
nosological form may be caused by different mutations. For example, in cystic fibrosis gene
mutations described above in 1000, about 300 of which causes the clinical manifestations.
In more than 30 phenylalanine hydroxylase gene mutations cause the clinical manifestations
of phenylketonuria
Each gene can occur up to several tens or even hundreds of mutations that lead to disease.
Consequently, it is easy to count how many monogenic diseases might be in humans.
Actually mutational change primary protein structure often leads to cell death and the
mutation does not occur in hereditary disease. These proteins are called monoformnymi.
They provide the basic functions of cells, maintaining stability of the specific organization.
Features of inheritance of genetic diseases is determined by the laws of Mendel.
Mutations can occur in any of the genes resulting in impaired (changes) the structure of the
respective polypeptide chains of the protein molecules. As in the human body according to
rough estimates are more than 100,000 different proteins, it becomes clear the extreme
diversity of clinical manifestations of monogenic diseases. Depending on the function of the
protein will be changed biochemical changes in the body, leading to specific clinical picture
of hereditary disease. For example, mutations in genes that control the structure of the protein
- collagen, there is a generalized loss of connective tissue. Mutation of the gene that
determines the sequence of the amino acid phenylalanine - an enzyme hydrolyzing
phenylalanine, there is a disease known as phenylketonuria (PKU). When globin gene
mutation develops a picture of severe anemia (hemoglobin disorders).
Many mutations lead to the formation of the molecular forms of proteins pathogenic action
which is detected only in the interaction of the organism with the specific environmental
factors. This is the so-called ekzogenticheskie options. For example, individuals with
clinically manifested deficiency of glucose-6-fosfatgidrogenazy (G-6-PDG) erythrocytes
horsebean use in food or medicines sulfanilamidnymi oral treatment leads to develop
hemolytic crisis (intravascular erythrocytolysis).
It should be emphasized that the absence of contact with certain substances in carrier
"ekzogeneticheskih" mutant alleles did not occur pathological reactions or disease.
Start the pathogenesis of any genetic disease associated with a primary defect of the mutant
allele. It can manifest itself in the following ways: lack of protein synthesis, synthesis of an
abnormal protein in primary structure; quantify the excess protein synthesis, protein synthesis
quantitatively insufficient.
The fundamental pathogenesis of genetic diseases can be represented as follows: mutant
allele → → pathological primary product of the subsequent chain of biochemical reactions
cells → → → body organs.
Diseases of metabolic disorders of aminoacids
The role of amino acids for the human body and especially to the child's extremely high. It is
known that amino acids are the basic structural elements of the protein are used for hormone
synthesis, immune bodies serve as a source of energy.
Nitrogen metabolism involves the reaction of synthesis and breakdown of proteins, nucleic
acids, amino acids and nucleotides, as well as a number of other nitrogen-containing
compounds. A common feature of nitrogen metabolism in children - a positive nitrogen
balance nitrogen, which is a necessary condition for growth.
Nitrogen food as much as possible is used by the body for the growing plastic targets.
Disturbances in the metabolism of amino acids may represent a significant threat to the
normal functioning of the human body.
Genetically determined diseases associated with metabolic disorders of amino acids, deserve
special attention.
Phenylketonuria (PKU)
Phenylpyruvic mental retardation was opened in 1934, Felling. It is an inherited disorder of
amino acid metabolism caused by mutations in the gene for phenylalanine hydroxylase, liver
enzyme phenylalanine hydroxylation reaction was carried out, ie its conversion into tyrosine.
Mutations within this large gene of the human genome affect different parts of it and damage
the function of different enzyme.
Frequency prevalence of this disease varies from 1: 7000 to 1: 10000 and more people.
The disease is common in populations where the spread of kinship marriage. Heterozygotes
occur in populations with a frequency from 1: 50 to 1: 1000.
The disease is transmitted in an autosomal recessive manner.
Pathogenesis.
Phenylalanine is an essential amino acid for human growth and development and is found in
all protein foods. The pathogenesis of disease is the failure of the liver enzyme phenylalanine hydroxylase, which leads to disruption of the exchange of phenylalanine and
increasing by more than 10 times the concentration of toxic products of metabolism disorders
- phenylacetic, phenyllactic and phenylpyruvic acids, which have neurotoxic effects.
Increasing the concentration of phenylalanine, tyrosine and restricts the transport of
tryptophan across the blood-brain barrier. The accumulation of phenylalanine in the brain of
the patient and depresses the activity of enzymes involved in the synthesis tserebrozidsulfatov
that protects the brain from demyelination.
CLINIC.
The disease usually manifests in the first few months after birth, delayed mental and motor
development.
Clinical manifestations are very diverse. Often, these patients are diagnosed as cerebral palsy,
mental retardation. Early manifestations of the disease are regurgitation, vomiting, and
diarrhea.
Neurological symptoms appear later in the form of sleep disturbance, seizures, mental
retardation. Develops muscular hypo-or hypertension. Motor development is delayed.
Children start with late sitting and walking, there is an odor of sweat and urine -'' mouse''
smell. Of the skin marked decrease or absence of pigmentation, dermatitis, eczema,
photosensitivity. Hair and irises also lose pigmentation. Violations of the cranial nerves
manifest strabismus, nystagmus, loss of coordination of movement. In later years there is a
characteristic posture sick -'' tailor'' posture and gait peculiar. Patients are wide apart, legs
bent at the knees and hips, lowering his shoulders and head. When walking, make small steps
and swaying.
In photos 1 and 2 show the brother and sister of PKU patients. At the time of shooting
brother, 16 years old, my sister - 14 years old. Children born of consanguineous marriage
(cousin brother - sister). Two other children of the family - are healthy. Both children clinic
disease is similar. In patients with profound degree of mental retardation.
DIAGNOSIS
Mounted on the basis of clinical and biochemical data, molecular genetic studies.
Because of the clinical polymorphism of PKU should be excluded from each of the retarded
child.
Sample Felling is the most affordable and simple. 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.
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.
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. Limited to products containing a large amount of
phenylalanine, including breast milk, and animal milk. 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.
The need for protein is provided by protein hydrolysates or mixtures of amino acids, such as
"Gipofenat'''''' etc. Berlafen
After reduction of phenylalanine in the blood to normal gradually administered animal
proteins under the control of biochemical studies to a total daily phenylalanine intake should
not exceed 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 given content of phenylalanine in limited quantities.
PREVENTION.
In 1954 he has been proven that a diet low in phenylalanine prevents the development of
clinical symptoms in patients who were diagnosed at birth. On this basis, was developed and
implemented in the practice of public health is the first program of mass screening (ie,
screening) newborns for PKU. After this program, mass screening of newborns for PKU
quickly spread around the world, and currently about 10 million newborns are tested for PKU
annually. Mass screening for PKU give 7-10 - fold economic benefit compared to their life in
homes for the disabled.
The object of testing in the current programs of mass screening is newborn capillary blood
collected and dried in the form of spots on special paper chromatography.
The method of testing - often bacteriological test inhibitory Guthrie, at least - fluorometric
method for measuring the concentration of phenylalanine. If the screening test is estimated
as> 4 mg% phenylalanine in the newborn blood is taken and re-tested. Mass screening of
newborns provides secondary prevention of PKU, as it does not prevent the birth of sick
children, and only aims to correct the clinical consequences of genetic disease. Primary
prevention is possible using the methods of prenatal diagnosis in families with a sick child.
At subsequent pregnancy in a family is taken of the fetus biological material for research chorionic biopsy at 8-10 weeks of pregnancy.
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. 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. In patients with
worsening appetite, there are constant thirst, constipation, vomiting after eating and drinking,
or non-feeding. Reduced resistance to infections a child. Developing eye disease in the form
of conjunctivitis, convergent strabismus. In the cornea and conjunctiva of the degenerative
changes are observed due to the deposition of cystine crystals in them. Sometimes expressed
photophobia. Later, in patients with increased liver and spleen, there is frequent urination
with impaired renal function. One of the typical symptoms of the disease is a progressive
growth retardation up to severe forms of dwarfism. Then join rahitopodobnyh changes of the
skeletal system. However, many children die before deployed rahitopodobnyh changes from
hyperthermia, coma, collapse.
In a separate part of the skeletal system of children changes the contrary, it is the main sign of
the disease. 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.
DIAGNOSIS
Established on the basis of characteristic clinical picture, data, laboratory studies:
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.
TREATMENT
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. 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 gomogentezinovuyu. 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).
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
glyukoaminofosfat diabetes, which causes changes rahitopodobnyh bone: osteoporosis,
osteomalacia, bending bones, etc. In many cases, delayed mental development.
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 paragidroksifenil-pyruvic acid in the urine). The absence of
the enzyme can be installed in histochemically punctates liver.
Differential diagnosis of conduct with the syndrome de Toni-Debre-Fanconi, where there is
no significant liver damage and negative samples for biochemical tyrosinosis, with inherited
prenatal hepatitis, manifested in contrast to the tyrosinosis already at birth with galactosemia,
mainly on the basis of biochemical data .
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
Homogentisuria
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.
CLINIC.
The disease is clinically 3 symptoms: dark urine, pigmentation of cartilage and connective
tissue, arthropathy.
Urine having at normal urination numbers, for 12-24 hours in air darkens. In connection with
this disease is detected too late, although there is a birth. In infant colored urine found in the
diapers. It is more often from dark pink to red. As a child, this symptom is the only
manifestation of the disease. Blue-gray pigmentation (ochronosis) appears after 20-30 years
of age.
Differential diagnosis of conduct with the syndrome de Toni-Debre-Fanconi, where there is
no significant liver damage and negative samples for biochemical tyrosinosis, with inherited
prenatal hepatitis, manifested in contrast to the tyrosinosis already at birth with galactosemia,
mainly on the basis of biochemical data .
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
Homogentisuria (alkaptonyria)
The disease is known for more than 100 years. A urine of patients allocated gomogentenzin
acid, which is absent in normal. In liver and kidneys of patients no enzyme gomogentenzin
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.
CLINIC.
The disease is clinically 3 symptoms: dark urine, pigmentation of cartilage and connective
tissue, arthropathy.
Urine having at normal urination numbers, for 12-24 hours in air darkens. In connection with
this disease is detected too late, although there is a birth. In infant colored urine found in the
diapers. It is more often from dark pink to red. As a child, this symptom is the only
manifestation of the disease. Blue-gray pigmentation (ochronosis) appears after 20-30 years
of age. Most often it happens in the ear and the sclera, sometimes on the nose, back, neck and
arms. After 30-40 years of joint symptoms occur, determine the severity of the disease.
Developing ankylosing "rheumatism", which affects the spine often, less often large joints. It
is manifested paroxysmal pain and leads to disability. X-ray examination detects changes in
the intervertebral discs, osteophytes and calcification.
The disease does not shorten life expectancy.
The diagnosis is established when an gomogentenzinovoy acid in the urine. Her blackening
by adding a solution NaS03 quite specific to the disease. A reliable diagnosis is made after
chromatographic urine.
The differential diagnosis spend with porphyria, Argyros, melanoma.
Treatment mainly symptomatic.
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).
The disease is inherited in different ways 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 acids.
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, erythematous rash
and other symptoms 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 is sometimes found, hypo-or hypertonic muscles, cerebellar ataxia.
In some cases histidinemia combined with iron deficiency anemia, kidney disease, bone, etc.
DIAGNOSIS. Unfortunately diagnosis is only large, well-equipped laboratories, as requires
the application of modern biochemical techniques. For patients with a high concentration of
histidine in the biological fluids. Histidine excretion by the kidneys is increased. There was
an increase of histidine in the cerebrospinal fluid.
In connection with the possibility for histidine catabolism main path compensatory increases
its conversion to other metabolites. The result is 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.
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. After
the load level rises histidine even greater extent and reaches up to 300-400 mg / l in 1-3 hours
(N - 2 to 25 mg / l) and returns to the original level is not earlier than 5 hours. In healthy after
histidine load level reaches the specified value and returns to normal after 3-4 hours.
Differentiate histidinemia to PKU.
Treatment consists in assigning low-protein diet with a reduced content of histidine.
Prognosis of the disease depends on the genetic variants of the disease.
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 marfanopodobnymi syndromes. 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;
2) changes in the nervous system: loss of intelligence, it is depleted, dizlaliya, spastic gait,
episyndrome;
3) breach of view lens subluxation, secondary glaucoma, changes in the fundus;
4) of the cardiovascular system: a violation of metabolic processes in the myocardium, the
tendency to arterial and venous thrombosis;
5) The external features: light, soft, large curls curly hair, blue iris.
Homocystinuria genetically heterogeneous. In addition to classical, there are still two forms:
a deficiency of vitamin B6 and folic acid metabolic disorders.
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 (violation of connective
tissue metabolism). For more Marfan's disease is characterized by:
1) The mitral and aortic valves;
2) muscular dystrophy;
3) intelligence is not always reduced, episyndrome missing.
Treatment consists in the appointment of a diet enriched with cystine and methionine lacking.
The effect of treatment depends upon the destination therapy. We also obtain satisfactory
results from treatment with pyridoxine, which stimulates other pathways serosoderzheschih
amino acids. The therapeutic effect of vitamin B6 is associated with increased activity
tsistationin sintetazy.
Disorders of carbohydrate metabolism disorders
Carbohydrate ingested in the form of monosaccharides (glucose, fructose), disaccharides
(lactose, maltose, sucrose), and polysaccharides (glycogen, starch). During the first months of
life is a major carbohydrate food disaccharide lactose or milk sugar comprising glucose and
galactose. Lactose content of human milk is an average of 70 g / l, bovine - 48 g / l. The
centerpiece of the carbohydrate metabolism is glucose. Disaccharides and polysaccharides
are digested in the gastrointestinal tract to monosaccharides. Galactose is converted to
glucose in the liver and erythrocytes. Of key importance in this process is an enzyme galactose -1 - phosphate uridiltransferaza.
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.
The basis of the primary biochemical defect is galactosemia enzyme deficiency of galactose1-fosfaturidiltransferazy (HA-1-BOP), resulting in the tissues of the body accumulates excess
galactose-1-phosphate and other products of incomplete decomposition of lactose causing
clinical manifestations galactosemia.
In classic galactosemia type are still two possibilities: Duarte form of a 50% enzyme activity
and Negro type in which the enzyme activity is reduced only in certain cells (red cells,
fibroblasts).
CLINIC
Can be of varying severity. Most mild cases are found in families where there are patients
with galactosemia. These children early refuse the breast and can not tolerate milk.
In the most severe clinical signs are detected in the first days after birth. Body weight at birth,
usually contained large (over 4 kg).
In patients after breast-feeding is plentiful and there is persistent vomiting, diarrhea, weight
loss, jaundice, hepatomegaly increases, there bleeding and hemorrhages in the skin. Often
marked hypoglycemia, seizures, cataracts appear in the future, the signs of cirrhosis of the
liver, and the lag in the neuro-psychological and physical development.
DIAGNOSIS. The large number of phenocopies and complexity of biochemical methods of
diagnosis of galactosemia explain the fact that the disease is not always recognized in a
timely manner. Often children with galactosemia come to the clinic with a diagnosis of
sepsis, biliary cirrhosis, acute indigestion, prolonged neonatal jaundice etc. A number of
diseases of the newborn period has similarities with the clinical manifestations of
galactosemia, hemolytic disease of the newborn, congenital hepatitis, biliary atresia,
cytomegalovirus, toxoplasmosis congenital, hereditary hyperbilirubinemia (such as Crigler Najjar), etc. The need for difdiagnostiki can occur when a prolonged jaundice and preterm
infants. Establishing an accurate diagnosis of galactosemia requires complex diagnostic
procedures. Detection of galactose in the urine of a newborn child is the basis for his
diligence for galactosemia. The most reliable diagnostic methods include determining the
concentration of blood galactose by chromatography paper, direct determination of the
activity of the enzyme galactose-1-phosphate - uridiltransferazy (HA-1-BOP) in erythrocytes
and galactose determination in urine. In addition to the diagnosis may help correct the
assembled family history.
TREATMENT. From the first days of life, the child should be transferred to a dairy-free diet.
As milk substitutes can be used a mixture prepared by almond and soy milk.
Dextrinosis
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.
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. Hepatic form
2. Muscular form
3. Generalized form
Hepatic form
The symptoms usually appear during the first year of life, although the child's development in
this period is going well or somewhat slower. Starting with 8-9 months of life, 1 every 2
months or more frequent episodes of hypoglycemia (loss of consciousness, clonic spasms of
limbs). Seizures begin before a meal or early in the morning, their appearance can be
prevented reception of sweet water.
Appearance of patients: small stature, big belly, disproportionately thin limbs, "doll face."
The liver is enlarged. The most difficult disease occurs between the ages of 4-5 years.
Intercurrent disease heavier during the main pathological process.
With age, the condition of patients can be improved, which can be explained by the
development of compensatory mechanisms for the exchange. Intelligence is usually not
disturbed.
Muscular form
The main symptoms of this form of the disease occur from 7 - 10 years. Patients become
inactive, tired quickly during physical exertion. In the future, muscle weakness progresses.
Aching muscles after intensive prolonged exercise, there is tachycardia, shortness of breath.
These symptoms generally appear for 25-35 years. Appearance patients usually does not
change. The boundaries of the heart usually expand. Of the liver and kidney marked changes
do not happen.
Prognosis mostly favorable, although known deaths in the age of 25-30 years.
Generalized form
This form of glycogen storage disease characterized by the fact that in almost all organs and
tissues of the patient collects a significant amount of glycogen.
The clinical picture of this form is not like the picture of the liver and muscle forms. This
form includes biochemical types of glycogen storage disease type III and IY (diseases and
Corey Anderson).
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.
DISEASE Gierke (I type)
Clinical illness caused by the absence of a specific enzyme activity of glucose-6-phosphatase
activity in the intestinal mucosa and liver, and in some cases and in the kidneys. The clinical
picture of the disease mainly causes the metabolism of glycogen in the liver. Clinical disease
is very similar to the shape of the hepatic disease, which has been described above. In the
neonatal period are the cardinal symptoms of hypoglycemic seizures, and hepatomegaly.
Stunting starts celebrated from the 1st year of life. Characterized by the appearance of
patients: big head, "doll face", a short neck, a big belly. A feature of this type of glycogen
storage disease is that in children aged 5-7 years are hemorrhagic rash, and frequent
nosebleeds. In 10% of cases there is xanthelasmatosis.
The disease is inherited in an autosomal recessive manner.
Pompe disease (II type)
The disease caused by the absence of the enzyme - acidic alpha - glucosidase or gamma amylase in liver and muscle, which leads to destructive changes in tissue and primarily
intensive muscle such as the heart muscle.
The disease usually manifests itself in the first year of life as a complex sipmtomo heart
failure. Shortly after the birth of a child develops anxiety, there is increasing cyanosis,
respiratory distress. On examination found "globular" heart, hepatomegaly, mild muscle
hypertrophy, macroglossia. Unlike glycogenosis type I not marked hypoglycemia and
acidosis. Sick children are killed at 1 year of age.
In the mild form of Pompe disease is absent activity of alpha-glucosidase only in the muscles.
In these cases, the disease usually appears later in life and on the clinical picture is similar to
the myopathy. The prognosis of this form is different, possibly fatal.
Treatment of glycogen storage is not enough developed. The use of adrenaline,
hydrocortisone able to increase the rate of sugar in the blood due to the breakdown of
glycogen was ineffective. Some authors recommend the use of small doses of glucagon and
tireoidina. The importance placed on diet, which is an increase in carbohydrate intake of
patients and in quickening the meal.
FRUKTOZEMIYA
The cause of the disease is a deficiency of the enzyme fructose - I-mono-phosphate aldolase
in the liver, kidneys, mucous membrane, as well as decreased activity of fructose-1 ,6difosfataldolazy. Changes in any of the enzyme affects the other. Deficiency of these
enzymes leads to the accumulation of blood and tissue fructose and fructose-I-phosphate,
having a toxic effect, and determining the disease symptoms. The most severe pathological
changes occur in the liver: cirrhosis, steatosis, necrosis of the cells.
The frequency of the disease-1:130000 population.
The disease is inherited in an autosomal recessive manner.
CLINIC. The disease manifests itself in a period when infants give fruit juices, sugar or early
transfer of children to mixed and artificial feeding. In children, there is persistent anorexia,
vomiting, malnutrition, hepatomegaly and jaundice have been observed in severe disease. In
benign form of early childhood observed only gastro-intestinal disorders and difficulty in
feeding. Children refuse foods containing glucose. With age, the patients begin easier to carry
small amounts of foods containing fructose. By increasing the amount of fructose in the diet
of patients with the condition worsens because of hypoglycemia and giperfruktozemii.
Disorders of lipid metabolism disorders
The role of lipids in the life of the human large.
It is known that at different stages of ontogeny lipid metabolism has its own characteristics.
In young children for normal processes of growth and development is very strong demand for
plastic materials and energy. Thus, the younger organism, the above need. In this regard,
important in lipid metabolism belongs quality food composition.
One of the features of the body of the young child is prone to ketosis, ie tissue accumulation
of ketone bodies.
Lipid disorders are a frequent companion of pathological processes in children. In its genesis,
they can be divided into 2 groups:
Hereditary and acquired diseases.
Hereditary defects in lipid metabolism are divided into 2 groups:
1). Lipidoses or sfingolipidozy - diseases violation katobolizma structural lipids, leading to
accumulation of sphingolipids in the cells of various tissues;
2). Diseases caused by metabolic disorders of lipids contained in the blood.
Allocate about 10 sfingolipidozov for which clarified the biochemical defect. Most of these
forms have a similar clinical picture due to violation of katobolizma different but structurally
related sphingolipids. The clinical picture is characterized by progressive dementia,
movement disorders, bone disease, internal organs (liver, spleen, kidney), skin and eyes.
The value of lipoproteins in the body is to transport and allocation of organs cholesterol and
triglycerides. Lipoprotein metabolism is not only controlled by genetic factors, but also
depends largely on the nature of the food. Therefore, disorders of lipid metabolism of blood
plasma are a complex group of states, of which only in recent years have been due to isolate
monogenic forms. Hyperlipidemia is an important factor in the development of
atherosclerosis and coronary heart disease. For most forms of hyperlipidemia is characterized
previously (aged 15-20 years) development of the atherosclerotic process with the clinical
picture of angina pectoris, myocardial infarction, xanthelasmatosis. Most hyperlipidemia is
inherited in an autosomal recessive manner.
Clinical symptoms and biochemical changes characteristic of hyperlipidemia, highly variable
and may be changed under the influence of a change of diet and other factors. Therefore, the
diagnosis can be made on the basis of the whole complex of clinical symptoms, the history
and laboratory findings.
Inherited disorders of lipid metabolism have attracted the attention of researchers in that they
cause the development of atherosclerosis and other forms of cardiovascular disease.
According to statistics, coronary heart disease (CHD) is one of the first places in the structure
of morbidity and mortality. A clear relationship between hyperlipidemia and increased risk of
coronary heart disease has been repeatedly confirmed by various researchers.
The degree of risk is determined based on the level of cholesterol in blood. The incidence of
this disease in the population is quite high - from 7 to 28%.
Amavrotiches idiocy ( Tay - Sachs disease)
Amavrotiches idiocy Tay - Sachs disease occurs predominantly among Ashkenazi Jews.
The incidence is 1: 6000 among Ashkenazi Jews and 1: 500,000, among other nationalities.
The frequency of heterozygous carriers of the recessive gene among Ashkenazi Jews is 1: 40,
among other nationalities - 1: 380. 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.
CLINIC. The disease begins to manifest itself in the age of 4-6 months. A child who was
previously active, and gradually loses interest in the outside world, no longer laugh, to play,
to learn the parents. Sooner found decreased vision. The child can not stare. In the fundus
revealed a symptom of "cherry pit." In the subsequent atrophy of the optic nerve and
blindness. In children, there is a decrease of intelligence to the level of idiocy. Movement
disorders lead to total immobility. Children startled by the sharp sound may experience
seizures. In the final stage of the disease develop cachexia and the state of decerebrate
rigidity. Death occurs within an average of 1.5 - 2 years after the onset of the disease.
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 an
enzyme sfingomielinidazy. Enzyme unit leads to the accumulation of sphingomyelin in
tissues. When this sphingomyelin and cholesterol accumulates in almost 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.
CLINIC. The disease begins to manifest itself in the first months after the birth of dyspeptic
disorders, deterioration of general condition, copious sweat, weight loss, frequent pulmonary
complications. The disease is characterized by brownish or greyish-yellowish pigmentation
of the skin and mucous membranes. On the tongue and gums are often observed inky blue
spots. Syndrome is the leading hepatosplenomegaly. Often marked by generalized
lymphadenopathy, osteoporosis.
Neurological syndrome characterized by muscular hypertension and disappearance of
physical activity. Mental degradation occurs gradually, reaching a total idiot. In the fundus
there is a bright red spot, characteristic amavroticheskoy idiocy Tay-Sachs disease. Hearing
gradually weakened to a full hearing. The disease progresses continuously and ends in death
within a few years.
Diagnosis is based on clinical presentation and on the detection of decreased activity of the
enzyme sfingomielinidazy punctates in the liver and kidneys.
Gaucher disease
Clinical picture. Known 3 clinical forms of the disease, different start time and the
prevalence of a symptom. 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.
Moderately enlarged liver. Bone changes are manifested as pain, deformities, pathologic
fractures. There are muscle rigidity, incoordination, convulsions. The disease progresses
slowly. In the terminal stages of severe neurological symptoms appear. Survival to 20-30
years of age and die of cachexia, hemorrhage.
Inheritance - autosomal recessive.
Diagnosis is based on clinical presentation, detection of metabolic defect caused by the lack
of the enzyme glucosidase.
Recommended reading:
1. NP Bochkov, AF Zakharov, VI Ivanov, "Medical Genetics", M - 1984
2. KN Nishonboev, F.A-Khamrayeva, O.E-Eshonkulov "TIBBIYOT genetikasi" Tashkent 2000
3. NP Bochkov, "Clinical Genetics", M - 1997
4. SI Kozlov et al, "Hereditary syndromes and medical genetic counseling ', M - 1987
5. RM Cohn, KS Roth, "Early diagnosis of metabolic diseases," M 19971.
6. VN Gorbunov, V. Baranov, "Introduction to molecular diagnostics and gene therapy of
inherited diseases", St. Petersburg, 1997