Download Lecture 2

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!