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Genetic Diseases.

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Presentation on theme: "Genetic Diseases."— Presentation transcript:

1 Genetic Diseases

2 All human diseases can be divided into three categories:
- genetically determined - environmentally determined - combination of both (both genetic and environmental factors play a role) Rapid and continuing progress in molecular research have revealed genetic component in many so-called environmental diseases (e.g. susceptibility to bacterial infections or immune response to them can be influenced by genetic factors) Commonly used adjectives - hereditary = derived from one´s parent - familial = transmitted through generations and affecting several members of a family - congenital = present at birth not all genetic disorders are congenital (Huntington disease: 3rd-4th decade) not all congenital diseases are of genetic origin (congenital syphylis, toxoplasmosis)

3 Major categories of genetic diseases
Mendelian disorders single-gene mutation of large effect - uncommon conditions (storage diseases, inborn errors of metabolism) - usually hereditary and familial Diseases with multifactorial (polygenic) inheritance - defects of multiple genes with small effect + environmental influences - some very common diseases (arterial hypertension, diabetes mellitus) Cytogenetic disorders - numeric or structural abnormalities of chromosomes

4 Mendelian disorders more than 5,000 disorders, many of them rare
although individually rare, together they account for 1% of adult hospital admissions and 6-8% of pediatric hospital admissions Patterns of inheritance - autosomal dominant - autosomal recessive - X-linked codominance: both alleles of a gene pair fully expressed in the heterozygote (e.g. blood group antigens) polymorphism: presence of many allelic forms of a single gene pleiotropy: single-gene mutation may lead to many phenotypic effects, e.g. Marfan syndrome: widespread effects affecting skeleton, eye and cardiovascular system genetic heterogeneity: several different types of mutation can cause the same phenotypic effect, e.g. retinitis pigmentosa (abnormal retinal pigmentation leading to visual impairment) can be caused by several different mutations

5 Autosomal dominant disorders
- manifested in heterozygous state (only one allele mutant) - at least one parent is affected - new mutation: both parents of affected person are healthy - when affected person marries unafected one → every child 50% chance of having the disease - both males and females can be affected - both males and females can transmit the disease clinical symptoms: 50% reduction in normal gene product - structure proteins and receptors involved - enzyme proteins usually not affected (50% loss of enzyme activity can be compensated for) clinical presentation can be modified by: reduced penetrance: some persons carrying mutant gene are phenotypically normal variable expressivity: all persons carrying mutant gene affected but in different extent among them, e.g. NF1 (from brownish skin pigmentations to multiple tumors and skeletal deformities)

6 Common autosomal dominant disorders
Nervous Huntington disease neurofibromatosis 1 and 2 myotonic dystrophy tuberous sclerosis Urinary polycystic kidney disease (adult type) Hematopoietic hereditary spherocytosis von Willebrand disease GIT familial polyposis coli Skeletal Marfan syndrom Ehlers-Danlos syndrome (some variants) osteogenesis imperfecta achondroplasia Metabolic familial hypercholesterolemia

7 Marfan syndrome - abnormality of fibrillin 1 (glycoprotein component of elastic fibers) - encoded by FBN1 gene (15q21), more than 500 mutations found - prevalence 1 in 20,000 - 75% cases familial - connective tissue throughout the body affected principal clinical manifestations related to skeleton, eye and cardiovascular system Skeletal abnormalities (overgrowth of bones) - slender and elongated habitus, dolichostenomelia (abnormally long legs and arms), arachnodactyly (abnormally long fingers) - high-arched (gothic) palate - hyperextensibility of joints - spinal deformities (kyphoscoliosis) - chest deformity (depressed sternum - pectus excavatum, pigeon breast)

8 Ocular changes - bilateral dislocation of lens (weakness of its suspensory apparatus; ciliary zonules are made up exclusively of fibrilin) Abnormalities of cardiovascular system - most serious - fragmentation of elastic fibers of tunica media - aneurysmal dilation of aorta → rupture (most common cause of death) - aortic dissection - dilation of aortic valve ring (loss of medial support) → aortic incompetence → congestive heart failure - myxoid degeneration of mitral valve → floppy valve syndrome (mitral valve is excessively distensible and regurgitant) → congestive heart failure

9 Ehlers-Danlos syndromes
- defects of collagen synthesis or structure - 30 collagen types encoded by different genes 6 variants of E-D syndromes (mutations in different collagen genes) Molecular bases of E-D sy - deficient synthesis of type III collagen (mutation of COL3A1 gene) - defective conversion of procollagen type I to collagen (mutation of COL1A1 and COL1A2 genes) - deficiency of enzyme lysyl hydroxylase (impairment of cross-links among collagen molecules) – autosomal recessive disorder Clinical manifestation (common to all variants): - extremely stretchable and fragile skin - hypermobile joints (grotesque contortions, e.g. bending the thumb backwards to touch the forearm) - impaired wound healing - ruptures of bowel and large arteries diaphragmatic hernia - ocular fragility (rupture of the cornea, retinal detachment)

10 Familial hypercholesterolemia
- quite common (prevalence 1 in 500) - mutations in LDL receptor gene (19p), more than 900 different mutations - impaired catabolism of LDL → accumulation of LDL in plasma - increased cholesterol traffic into macrophages and vascular walls via scavenger receptors → accelerated development of atherosclerosis, multiple xanthomas (accumulation of foamy macrophages in the skin and along tendon sheats) - heterozygotes: 2-3fold elevation of LDL - homozygotes: 5fold elevation of LDL (myocardial infarction before the age of 20)

11 Neurofibromatoses Neurofibromatosis 1 (von Recklinghausen’s disease)
- mutation of neurofibromin gene (17q) - quite frequent (1 in 3,500) - multiple neurofibromas, skin pigmentations (cafe-au- lait spots), iris hamartomas (Lisch nodules – brownish spots) Neurofibromatosis 2 - mutation of merlin gene (22q) - much less frequent (1 in 25,000) - bilateral acoustic schwannomas (deafness), multiple meningiomas, skin pigmentations (cafe-au- lait spots)

12 Huntington disease - degeneration of the striatum (caudate nucleus and putamen) - mutation (trinucleotide CAG repeat expansion) of the gene for huntingtin (large protein) on 4p16.3 - striking atrophy of the caudate nucleus (severe loss of neurons, fibrillary gliosis) - onset of clinical symptoms usually in the 4th decade of life (the larger the number of CAG copies, the earlier the onset of the disease) - progressive movement disorder (jerky, hyperkinetic movements) and dementia - death after a course of about 15 years

13 Adult polycystic kidney disease
- quite frequent (1 in 500 to 1000 persons), 10% cases of chronic renal failure % mutation of PKD1 gene (chromosome 16p) encoding polycystin-1 % mutation of PKD2 gene (chromosome 4) encoding polycystin-2 - polycystin-1 and 2 form heterodimers and they acts together: the same phenotype in both mutations - pathogenesis unclear, but probably defect of polycystin-1 → alteration of proliferation, adhesion and matrix production of tubular epithelial cells → formation of cysts - cases with mutation of polycystin-2: slower rate of disease progression - cysts develop early, but the onset of symptoms in the 4th decade - flank pain, arterial hypertension, renal failure at the age of 50 - berry aneurysm of brain arteries (10-30%) → high incidence of subarachnoid hemorrhage - very large kidneys (up to 4 kg each), multiple cysts (up to 4 cm) with nearly no intervening parenchyma

14 Familial adenomatous polyposis (FAP)
- mutation of APC gene on chromosome 5q21 (tumor suppressor gene) - 500 to 2500 colonictubular adenomas (minimum number of 100 requred for diagnosis), multiple adenomas elsewhere in the alimentary tract - onset usually in adolescence or early adulthood - 100% risk of colonic adenocarcinoma by midlife (prophylactic colectomy)

15 Osteogenesis imperfecta („brittle bone disease“)
- gene mutations in the coding sequence for α1 and α2 chains of type I collagen → defective synthesis of type I collagen - 4 subtypes with broad range of clinical picture - extreme skeletal fragility, multiple fractures - blue sclerae (higher transparency due to decreased collagen content) - hearing loss (conduction defect due to involvement of middle ear bones) - small misshapen teeth (dentin deficiency) Achondroplasia - mutation of gene encoding FGFR3 (fibroblast growth factor receptor 3) → activation of FGFR3 → inhibition of chondrocyte proliferation - disorganized and hypoplastic epiphyseal growth plates → dwarfism, marked disproportionate shortening of proximal extremities, bowing of legs

16 Autosomal recessive disorders
- largest group of mendelian disorders - both of the alleles at a given gene must be mutant (homozygot) - parents: usually not affected (heterozygotes, carriers) - child: 25% chance to be affected (homozygot) Differences in contrast to autosomal dominant disorders: - more uniform expression (all persons affected in the same extent) - common complete penetrance (all homozygotes carrying mutant gene affected) - onset frequently early in life - metabolic disorders - enzymopathies - hematopoietic disorders - thalassemias, sickle cell anemia

17 Cystic fibrosis (mucoviscidosis)
- very common autosomal recessive disorder in whites (frequency 1 in 3200), rare in Asians (1 in 31,000) and Afroamericans (1 in 15,000) - high carrier frequency (1 in 25-30) - mutation at CFTR gene (cystic fibrosis transmembrane conductance regulator) chromosome 7p31.2, more than 800 mutations known („mild“ and „severe“), most common mutation δF508 („severe“, 70% patients) Pathogenesis - defective transport of chloride across epithelium Sweat glands: - decreased reabsorption of chloride and sodium → hypertonic sweat Respiratory and intestinal epithelium: - reduction or loss of chloride secretion into the lumen, increased luminal sodium absorption → increased passive water reabsorption → dehydrated, viscid mucus

18 Pathology - many organs involved Pancreas (85-90% of patients) - plugging of ducts by viscid mucus → atrophy of exocrine pancreas, progressive fibrosis - Langerhans islets spared - fibrocystic changes Small intestine (infants) obstruction of small bowel by thick mucus plugs → meconium ileus Lungs - most serious complication - obstruction of bronchioles by thick viscid mucus → dilation and secondary infection → chronic bronchitis, bronchiectasis, lung abscess - common infective agents: Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, Burkholderia cepacia (very severe course) Liver - plugging of bile canaliculi by thick mucus → secondary biliary cirrhosis Male reproductive tracts - azoospermia and infertility (95%)

19 Clinical presentation
- extremely variable, symptoms range from mild to severe, various involvement of individual organs - meconium ileus (5-10%, at birth or soon after) → bowel rupture, peritonitis - exocrine pancreatic insufficiency → malabsorption of protein and fat: large stools, poor weight gain, hypoproteinemia, avitaminosis ADEK cardiopulmonary complications: chronic cough, persistent lung infection, obstructive lung disease → cor pulmonale (most common cause of death) Diagnosis - elevated chloride and sodium concentrations in sweat (iontophoresis) - mother’s diagnosis („salty child“) - gold standard: sequencing of CFTR gene Treatment - symptomatic life expectancy: 30 years (continues to increase) - clinical trials with gene therapy still in early stages

20 Phenylketonuria (PKU)
- frequency 1 in 12,000 live births Classic PKU (most common form) - quite common in Scandinavians - mutation of gene (12q), 400 mutant alleles have been identified - lack of phenylalanine hydroxylase → hyperphenylalaninemia and phenylketonuria (inability to convert phenylalanine into tyrosine) - homozygotes normal at birth, high plasma phenylalanine levels → impaired brain development → severe mental retardation at age of 6 months - decreased pigmentation of skin and hair (lack of phenylalanine hydroxylase → lack of thyrosine – melanin precursor) - mousy odor (presence of intermediate metabolites of phenylalanin within sweat and urine) - hyperphenylalaninemia can be avoided by phenylalanin-free diet early in life: routine screening (Guthrie test) just after birth

21 PKU variants Maternal PKU - female PKU patients treated with diet discontinued after reaching adult life  hyperphenylalaninemia  transplacental transport  child: severe mental defect and multiple congenital malformations (although heterozygous – teratogenic effect of phenylalanine) - phenylalanine-free diet before conception Benign hyperphenylalaninemia - partial deficiency of phenylalanine hydroxylase - clinical features of PKU absent Deficiency of dihydropteridine reductase (DHPR) - 2-3% of all cases - clinical importance: cannot be treated by phenylalanine-free diet

22 Galactosemia - disorder of galactose metabolism, 1 in 30,000
- lactose (milk) cleaved into glucose + galactose - galactose converted into glucose (galactose-1-phosphate-uridyltranferase required) - lack of galactose-1-phosphate-uridyltranferase (gene 9p) → accumulation of galactose-1-phosphate and galactitol (liver, spleen, lens, kidney, cerebral cortex) - vomiting and diarrhea after milk ingestion - liver: jaundice and hepatomegaly (steatosis, later cirrhosis) - lens: cataract (opacification) - brain: loss of neurons, gliosis, edema → neurologic deficits, mental retardation - changes prevented by galactose-free diet

23 Wilson disease (hepatolenticular degeneration)
- disorder of copper metabolism, rare (1 in 30,000) - mutation of gene ATP7B (chromosome 13) encoding ATPase metal ion transporter (hepatocytes) - impaired incorporation of copper into ceruloplasmin → diminished biliary excretion → progressive accumulation of copper Sites of copper accumulation: - liver: fatty change, acute or chronic hepatitis, cirrhosis - brain: basal ganglia (neurologic an psychiatric symptoms) - eye: green brown deposits in corneal limbus (Kayser-Fleischer ring) Diagnosis: chemical detection of copper within liver tissue (more than 250μg/g dry weight)

24 Glycogen storage diseases (glycogenoses)
- disordered glycogen synthesis or degradation (enzyme deficiency) → accumulation of glycogen or its abnormal forms within cytoplasm or nuclei (pale color, PAS +, Best´s carmine +) 12 forms described (classified according to lacking enzyme) Glycogenosis I (von Gierke disease) - lack of glucose-6-phosphatase - hepatomegaly (glycogen accumulation) - hypoglycemia (failure to produce glucosis) Glycogenosis II (Pompe disease) - lack of acid maltase (lysosomal enzyme) - glycogen deposition in virtually every organ - cardiomegaly most prominent Glycogenosis V (McArdle disease) - lack of phosphorylase - decreased glycolysis → glycogen storage in muscles, muscle weakness (impaired energy production) - muscle cramps during exercise, myoglobinuria

25 Lysosomal storage diseases
- lysosomes: variety of hydrolytic enzymes, cleavage of complex substrates (sphingolipids, mucopolysaccharides) into soluble end products - lack of lysosomal enzymes → incomplete catabolism of sphingolipids and mucopolysaccharides → accumulation of intermediate insoluble metabolites within lysosomes - approximately 40 diseases, most of them very rare

26 Tay-Sachs disease (GM2 gangliosidosis)
- lack of α-subunit of hexosaminidase A - most common among Ashkenazi Jews - CNS: storage of GM2 ganglioside within neurons and glial cells → swollen foamy appearance - retina and peripheral nerves involved as well - clinical presentation: mental retardation, blindness, severe neurologic deficits death within 2-3 years Niemann-Pick disease - lack of acid sphingomyelinase → accumulation of sphingomyelin - macrophages and neurons → fine foamy vacuolation of cytoplasm - most severely affected organs: spleen, liver, bone marrow, lymph nodes, CNS - severe visceromegaly (especially spleen) and neurologic deterioration - death within first 3 years of life

27 Gaucher disease - lack of glucocerebrosidase → accumulation of glucocerebroside within macrophages - macrophages → Gaucher cells: abundant pale cytoplasm with „wrinkled tissue paper“ appearance - commonly affected organs: spleen (red pulp), liver (sinuses), bone marrow Type I (chronic nonneuronopathic form, 99%) - hepatosplenomegaly - bone involvement (osteopenia, osteolytic defects, osteonecrosis) - absence of CNS involvement - compatible with long life Type II and III - neurologic disturbances dominate, liver and spleen affected as well - type II: early onset (within 2 years), lethal - type III: symptoms appear later and are milder

28 Mucopolysaccharidoses
- defective degradation of mucopolysaccharides → storage in various tissues - progressive involvement of many organs (liver, spleen, heart, blood vessels) - coarse facial features (gargoylism), clouding of cornea, mental retardation - 7 variants

29 X-linked disorders - overwhelming majority X-linked recessive
- transmitted by heterozygous mothers only to sons (50% affected, 50% healthy) - daughters can be only carriers (50% carriers, 50% healthy) - children of diseased father: sons are healthy, all daughters are carriers - hemophilias A and B, Duchenne muscular dystrophy - very rare X-linked dominant - transmission to 50% sons and daughters of affected heterozygous female - all daugters of affected male are diseased, all sons are healthy - vitamin D - resistant rickets

30 Hemophilia B (Christmas disease)
Hemophilia A - decrease in factor VIII activity - frequency: 1 in 10,000 - 30% of patients: new mutations (no family history) - males, very rarely heterozygous females (inactivation of normal X chromosome in most cells) - varying degree of F VIII deficiency (many different mutations) - less than 1% of normal F VIII activity → symptoms - easy bruising, massive hemorrhage after trauma or operation - spontaneous bleeding into joints → joint deformities Hemophilia B (Christmas disease) - deficiency of factor IX - frequency: 1 in 50,000 clinically indistinguishable from hemophilia A Duchenne muscular dystrophy - absence of dystrophin - frequency: 1 in 3,500 - skeletal muscle and myocardium - impaired contractile activity → muscle weakness

31 Disorders with multifactorial (polygenic) inheritance
- additive effect of two or more genes of small effect conditioned by environmental (nongenetic) influences - treshold effect (certain minimal number of effector genes as well as environmental influences must be involved) - severity of disease is proportional to number and degree of influence of pathologic genes - higher risk of multifactorial disorder in first-degree relatives (reason for taking family history) - some physiologic characteristics (weight, height, hair color) - examples of diseases: - diabetes mellitus type II - essential systemic hypertesion - gout - schizophrenia, bipolar disorder -congenital heart defects - neoplasms (breast, ovary, colon)

32 Cytogenetic disorders
- alternations in the number or structure of chromosomes - both autosomes and sex chromosomes - cytogenetic disorders relatively frequent - 1 in 200 newborns - 50% of spontaneous first-trimester abortions - de novo changes in most cases (parents are normal)

33 Numeric abnormalities
Euploidy (normal chromosomal count): 46 (2n) Polyploidy (3n or 4n): spontaneous abortion Aneuploidy (not exact multiple of n) - trisomy (an extra chromosome 2n+1=47): compatible with life - monosomy (one less chromosome 2n-1=45): - autosomal monosomy: incompatible with life - sex chromosomal monosomy: compatible with life

34 Structural abnormalities
- usually result from chromosomal breakage → loss or rearrangement Translocation (one part of chromosome is transferred to another) - ballanced reciprocal: entire broken fragments exchanged centric fusion type (robertsonian): breaks close to centromere → very large chromosome and short one (lost) → 45 chromosomes Deletion: loss of a portion of chromosome Inversion: two breaks and subsequent reunion after turnaround

35 Down syndrome - trisomy 21 (47)
- most common chromosomal disorder (1 in 700 births) - incidence strongly influenced by maternal age - younger than 20 years: 1 in 1,550 - older than 45 years: 1 in 25 Clinical manifestation - flat facial profile, epicanthic folds, simian crease on palms - mental retardation (IQ 25 to 50) - congenital malformations (cardiac malformations in 40%) - increased susceptibility to infections (not understood) - increased risk of developing acute leukemias - Alzheimer disease (dementia) in middle age - median age at death: 47years

36 Edwards syndrome Patau syndrome - trisomy 18 - 1 in 8,000 births
- prominent occiput, micrognathia, low set ears, overlapping fingers, rocker-bottom feet - mental retardation congenital heart defects, renal maformations Patau syndrome - trisomy 13 - 1 in 15,000 births - microcephaly, microphthalmia, cleft lip and palate, polydactyly, rocker-bottom feet - congenital cardiac and renal defects

37 Sex chromosomal disorders
Special features of sex chromosomes: - females: only one X chromosome genetically active (lyonisation) → number of karyotypes ranging from 45(X0) to 49 (XXXXY) compatible with life (all but one X chromosome inactivated) - Y chromosome carries small amount of genetic information → two or three Y chromosomes in phenotypically normal males

38 Klinefelter syndrome - at least two X chromosomes and one or more Y chromosomes (47, XXY) - 1 in 1,000 - risk factors: advanced maternal age, history of irradiation of either parent - male hypogonadism (most common cause) - testicular atrophy → decreased serum testosterone levels, sterility - elongated body, eunuchoid habitus - reduced facial, body and pubic hair - gynecomastia - mild (sometimes undetectable) mental retadation - greater risk of developing breast cancer and SLE

39 Turner syndrome - monosomy of short arm or the whole X chromosome (45, X) - 1 in 3,000 female births - female hypogonadism (severe ovarian atrophy → primary amenorrhea) - growth retardation (short stature) - shield-like chest, widely spaced nipples - distended lymphatic channels of neck (cystic hygroma) → webbing of the neck in older age - adolescence: infantile breasts and outer genitalia, little pubic hair - congenital malformations: - bicuspid aortic valve, coarctation of aorta - horseshoe kidney - autoimmune hypothyreoidism - mental status usually normal

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