connective tissue disorders by dr ashok kumar j
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Disorders of connective tissueTRANSCRIPT
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 1
Connective tissue disorders
Dr. Ashok Kumar J. International School of Medicine
Management and science universityMalaysia
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 2
OBJECTIVES : To learn …….
• What is a connective tissue? • Importance of connective tissue• Briefly about the composition of connective tissue• Disorders related to collagen and elastin synthesis and function• Scurvy and lathyrism• Important connective tissue disorders related to autoimmunity
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 3
Space between organs and tissues filled with connective tissueComposed of network of insoluble tough protein fibers1. Collagen (Glycoprotein ) 3. Fibrillin2. Elastin (Non glycoprotein )
embedded in a matrix of proteoglycans (ground substance), mainly secreted by fibroblasts
Connective Tissue
Connective tissue proteins and proteoglycans are synthesized by connective tissue cells
- Fibroblasts- Chondroblasts- Osteoblasts
Adipose tissue is a special form of connective tissue
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 4
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 5
• The unique property of each connective tissue
e.g:
Flexibility of skin
Rigidity of bone
Elasticity of large arteries
Strength of tendons
Depends upon the composition and organization of collagen and other matrix components
- Bind tissues together - Provide support to the organs and other structures
of the body
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 6
Collagen
tough and have high tensile strength
Component of Skin; Connective tissue; Blood vessel
walls Sclera of the cornea of eye
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 7
• Without collagen, a human being would be reduced to a clump of cells
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 8
Composed of three chains that form a trimer in the shape of a triple helix
polypeptide is characterized by a repeating sequence in
which glycine is in every third position (Gly-X-Y)
Prolyl residues in the Y-position are characteristically hydroxylated to produce hydroxyproline, which serves to stabilize the triple helix
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 9
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 10
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 11
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 12
• Inter and intrachain crosslinking by- non covalent bond hydrogen bond - covalent linkage involving the lysyl and
hydroxylysyl stabilize collagen
Hydroxylation necessary for crosslinking ;Cross-linking is one of the factor responsible for tensile strength of the collagen
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 13
allysine allysine
Aldol Cross link
Lysine residues
Aldehyde derivative
Lysyl oxidase O2
e
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Defects in any one of the many steps in
collagen fiber synthesis or change in aminoacid
sequence
Inability of collagen to form fibers properly
Not provide tissues with the needed tensile strength normally
provided by collagen
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 15
Ehlers-Danlos syndrome (EDS):
Heterogeneous group of generalized connective tissue disorders
Result from inheritable defects in the metabolism of fibrillar collagen
molecules
Can result from a deficiency of collagen-processing enzymes
Lysyl hydroxylase deficiency procollagen peptidase deficiencyChange in the amino acid sequences of collagen
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 16
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 17
hypermobile and lax joints (Hyperextensible joints)
Stretchy skin of Ehlers-Danlos syndrome
Defects in collagen type I fibrilsResults in fragile, stretchy skin and loose joints
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 18
• Velvety skin• Rubber man syndrome;
• Mitral valve prolapse
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Osteogenesis imperfecta (OI):
• Disease known as “brittle bone syndrome”• Heterogeneous group of inherited disorders• Distinguished by bones that easily bend and fracture• Retarded wound healing• Rotated and twisted spine leading to a “humped-back”
appearance
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 20
Type I osteogenesis imperfecta
• Type I is called osteogenesis imperfecta tarda • Decreased production of α1 and α2 chains• Presents in early infancy with fractures secondary to minor trauma• May be suspected if prenatal ultrasound detects bowing or fractures
of long bones
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 21
Type II osteogenesis imperfecta
• Type II is called osteogenesis imperfecta congenita• More severe form• Patients die of pulmonary hypoplasia in utero or during the neonatal
period• Most patients with severe “OI” have mutations in the gene coding for
pro-α of type I collagen• Most common mutations cause the replacement of glycine residues (in
-Gly–X–Y–) by amino acids with bulky side chains• Resultant structurally abnormal chains prevent the formation of the
required triple-helical conformation
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 22
Lethal from of osteogenesis imperfect:Fractures appear in utero
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Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 24
Alport syndrome
• Alport syndrome or hereditary nephritis • Named after a British doctor, Cecil A. Alport
- Presence of blood in the urine (hematuria) is almost always found- Affects the eyes causing eye abnormalities including cataracts, lenticonus, kerataconus, as well as retinal flecks in the macula and mid periphery
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 25
Alport syndrome• Mutation of genes - prevent the proper production
or assembly of the type IV collagen network• It is an important structural component of
basement membranes in the kidney, inner ear, and eye
• Basement membranes are thin, sheet-like structures that separate and support cells in many tissues
• Basement membranes of the kidneys are not able to filter waste products from the blood
• allow blood and protein into the urine
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 26
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 27
Scurvy
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Vitamin C deficiency
Bleeding spongy gums
Subcutaneous hemorrhage
Delayed wound healing
Biochemical basis:Vitamin C is required for prolyl hydroxylase
and lysyl hydroxylase involved in hydroxylation of proline and lysine of collagen chain
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 29
Elastin• Protein with rubber-like properties• Elastic fibers composed of elastin and glycoprotein microfibrils • Found in the lungs, the walls of large arteries, and elastic ligaments, in
the uterus, skin• Peripheral microfibrillar network that surrounds the core consists largely
of fibrillin, a glycoproteinElastin core
Microfibrils
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• Can be stretched to several times their normal length• Recoil to their original shape when the stretching force is relaxed
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 31
Marfan’s SyndromeInherited
defects in
fibrillin
formation of abnormal
elastic fibers
Marfan’s
syndrome
Disorder characterized by impaired structural integrity in the skeleton, the eye, and the cardiovascular system
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 32
Long thin extremities
associated with other skeletal deformities
Reduced vision as a result of
dislocation of the lenses (ectopia
lentis)
Aortic aneurysms that typically
begins at the base of the aorta
Characterized by triad of features
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Skeletal Abnormalities and high arched pallet
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 34
• Elastin is an insoluble protein polymer • Synthesized from a precursor, tropoelastin• Is a linear polypeptide• Contains primarily small and nonpolar amino acids
(for example, glycine, alanine, and valine)
• Elastin is also rich in proline and lysine
Elastin
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 35
Role of α1-antitrypsin in elastin degradation
• Blood and other body fluids contain a protein, α1-antitrypsin (α1-AT, AAT, currently also called α1-antiproteinase)
• Originally named α1-antitrypsin because it inhibits the activity of trypsin synthesized by the pancreas
• Important physiologic role is to inhibit neutrophil elastase • Elastase is a powerful protease that is released into the extracellular
space by neutrophils• It degrades elastin of alveolar walls as well as in other tissues
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 36
• Most of the α1-AT found in plasma is synthesized and secreted by the liver
• The remainder is synthesized by several tissues including monocytes and alveolar macrophages
• α1-AT is important in the prevention of local tissue injury by elastase.
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 37
Role of α1-AT in the lungs:
• In the normal lung- Alveoli are chronically exposed to low levels of neutrophil
elastase released from activated and degenerating neutrophils
- Proteolytic activity can destroy the elastin in alveolar walls if unopposed by the inhibitory action of α1-AT
- Destruction of the connective tissue of alveolar walls
- Lung tissue cannot regenerate – results in emphysema
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 38
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 39
• Smoking causes the oxidation and subsequent inactivation of that methionine residue, thereby rendering the inhibitor powerless to neutralize elastase
• Smokers with α1-AT deficiency, therefore, have a considerably elevated rate of lung destruction and a poorer survival rate than nonsmokers with the deficiency.
• The deficiency of elastase inhibitor can be reversed by weekly intravenous administration of α1-AT
• The α1-AT diffuses from the blood into the lung
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 40
Epidermolysis bullosa
• Characterized by severe blistering of the skin and epithelial tissue
• Defect in the structure of type VII collagen
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 41
Lathyrism
• Diet induced disease• Due to inhibition of lysyl oxidase by the
β aminopropionitrile of Lathyrus odoratous seeds ( sweet pea) or β oxalylaminoalanine found in kesari dal
• Affects cross-linking of collagen • Characterized by deformation of spine ,
dislocation of joints, demineralization of bines, aortic aneurysm and joint hemorrhage
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 42
Williams Syndrome
• Defect in the elastin synthesis• low nasal bridge• developmental delay • coupled with strong language
skills• supravalvular aortic stenosis
• Rare genetic condition. The clinical manifestations include a distinct facial appearance, cardiovascular anomalies that may be present at birth or may develop later in life, idiopathic hypercalcemia
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 43
Rheumatoid Arthritis
• Women are affected twice as often as men• Peak incidence is• between the fourth and sixth decades• morning stiffness, symmetric polyarthritis,
inflammatorysynovitis, and the presence of rheumatoid
factor (RF)
[An immune mediated inflammatory disease (IMID)]
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 44
LUPUS ERYTHEMATOSES
It exists in two forms :a) Systemic lupus erythematosusb) Discoid lupus erythematosusClinical features: Erythematous patches on face (cheeks and
bridge of nose), neck, upper arm, shoulder and fingersKidney –fibrous thickening of glomerular capillariesHeart-atypical endocarditis.Oral manifestations:-superficial ulceration and bleeding of
oral mucosa, commonly buccal mucosa,palate and tongue.Tongue shows atrophy of papillae
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 45
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 46
It is a multiple organ disease and almost always associated with Raynaud`s phenomenon
The fibroblasts are defective with accentuated fibrillogenesis (abnormal diameter of fibers) increase in type VI collagen
Skin takes a waxy appearance due to hardening and cannot be wrinkled. Hands become claw like
Scleroderma
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 47
• Thank you