Diseases associated with Collagen structure

Collagen structural defectsDr.S.Chakravarty ,MBBS, MD Diseases associated with Collagen structureScurvy Osteogenesis ImperfectaEhler Danlos syndromeAlport syndromeFuchs dystrophyMenkes diseaseGoodpasture syndrome2Scurvy

32/3 rd of Vasco di Gamas sailors had died due to Scurvy by the time he reached India.4

ScurvyBarlows disease.Vitamin C is required for collagen synthesisHydroxylation of lysine and proline.Lysyl and prolyl hydroxylase.Important for stabilizing pro-collagen peptides.Bleeding gums, joints-hemarthrosis, fragile blood vessels.

5Osteogenesis ImperfectaBrittle bone disease

Lobstein disease.

Type-1 collagen disease.

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Osteogenesis ImperfectaAutosomal Dominant disease.

Substitution of Glycine with bulkier aminoacids.

Larger side chains-Steric hinderance between the chains causing bulges

Body hydrolyses the improper collagen structure.

8Signs and SymptomsBlue sclerae, short stature, hearing loss, respiratory problems, dentiogenesis imperfecta

Brittle bone multiple fractures on mild pressure

9Stress state within collagen fibrils is altered at the locations of mutations10

MULTIPLE FRACTURES11

8 TYPES OF OI12TypeDescriptionGeneOMIMMode of InheritanceImildNull COL1A1 allele166240 (IA), 166200 (IB)autosomal dominant, 60% de novo [5]IIsevere and usually lethal in the perinatal periodCOL1A1, COL1A2,166210 (IIA), 610854 (IIB)autosomal dominant, ~100% de novo [5]IIIconsidered progressive and deformingCOL1A1, COL1A2259420autosomal dominant, ~100% de novo [5]IVdeforming, but with normal sclerasCOL1A1, COL1A2166220autosomal dominant, 60% de novo [5]Vshares the same clinical features of IV, but has unique histologic findings ("mesh-like")unknown610967autosomal dominant [5]VIshares the same clinical features of IV, but has unique histologic findings ("fish scale")unknown610968unknown [5]VIIassociated with cartilage associated proteinCRTAP610682autosomal recessive [5]VIIIsevere to lethal, associated with the protein leprecanLEPRE1610915autosomal recessive13Type 1 mildest form Type 2 lethal Type 4 no blue sclera (the blue-gray color of the sclera is due to the underlying choroidal veins which show through the thin sclera)Blue sclerae, short stature, hearing loss, respiratory problems, dentiogenesis imperfectaBrittle bone multiple fractures on mild pressure

Ehler Danlos SyndromeCutis hyperplastica.

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Ehler Danlos syndrome:Group of genetic defects involving synthesis of collagen(COL5A, COL 3A) and associated proteins.

Collagen in connective tissue helps tissues to resist deformation (decreases its elasticity) due to defect in collagen synthesis hyperelastic 17Classification:Hypermobility tenascin gene Type 3 defectThis gene encodes a member of the tenascin family of extracellular matrix glycoproteins.Here collagen density is also reduced .Classical (type1 and 2) affects collagen type 5.

Vascular- type 3 collagen

18Clinical features:Hypermobility of the joints

Hyperelastic skin

Fragile tissue easy bruising, scaring, wounding.19Alport syndrome:(Hereditary Nephritis )X-linked recessive.May be Autosomal recessive.Glomerulonephritis,Deafness Hematuria.Type 4 collagen defect.IMPROPER Basement membrane basket weave appearanceSensorineural hearing loss.Alport syndrome is caused by mutations in COL4A(n) COL4A3, COL4A4, and COL4A5, collagen biosynthesis genesFuchs Corneal dystrophyDegenerative disorder of corneal endothelium.

Defect in collagen type 8.

Autosomal dominant

Fuchs' endothelial dystrophy, is a slowly progressing corneal disease that usually affects both eyes Females>Male

21Fuchs Corneal dystrophyBlurred vision that will gradually clear during the day

Later stages - Swelling will remain constant and reduce vision throughout the day.

CORNEAL OEDEMA and LOSS of VISION

22Menkes disease

Kinky hair disease or menke kinky hair syndrome

Mutationsin theATP7Ageneon chromosome Xq13

X- linked recessive

23Menkes disease Copper accumulates in some tissues, such as thesmall intestineandkidneys

The decreased supply of copper reduce the activity of numerous copper-containingenzymes - lysyl oxidase.

coarse hair, growth failure, and deterioration of the nervous system24Goodpasture syndrome:

Anti-glomerular basement membrane antibody disease.

Auto-immune reaction against goodpasture antigen.

Glomerulonephritis and hemorrhage of the lungs.25Goodpasture syndrome:Sometimes this disorder is triggered by a viral respiratory infection or by breathing in hydrocarbon solvents-Type II hypersensitivity reaction to Goodpastures antigens on the basement membrane of lungs and kidney.

Produces IgG antibodies against Alpha-3 chain of Type IV collagen.

clinical features- cough, hemoptysis, Hematuria, Renal failure

26Marfan syndrome :Autosomal dominant disease

Mutation in geneFBN1 encoding for fibrillin protein.

Fibrillin also regulates TGF-. Defect causes abnormalities in lungs, aorta and heart valves.

Lens dislocation supero temporal

27Clinical features:Arachnodactyly long and slender fingers.

Uppersegment longer than lower segment.

Scoliosis and pectus excavatum/carinatum.

Mitral valve prolapse / aortic regurgitation/ aortic aneurysms.

Lungs spontaneous pneumothorax.

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Alpha -1 antitrypsin deficiencyAutosomal co-dominant/ recessiveSERPINA1 gene mutation Either decrease or abnormal synthesis.Allelles MM-Normal SS- Intermediate ZZ- worst.Neutrophil elastase damages lungs.29Clinical features:Development of emphysema Clinical features: difficulty in breathing, wheezing, shortness of breath, respiratory infections, barrel shaped chest.

development of Cirrhosis: jaundice, portal hypertension swollen abdomen, swollen limbs.30Pseudoxantoma elasticumPseudoxanthoma elasticum is a progressive disorder that is characterized by the accumulation of deposits of calcium and other minerals (mineralization) in elastic fibers, which are a component of connective tissue.

Autosomal recessive ABCC6 geneChromosome 16GrnbladStrandberg syndrome

31Angioid streaksFeaturesfragmentation and mineralization of elastic fibers in some tissues.Small, yellowish papular lesions axillae, neck, groin, elbow, knee.dimpling of theBruch membrane - peau d'orange appearance.Angioid streaks calcification of blood vessels.CAD and MI

32MCQ 1 A 4 month old infant who failed to grow and appeared to be mentally retarded was brought to the clinic for testing .The physician noted that the infant had abnormally kinky and hypopigmented hair. Arteriograms showed tortuosity of the major arteries.

Blood test showed that the infant had low serum ceruloplasmin and only 10% of normal copper levels.What is the clinical disorder?1)Osteogenesis imperfecta 2)Scurvy3) Menkes disease4)Blue baby syndrome5)Phenylketonuria33Menkes disease3435EXTRA CELLULAR CLEAVAGE36Marfans Syndrome