42/3 rd of Vasco di Gama’s sailors had died due to Scurvy by the time he reached India.
5Scurvy Barlow’s disease. Vitamin C is required for collagen synthesis Hydroxylation of lysine and proline.Lysyl and prolyl hydroxylase.Important for stabilizing pro-collagen peptides.Bleeding gums, joints-hemarthrosis, fragile blood vessels.
6Osteogenesis Imperfecta Brittle bone diseaseLobstein disease.Type-1 collagen disease.
8Osteogenesis Imperfecta Autosomal Dominant disease.Substitution of Glycine with bulkier aminoacids.Larger side chains-Steric hinderance between the chains causing bulgesBody hydrolyses the improper collagen structure.
9Signs and SymptomsBlue sclerae, short stature, hearing loss, respiratory problems, dentiogenesis imperfectaBrittle bone – multiple fractures on mild pressure
10Stress state within collagen fibrils is altered at the locations of mutations
128 TYPES OF OI Type Description Gene OMIM Mode of Inheritance I mild Null COL1A1 allele(IA), (IB)autosomal dominant, 60% de novo IIsevere and usually lethal in the perinatal periodCOL1A1, COL1A2,(IIA), (IIB)autosomal dominant, ~100% de novo IIIconsidered progressive and deformingCOL1A1, COL1A2259420IVdeforming, but with normal scleras166220Vshares the same clinical features of IV, but has unique histologic findings ("mesh-like")unknown610967autosomal dominant VIshares the same clinical features of IV, but has unique histologic findings ("fish scale")610968unknown VIIassociated with cartilage associated proteinCRTAP610682autosomal recessive VIIIsevere to lethal, associated with the protein leprecanLEPRE1610915autosomal recessive
13dentiogenesis imperfecta Brittle bone – Type 1 – mildest formType 2 – lethalType 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
17Ehler 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
18Classification: Hypermobility – tenascin gene Type 3 defect This 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
19Clinical features: Hypermobility of the joints Hyperelastic skin Fragile tissue – easy bruising, scaring, wounding.
20Alport syndrome: (Hereditary Nephritis ) X-linked recessive.May be Autosomal recessive.Glomerulonephritis,DeafnessHematuria.Alport syndrome is caused by mutations in COL4A(n)COL4A3, COL4A4, and COL4A5, collagen biosynthesis genesType 4 collagen defect.IMPROPER Basement membrane – basket weave appearanceSensorineural hearing loss.
21Fuchs Corneal dystrophy Degenerative disorder of corneal endothelium.Defect in collagen –type 8.Autosomal dominantFuchs' endothelial dystrophy, is a slowly progressing corneal disease that usually affects both eyesFemales>Male
22Fuchs Corneal dystrophy Blurred vision that will gradually clear during the dayLater stages - Swelling will remain constant and reduce vision throughout the day.CORNEAL OEDEMA and LOSS of VISION
23Menkes disease Kinky hair disease or menke kinky hair syndrome Mutations in the ATP7A gene on chromosome Xq13X- linked recessive
24Menke’s diseaseCopper accumulates in some tissues, such as the small intestine and kidneysThe decreased supply of copper reduce the activity of numerous copper-containing enzymes - lysyl oxidase.coarse hair, growth failure, and deterioration of the nervous system
25Goodpasture syndrome: Anti-glomerular basement membrane antibody disease.Auto-immune reaction against goodpasture antigen.Glomerulonephritis and hemorrhage of the lungs.
26Goodpasture syndrome: Sometimes this disorder is triggered by a viral respiratory infection or by breathing in hydrocarbon solvents-Type II hypersensitivity reaction to Goodpasture’s 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
27Marfan syndrome : Autosomal dominant disease Mutation in geneFBN1 encoding for fibrillin protein.Fibrillin also regulates TGF-β. Defect causes abnormalities in lungs, aorta and heart valves.Lens dislocation – supero temporal
28Clinical 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.
30Clinical 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.
31Pseudoxantoma elasticum Pseudoxanthoma 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 recessiveABCC6 geneChromosome 16Grönblad–Strandberg syndromeAngioid streaks
32Featuresfragmentation and mineralization of elastic fibers in some tissues.Small, yellowish papular lesions –axillae, neck, groin, elbow, knee.dimpling of the Bruch membrane - peau d'orange appearance.Angioid streaks – calcification of blood vessels.CAD and MI
33MCQ 1A 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 imperfecta2)Scurvy3) Menke’s disease4)Blue baby syndrome5)PhenylketonuriaMenke’s disease