Collagen structural defects Dr.S.Chakravarty ,MBBS, MD

Diseases associated with Collagen structure Scurvy Osteogenesis Imperfecta Ehler Danlos syndrome Alport syndrome Fuch’s dystrophy Menke’s disease Goodpasture syndrome

Scurvy

2/3 rd of Vasco di Gama’s sailors had died due to Scurvy by the time he reached India.

Scurvy 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.

Osteogenesis Imperfecta Brittle bone disease Lobstein disease. Type-1 collagen disease.

Osteogenesis Imperfecta Autosomal Dominant disease. Substitution of Glycine with bulkier aminoacids. Larger side chains-Steric hinderance between the chains causing bulges Body hydrolyses the improper collagen structure.

Signs and Symptoms Blue sclerae, short stature, hearing loss, respiratory problems, dentiogenesis imperfecta Brittle bone – multiple fractures on mild pressure

Stress state within collagen fibrils is altered at the locations of mutations

MULTIPLE FRACTURES

8 TYPES OF OI Type Description Gene OMIM Mode of Inheritance I mild Null COL1A1 allele 166240 (IA), 166200 (IB) autosomal dominant, 60% de novo [5] II severe and usually lethal in the perinatal period COL1A1, COL1A2, 166210 (IIA), 610854 (IIB) autosomal dominant, ~100% de novo [5] III considered progressive and deforming COL1A1, COL1A2 259420 IV deforming, but with normal scleras 166220 V shares the same clinical features of IV, but has unique histologic findings ("mesh-like") unknown 610967 autosomal dominant [5] VI shares the same clinical features of IV, but has unique histologic findings ("fish scale") 610968 unknown [5] VII associated with cartilage associated protein CRTAP 610682 autosomal recessive [5] VIII severe to lethal, associated with the protein leprecan LEPRE1 610915 autosomal recessive

dentiogenesis imperfecta Brittle bone – Type 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 imperfecta Brittle bone – multiple fractures on mild pressure

Ehler Danlos Syndrome Cutis hyperplastica.

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

Classification: 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

Clinical features: Hypermobility of the joints Hyperelastic skin Fragile tissue – easy bruising, scaring, wounding.

Alport syndrome: (Hereditary Nephritis ) X-linked recessive. May be Autosomal recessive. Glomerulonephritis, Deafness Hematuria. Alport syndrome is caused by mutations in COL4A(n) COL4A3, COL4A4, and COL4A5, collagen biosynthesis genes Type 4 collagen defect. IMPROPER Basement membrane – basket weave appearance Sensorineural hearing loss.

Fuchs Corneal dystrophy Degenerative 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

Fuchs Corneal dystrophy Blurred 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

Menkes disease Kinky hair disease or menke kinky hair syndrome Mutations in the ATP7A gene on chromosome Xq13 X- linked recessive

Menke’s disease Copper accumulates in some tissues, such as the small intestine and kidneys The decreased supply of copper reduce the activity of numerous copper-containing enzymes - lysyl oxidase. coarse hair, growth failure, and deterioration of the nervous system

Goodpasture syndrome: Anti-glomerular basement membrane antibody disease. Auto-immune reaction against goodpasture antigen. Glomerulonephritis and hemorrhage of the lungs.

Goodpasture 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

Marfan 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

Clinical 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.

Alpha -1 antitrypsin deficiency Autosomal co-dominant/ recessive SERPINA1 gene –mutation Either decrease or abnormal synthesis. Allelles – MM-Normal SS- Intermediate ZZ- worst. Neutrophil elastase – damages lungs.

Clinical 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.

Pseudoxantoma 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 recessive ABCC6 gene Chromosome 16 Grönblad–Strandberg syndrome Angioid streaks

Features fragmentation 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

MCQ 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)Scurvy 3) Menke’s disease 4)Blue baby syndrome 5)Phenylketonuria Menke’s disease

EXTRA CELLULAR CLEAVAGE

Marfan’s Syndrome