Osteogenesis imperfecta Flashcards
What 3 components make up connective tissues?
- Fibres
- Ground substance
- Cells
What is ground substance?
Gel-like substance in the extracellular space containing all components of the extracellular matrix except for fibrous material e.g. collagen and elastins
What are the cells of connective tissue? (5)
- Fibroblasts
- Adipocytes
- Macrophages
- Mast cells
- Leucocytes
What are the fibres of connective tissue? (2)
- Collagen
- Elastins
What is the function of connective tissue? (3)
- Acts as a cellular glue
- Supports and connects internal organs
- Forms bones, walls of blood vessels, gives skin elasticity, attaches muscle to bone, protects the organs
What are examples of genetic connective tissue disorders? (3)
- Osteogenesis imperfecta
- Ehlers Danlos syndrome
- Marfan syndrome
What are examples of autoimmune connective tissue disorders? (2)
- Lupus
- Scleroderma
What are sarcomas?
Cancers that arise in connective tissues
What is osteogenesis imperfecta? (2)
- Collective term for a heterogeneous group of connective tissue syndromes characterised by liability to fractures throughout life
- Commonly caused by defects in collagen
What is the incidence of osteogenesis imperfecta?
1 in 20 000 births
What are the clinical features of osteogenesis imperfecta? (7)
- Bone fractures with little trauma (brittle bones)
- Loose joints
- Weak teeth (dentinogenesis imperfecta)
- Blue sclera
- Bowed legs and arms
- Short stature
- Hearing loss
What type of genetic testing is required for an OI referral? (2)
- Targeted NGS for OI genes, don’t need whole genome sequencing
- There are 30+ genes associated with OI so Sanger is too long, expensive and labour intensive
What is the main genetic cause of OI? (3)
- 90% variants are in COL1A1 and COL1A2 collagen genes and are dominant
- There are autosomal recessive genes e.g. BMP1 and X-linked genes e.g. PLS3
- All genes causing OI cause collagen defects
What are the features of collagen? (4)
- Can undergo biomineralisation to stiffen tissues
- Produced by osteoblasts and fibroblasts
- Fibrous protein which forms part of the extracellular
- Most abundant protein in humans
What are the types of OI associated with COL1A1 and COL1A2? (4)
- Type 1: classic
- Type 2: lethal
- Type 3: progressively deforming
- Type 4: common variable OI with normal sclerae
(All autosomal dominant)
What are the features of type 1 OI? (9)
- Classic
- Mild
- Fractures
- Normal stature
- Little or no deformity
- Blue sclera
- 50% have hearing loss
- Joint hypermobility
- No dentinogenesis imperfecta
What are the features of type 2 OI? (5)
- Lethal in pregnancy
- Multiple fractures
- Unmineralised bones
- Beaded ribs (rib cage collapses and damages internal organs)
- Short/bowed long bones
What are the features of type 3 OI? (9)
- Progressively deforming
- Severe but non-lethal
- Apparent at birth
- Multiple fractures
- Bone deformity
- Grey/white sclera
- Short stature
- Wheelchair bound
- Dentinogenesis imperfecta
What are the features of type 4 OI? (7)
- Common variable OI with normal sclerae
- Moderate severity
- Fractures
- Normal to grey sclera
- Variable short stature
- Dentinogenesis imperfecta
- Adult onset hearing loss
What is OI type 5? (3)
- Caused by a single variant c.-14C>T in IFITM5 gene
- Variant is in the 5’ non coding DNA before the first exon and interferes with correct transcription
- Autosomal dominant inheritance
Why is NGS analysis of many genes necessary?
Many genes can be involved in causing one type of disorder
Which type of OI do you expect to see in children?
Type 3 (quite severe)
How do you go about a referral for OI genetic testing? (2)
- Targeted NGS to identify variants
- Variant analysis to classify variant
What is the structure of collagen genes? (5)
- Each gene consists of approximately 50 exons
- Each exon codes for approximately 20 amino acids
- Each exon begins and ends on a complete triplet codon
- N and C terminal exons encode the N and C terminal propeptide regions which are important for processing and formation of collagen fibrils
- Triplet repeat in about 40/50 exons with a glycine in every third position (Gly-X-Y repeat)
What is the role of glycine in collagen? (5)
- Helix is formed by intertwining 3 collagen COL1A chains (2xCOL1A1, 1xCOL1A2)
- Vital for the structural integrity of the repeating helix
- Every third amino acid is the centre of the helix (Glycine)
- Glycine is the smallest amino acid so the only one that can be here and maintain the helix
- Any swap disrupts the helix structure
What are qualitative COL1 defects? (2)
- Where mutations result in the synthesis of a structurally abnormal alpha collagen that then tries to form a helix with structurally normal alpha collagens (e.g. missense)
- Causes disturbed helical folding so can’t function properly
Which types of OI are caused by qualitative defects?
Types 2 and 4
What are quantitative COL1 defects? (2)
- Mutations that lead to premature truncation (nonsense, frameshifts, targeted by NMD) resulting in a reduction in the amount of collagen
- The remaining WT collagen is fine but the reduction is enough to cause the phenotype
Which types of OI are caused by quantitative defects?
Mostly type 1 (milder)
What are the benefits of doing familial testing? (2)
- Members with the variant can start treatment early, make informed lifestyle choices, have prenatal testing for future offspring
- Members without the variant can get reassurance that they don’t have it and can’t pass it on
What is the treatment for OI? (2)
- Bisphosphonates to attempt to increase bone density
- No cure
