Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Concepts of Disease > Musculoskeletal diseases > Flashcards

Musculoskeletal diseases Flashcards

1
Q

What genetic phenomenon do chondroplasias show?

A

Locus heterogeneity - defects in different genes can give the same clinical phenotype.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

In general what mutations usually cause chondroplasias?

A

Those in the collagen present in cartilage, affecting endochondral ossification.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

How many different types of chrondroplasia are there?

A

150 - variable severity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Describe the process of endochrondral ossification

A
  1. cartilage formation: mesenchymal cells divide and differentiate into chondroblasts, these secrete cartilage and become embedded in lacunae within the matrix.
  2. Vascular invasion and longitudinal growth: ring of woven bone formed in the mid-shaft, osteoclasts allow vascular invasion if woven bone and cartilage, growth plate forms.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What mutations are involved in achondroplasia?

A

Gain of function mutations in fibroblast growth factor receptor 3 (FGFR3).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the effects of the causative mutation in achondroplasia?

A

Inhibits the transition between prehypertrophic and hypertrophic state of the chondrocytes, resulting in abnormal endochrondral ossification. Inhibits proliferation and terminal differentiation of growth plate chondrocytes and ECM synthesis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is Vosoritide?

A

A drug used to treat achondroplasia. A C-natriuretic peptide (CNP - involved in endochonral ossification and longitudinal bone growth) analogue that inhibits the MAPK activity of the overactive FGFR3, increasing growth velocity.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are the 4 main causes of chondroplasias?

A

Extracelluar matrix protein defects
Metabolic pathway defects (enzymes, ion channels transporters)
Defects in folding, processing, transport and degradation of macromolecules

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Which types of collagen can be mutated in chondroplasias?

A

Types 2, 9, 10, 11

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Name and describe the syndrome caused by mutation in type II or XI collagen

A

Stickler syndrome: affects the eyes, ears, and skeleton. Cleft palate, hearing impairment, ligament laxity, irregular ossification of epiphyses, early onset osteoarthritis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Mutations in which genes cause Multiple Epiphyseal Dysplasia?

A

Type IX collagen (COL9A1, COL9A2, COL9A3), COMP (cartilage oligomeric matrix protein), Matrillin-3, DYDST (diastrophic dysplasia sulphate transporter)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Describe Multiple Epiphyseal Dysplasia

A

Short limbs/bones, irregular epiphyses, abnormal knees, joint pain, premature osteoarthritis.
COMP mutations affect interaction of type IX collagen with types I and II.
Matrillin-3 mutations disrupt the organisation and structure of the growth plate.
DYDST mutations impair sulphation of of proteoglycans in the cartilage matrix, and so affect cartilage strength.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Name and describe the condition caused by mutation in type X collagen

A

Schmid Metaphyseal Chondrodysplasia: affects the metaphyses (contains the growth plate) resulting in short stature, joint pain, bowing of lower limbs.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Which collagen type maintains constant swelling pressure and how?

A

Type II: fibril network contains highly sulphated aggrecan, making the cartilage highly compressible - releases water which is drawn back in by the proteoglycans. This gives quick recovery from compressive, giving cartilage in joints some give and elasticity.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What genetic phenomenon does osteogenesis imperfecta show?

A

Dominant negative effect - mutant gene product not only loses its own function but also prevents other gene products functioning correctly. Common in multimers. OI is Autosomal Dominant.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Mutations in which genes cause osteogenesis imperfecta?

A

COL1A1, COL1A2 - those encoding type I collagen. Point mutations.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Which type of osteogenesis imperfecta is the most severe?

A

Type II

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Which type of osteogenesis imperfecta is caused by mutations in just COL1A2?

A

Type IV

19
Q

What is meant by “included type” osteogenesis imperfecta?

A

The abnormal gene product is incorporated into the matrix. Results in reduced secretion of collagen but what is laid down in the matrix includes abnormal collagen molecules as well as normal. This type is more severe due to the dominant negative effect.

20
Q

What is meant by “excluded type” osteogenesis imperfecta?

A

Results from a null allele. The abnormal gene product is not incorporated into the matrix. There is only half the collagen laid down in the matrix but all of what is deposited is normal. This is less severe as we do better with less but normal collagen than more but mutated collagen.

21
Q

Which types of osteogenesis imperfecta are included type?

A

Types II, III, IV

22
Q

Which types of osteogenesis imperfecta are excluded type?

A

Type I

23
Q

Describe the 4 types of osteogenesis imperfecta?

A

Type I: mild, excluded. Little bone deformity, blue sclerae, hearing loss.
Type II: lethal, included. Ribs cannot support respiration due to patchy mineralisation, some limbs have no bones.
Type III: severe and progressive, included. Both II and III show short stature, deficient and defective matrix, dentinogenesis imperfecta, bone deformities.
Type IV: mild, included. Mutations in COL1A2 so although included symptoms are milder (only 1/3 helices is α2). Normal sclerae, slightly short stature, some hearing loss.

24
Q

What % of abnormal collagen will you have resulting from mutations in COL1A1 or COL2A2?

A

COL1A1: 75%
COL1A2: 50%

25
Q

Describe 4 factors affecting the severity of osteogenesis imperfecta?

A
  1. Which gene is mutated: COL1A1 mutations are more severe than COL1A2
  2. Nature of the mutation: which amino acid replaces glycine. Ala/Ser < Cys < Arg < Val < Glu/Asp
  3. Position of the mutation: mutations at the 3’ end of the gene result in a higher degree of post-translational modification, the triple helix of collagen assembled from the C-terminal end. Therefore mutations closer to the C-terminus are more severe than those at the N-terminus.
  4. Is the mutated protein included or excluded?
26
Q

What is the result of over modification of the collagen?

A

Reduces the thermal stability of the collagen, resulting in increased intracellular degradation and slower secretion.
Over-modification results in abnormal molecules which give abnormal fibrils - ineffcient cleavage of the propeptides affects fibrillogenesis. These abnormal fibrils are poor templates for mineralisation - an essential process in bone formation.

27
Q

Describe some options for treatment of OI

A
  • Antiresporptive therapy: bisphosphonates reduce osteoclast activity which increases bone volume but cannot repairs all the mirco-cracks in the matrix, reduces fracture number in children.
  • Anabolic therapy: drugs that switch on bone formation. Teriparatide is effective in middle affected adults and only used for short term treatment due to associated risks. Anti-sclerostin antibodies activate wnt signalling but this has not yet been trialled in humans for OI. Recombinant GH can be used to alleviate short structure in children.
  • Orthropaedic surgery is currently the predominant treatment, pinning the bones in place. This is challenging due the weakness of the bones.
28
Q

What genetic phenomenon is demonstrated by Duchenne Muscular Dystrophy?

A

Mutational heterogeneity: different mutations in the same gene can result in the same clinical phenotype.

29
Q

What is the inheritance pattern of DMD?

A

X-linked recessive

30
Q

What mutations cause DMD?

A

Loss of function mutations in the dystrophin gene.
60-65% of patients have deletions - often multiple exons
5-15% of patients have duplications
20-30% have small mutations such as intron deletions or exon insertions.
Mutations are generally frameshift mutations.
Result in nonsense mediated mRNA decay, and so no detectable dystrophin expression.

31
Q

What is the result of frame neutral deletions in the dystrophin gene?

A

Beckers’ Muscular Dystrophy - less severe symptoms due to a lower Mw form of dystrophin

32
Q

What has occurred in the only 20 females worldwide with DMD?

A

X-autosome translocations between Xp21 (dystrophin locus) and a critical region chromosome 21. Results in one normal X chromosome and the other X now has the critical region from chromosome 21. X-inactivation then occurs. If the X:21 chromosome is inactivated then one copy of the critical region is lost and the cells are not viable. If the normal X is inactivated, the cells are viable but will have DMD due to the disruption of the Xp21 dystrophin locus.
Therefore in these 20 females X-inactivation favours DMD.

33
Q

What is the role of dystrophin?

A

A protein in muscle, links the dystrophin-associated protein complex at the sarcolemma to the cytoskeleton. Maintains the strength, flexibility and stability of the muscle fibres. Has some crucial domains - as long as these are maintained then the protein is functional.

34
Q

What happens in the muscle when the dystrophin-associated protein complex is lost?

A

Continual influx of inflammation, cycles of necrosis and regeneration, satellite cell depletion (skeletal muscle precursors), necrosis and fibrosis, muscle wasting, contraction induced injury in myofibres.

35
Q

How does DMD cause death?

A

Cardiac and respiratory failure

36
Q

What is the incidence of DMD?

A

1 in 5000 males

37
Q

Describe some problems with using gene therapy to combat DMD

A

The dystrophin gene is very large so vector and delivery are challenging
Muscle cells are post mitotic so cannot use retro virus
Adenovirus can be used but it is non-integrating so requires repeated treatments
Requires delivery to all muscle cells

38
Q

Describe some solutions for using gene therapy to combat DMD

A

Use mini genes with the crucial domains
Micro- and mini- dystrophin have been delivered using adeno associated viruses
Adenovirus vectors - taken up by non-dividing cells
Substitute dystrophin with utrophin
Correct the reading frame with exon skipping

39
Q

How can exon skipping be used to combat DMD?

A

Antisense mediated exon skipping using antisense oligonucleotides: can correct the reading frame
Targeted to the splice site of mutation-containing exon
Exon 45 is commonly deleted in DMD; inducing skipping of exon 46 as well corrects the reading frame.
This results in BMD as although the frame is corrected it still results in a truncated dystrophin protein but it is still partially functional so can alleviate the severe symptoms of DMD.

40
Q

What is utrophin?

A

A protein with similar function to dystrophin but expressed in development and switched off in adults. Switching it back on could alleviate the symptoms of DMD.

41
Q

Describe the genetic testing used for DMD

A

It is difficult - caused by many different mutations (various sites and natures) in a very large gene.
There are mutation “hotspots” in exons 2-19 and 45-55. Multiplex PCR assays can be used to reveal 98% of all deletions.

42
Q

What has been achieved by cloning the dystrophin gene?

A
  • Characterise the mutations associated with DMD
  • Predict the function of the protein encoded bu the gene
  • Reveal the molecular pathology underlying DMD
  • Generate diagnostic tests
  • Design new treatments to correct the effects of the mutations
43
Q

What method was used to identify the gene causing DMD?

A

Cytogenetics

Revealed visible deletions in the X chromosome at Xp21 and X:21 translocations in female with DMD

Concepts of Disease (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions