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Investigation Of Human Disease > connective tissue disorder 2 > Flashcards

connective tissue disorder 2 Flashcards

1
Q

Describe osteogenesis imperfecta.

A

Osteogenesis imperfecta, also known as ‘Brittle disease,’ is a collagen disorder characterized by low bone mass, decreased bone strength, and increased bone fragility.

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2
Q

What are the common mutations associated with osteogenesis imperfecta?

A

Mutations in COL1A1 or COL1A2 genes, which encode the procollagen Glycine substitutions in the triple helical domain are very common.

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3
Q

What are the consequences of osteogenesis imperfecta in terms of bone fractures?

A

It can present as mild forms with fractures or severe forms that can be lethal in utero.

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4
Q

Define the dominant form of osteogenesis imperfecta.

A

The dominant form involves defects in the quantity or structure of type I procollagen, impacting bone matrix structure and mineralization.

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5
Q

How does the recessive form of osteogenesis imperfecta manifest?

A

The recessive form is characterized by a deficiency of proteins that interact with collagen, affecting its post-translational modification or folding (involving CRTAP, P3H1, PPIB, Serpin H1, and FKBP10).

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6
Q

Describe the diagnosis of Osteogenesis Imperfecta (OI)

A

Diagnosis involves clinical and radiographic findings such as fractures, deformities of long bones, and short stature.

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7
Q

Explain the management of Osteogenesis Imperfecta (OI)

A

Management includes a multidisciplinary team providing physical rehabilitation, genetic, hearing, dental, neurological, endocrine, and surgical care.

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8
Q

What is the impact of bisphosphonates in Osteogenesis Imperfecta (OI) management?

A

Bisphosphonates are widely used and have positive effects on bone mass and vertebral geometry, but they can cause a decline in bone material quality.

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9
Q

Describe Osteogenesis Imperfecta.

A

Oogenesis Imperfecta is a generalized connective tissue disorder characterized by skeletal manifestations such as macrocephaly, scoliosis, and chest wall deformities, as well as non-skeletal features like joint hypermobility, blue sclera, hearing loss, dental issues, and heart valve defects.

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10
Q

What are some skeletal manifestations of Osteogenesis Imperfecta?

A

Some skeletal manifestations of Osteogenesis Imperfecta include macrocephaly, scoliosis, and chest wall deformities.

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11
Q

What are some non-skeletal features associated with Osteogenesis Imperfecta?

A

Non-skeletal features of Osteogenesis Imperfecta include joint hypermobility, blue sclera, hearing loss, dental issues, and heart valve defects.

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12
Q

What type of disorder is Osteogenesis Imperfecta?

A

Osteogenesis Imperfecta is a generalized connective tissue disorder.

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13
Q

How is Osteogenesis Imperfecta usually inherited?

A

Osteogenesis Imperfecta is usually inherited in a dominant form.

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14
Q

What is a common feature of Osteogenesis Imperfecta related to the joints?

A

Joint hypermobility is a common feature of Osteogenesis Imperfecta.

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15
Q

Define macrocephaly in the context of Osteogenesis Imperfecta.

A

Macrocephaly in the context of Osteogenesis Imperfecta refers to abnormally large head size.

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16
Q

What are some dental issues associated with Osteogenesis Imperfecta?

A

Dental issues associated with Osteogenesis Imperfecta may include problems with tooth development or fragility.

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17
Q

What is a characteristic eye feature seen in Osteogenesis Imperfecta?

A

Blue sclera is a characteristic eye feature seen in Osteogenesis Imperfecta.

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18
Q

What type of deformity can be observed in the chest wall of individuals with Osteogenesis Imperfecta?

A

Individuals with Osteogenesis Imperfecta may exhibit chest wall deformities.

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19
Q

Describe the Sillence classification of Osteogenesis Imperfecta.

A

It categorizes OI into Type I (mild), Type II (perinatal lethal), Type III (deforming), and Type IV (mild deforming) based on specific characteristics.

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20
Q

What are the characteristics of OI Type I according to the Sillence classification?

A

It includes blue sclera, bone fragility, near normal stature, and hearing loss in adolescence to adulthood.

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21
Q

What distinguishes OI Type II in the Sillence classification?

A

It is characterized by short, deformed extremities, severe bone fragility, and absence of calvaria mineralization, making it perinatal lethal.

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22
Q

How does OI Type III present according to the Sillence classification?

A

It shows bone fragility, progressive deformity, marked short stature, hearing loss in early adulthood, and shortened survival.

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23
Q

Define OI Type IV in the Sillence classification.

A

It is described as mild deforming OI with characteristics such as bone fragility, mild bone deformity, short stature, and hearing loss in early adulthood.

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24
Q

Describe OI/EDS overlap syndrome.

A

It is a rare condition where patients exhibit clinical symptoms of both Osteogenesis Imperfecta (OI) and Ehlersanlos Syndrome (EDS) with levels of joint laxity, skin hyperextensibility, atrophic scars, easy bruising, and bone fractures.

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25
Q

What can cause OI/EDS phenotypes?

A

Mutations affecting the amino-terminal portion of the collagen type I triple helix, with some genotype-phenotype correlation.

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26
Q

How do mutations affecting the N-terminal portion of the collagen type I triple helix contribute to OI/EDS overlap syndrome?

A

They lead to a delay in the removal of procollagen N-propeptide by N-proteinase (ADAMTS-2), resulting in the production of immaturely cross-linked collagen.

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27
Q

Define BIO-5016B1 in the context of OI/EDS overlap syndrome.

A

It refers to the immaturely cross-linked collagen produced due to mutations affecting the N-terminal portion of the collagen type I triple helix, contributing to the syndrome.

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28
Q

Do patients with OI/EDS overlap syndrome have mutations affecting a specific part of the collagen triple helix?

A

Yes, they have mutations that predominantly affect the N-terminal portion of the triple helix.

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29
Q

Describe the clinical manifestations seen in patients with OI/EDS overlap syndrome.

A

They may exhibit joint laxity, skin hyperextensibility, atrophic scars, easy bruising, and bone fractures, which are characteristic symptoms of both Osteogenesis Imperfecta and Ehlers-Danlos Syndrome.

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30
Q

How does delayed removal of procollagen N-propeptide contribute to OI/EDS overlap syndrome?

A

It results in the production of immaturely cross-linked collagen, specifically BIO-5016B1, which is associated with the syndrome.

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31
Q

Define ADAMTS-2 in the context of OI/EDS overlap syndrome.

A

It is the N-proteinase responsible for the removal of procollagen N-propeptide, and mutations affecting its function can lead to the production of immaturely cross-linked collagen in the syndrome.

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32
Q

Describe the condition in a man discussed in the content.

A

Osteogenesis imperfecta III/Ehlers-Danlos overlap syndrome.

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33
Q

What mutation was detected in the individual with the condition?

A

Mutation in1A2.

34
Q

What specific amino acid change occurred in the mutation detected?

A

Glycine (GGA) to Glutamic Acid (GAA) change.

35
Q

How do the GLY substitutions affect collagen helix propagation?

A

The GLY substitutions disrupt the propagation of collagen helix.

36
Q

Describe the characteristic of individuals with Mild Osteogenesis Imperfecta (Type I).

A

They make reduced amounts of normal type I collagen.

37
Q

What is the ratio of proa1(1) to proa1(III) in affected individuals with Osteogenesis Imperfecta?

A

1:1.

38
Q

What is the ratio proa1(1) to proa1(III) in unaffected individuals?

A

3:1.

39
Q

What type of collagen was analyzed using SDS-PAGE in the study by Willing et al. in 1990?

A

3H proline labelled collagen.

40
Q

Where was the study on collagen ratios published by Willing et al. in 1990?

A

J Clin Invest.

41
Q

When was the study by Willing et al. on collagen ratios published?

A

1990.

42
Q

Define SDS-PAGE.

A

Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis.

43
Q

Describe the impact of a Lethal OI (Type II) mutation on collagen.

A

Results in abnormal collagen with altered mobility of COL 1 alpha chains and increased post-translation modification.

44
Q

What is the consequence of a Lethal OI (Type II) mutation on collagen structure?

A

Formation of disulphide bond between adjacent alpha 1 chains.

45
Q

What technique was used to analyze the collagen in this study?

A

SDS-PAGE (Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis).

46
Q

Define Osteogenesis imperfecta.

A

A genetic disorder characterized by fragile bones that break easily, often caused by mutations affecting collagen production.

47
Q

How does a Lethal OI (Type II) mutation affect collagen mobility?

A

Results in altered mobility of COL 1 alpha chains.

48
Q

What post-translational modification is increased in collagen due to a Lethal OI (Type II) mutation?

A

Increased post-translation modification.

49
Q

Describe the abnormal collagen structure resulting from a Lethal OI (Type II) mutation.

A

Mutant collagen has disulphide bond formation between adjacent alpha 1 chains.

50
Q

Who conducted the study mentioned in the content?

A

Vogel et al.

51
Q

When was the study on abnormal collagen published?

A

1987.

52
Q

What is the reference for the study on abnormal collagen?

A

J Biol Chem 1987;262:14737-14744.

53
Q

Describe the reported mutations causing severe deforming Oste Imperfecta (Type III).

A

Mutations include Gly 154 Arg substitution in COL1A1, Gly 526 Cys substitution in COL1A1 Gly 751 Ser substitution in COL1A2, deletion of three bases in COL1A2, loss of COL1A2 leading to the formation of COL1A1 homotrimer, and a point mutation increasing mannose binding at the C terminus.

54
Q

What is the impact of Gly 154 Arg substitution in COL1A1 on Osteogenesis Imperfecta (Type III)?

A

It is one of the reported mutations causing severe deforming OI (Type III).

55
Q

How does the loss of COL1A2 contribute to Osteogenesis Imperfecta (Type III)?

A

It leads to the formation of COL1A1 homotrimer, which is associated with severe deforming OI (Type III).

56
Q

Define Osteogenesis Imperfecta (OI) Type III.

A

It is a severe form of OI characterized by multiple fractures, bone deformities, and other skeletal abnormalities.

57
Q

What is the significance of the point mutation increasing mannose binding at the C terminus in Osteogenesis Imperfecta (Type III)?

A

It is one of the reported mutations causing severe deforming OI (Type III).

58
Q

Describe the position of the (Gly>Cys) point mutation in COL1A1 and its association with severity.

A

The (Gly>Cys) point mutation in COL1A1 is associated with severity in Osteogenesis imperfecta, with varying levels of severity in Type I Type II, Type III, and Type IV.

59
Q

What is Marfan syndrome (MFS)?

A

Marfan syndrome is a genetic disorder that affects connect tissue in various parts of the body such as the heart, eyes, lungs, and skeleton.

60
Q

What is the main of death in individuals with Marfan syndrome?

A

Cardiovascular collapse is the main cause of death in individuals with Marfan syndrome.

61
Q

How does Marfan syndrome typically progress in individuals?

A

Some people are born with features of Marfan syndrome, while others develop them throughout life. Ageing is usually detrimental for this disease.

62
Q

Define adolescent idiopathic scoliosis.

A

Adolescent idiopathic scoliosis is a condition characterized by an abnormal sideways curvature of the spine in adolescents, which may require corrective surgery.

63
Q

What are some challenges associated with diagnosing Marfan syndrome?

A

Marfan syndrome is difficult to diagnose and requires early detection for effective treatments.

64
Q

Is there a cure for Marfan syndrome?

A

There is no cure for Marfan syndrome, but management options include medication, therapy, and surgery.

65
Q

What are Marfan and Marfan-like syndromes?

A

Marfan and Marfan-like syndromes are genetic disorders that affect connective tissue and share similarities with Marfan syndrome.

66
Q

Describe Marfan and Marfan like syndromes.

A

Conditions associated with a defect in theBN1 gene, characterized by abnormalities in connective tissues and elastic fibers.

67
Q

What is the F1 gene defect associated?

A

Mar and Marfan like syndromes.

68
Q

Define FBN1 gene.

A

A gene responsible for encoding a cysteine-rich, large modular glycoprotein that is a major component of 10nm microfibrils.

69
Q

How is the FBN1 gene described?

A

As a cysteine-rich, large modular glycoprotein.

70
Q

What are the major components of 10nm microfibrils?

A

Products of the FBN1 gene.

71
Q

Do Marfan and Marfan like syndromes affect only specific tissues?

A

No, they are found in all connective tissues.

72
Q

Describe the elastic fibers in tendon associated with these syndromes.

A

They show co-localization of elastin and fibrillins.

73
Q

What study by Grant et al in 2013 is related to these syndromes?

A

J Anat 2013;222:573-9.

74
Q

Describe the role of elastic microfibrils in regulating TGFbeta activity.

A

Elastic microfibrils bind latent TGFbeta complex and are critical for regulating the activation of latent TGFbeta.

75
Q

What is the impact of defective Fibrillin-1 in Marfan syndrome?

A

Defective Fibrillin-1 in Marfan syndrome causes increased TGFbeta signaling.

76
Q

What are some possible extracardiac predictors of aortic dissection in Marfan syndrome according to Ágg et al. (2014)?

A

Extracardiac predictors of aortic dissection in Marfan syndrome may include factors identified in the study by Ágg et al. (2014).

77
Q

How do Takeda et al. (2016) describe the pathophysiology and management of cardiovascular manifestations in Marfan and Loeys-Dietz syndromes?

A

Takeda et al. (2016) discuss the pathophysiology and management of cardiovascular manifestations in Marfan and Loeys-Dietz syndromes in their publication in the International Heart Journal.

78
Q

Describe the focus of the study conducted by Yanting Zeng et al.

A

Correction of the Marfan Syndrome Pathogenic FBN1 Mutation by Base Editing in Human Cells and Heterozygous Embryos.

79
Q

What is the title of the research paper published by Yanting Zeng et al.?

A

Correction of the Marfan Syndrome Pathogenic FBN1 Mutation by Base Editing in Human Cells and Heterozygous Embryos.

80
Q

Define Marfan Syndrome.

A

A genetic disorder that affects the body’s connective tissue, leading to various skeletal, cardiovascular, and ocular abnormalities.

81
Q

How did the researchers propose to correct the pathogenic FBN1 mutation in the study?

A

By using base editing in human cells and heterozygous embryos.

82
Q

Do the findings of the study suggest potential new therapies for Marfan Syndrome and related conditions?

A

Yes, the study explores new potential therapies for Marfan and Marfan-like syndromes.

Investigation Of Human Disease (19 decks)

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