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PBLs FunMed > Week 5 - Ehlers Danlos > Flashcards

Week 5 - Ehlers Danlos Flashcards

1
Q

Where is the point mutation in COL5A1 in this case of Classic Ehlers Danlos?

A

Mutation in exon 3 of the COL5A1 gene
Cytosine to Thymine

Going from Glutamine to a stop codon
Nonsense mutation
Premature stop codon means the gene isn’t functional

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2
Q

Define child abuse.

(2 marks)

A

An abused child is a boy or girl under the age of 18 years who has suffered physical injury, neglect, emotional or sexual abuse which the person or persons who had custody, charge or care of the child either caused or knowingly failed to prevent.

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3
Q

What is the normal role of collagen V in the connective tissue?

(1 mark)

A

It regulates the diameter of collagen type I fibrils

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4
Q

What type of joint is the shoulder joint?

1 mark

A

Synovial ball and socket

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5
Q

What is the role of the Children and Family Court Advisory and Support Service in cases like this?

2 marks

A

Any 2 relevant points:

When a local authority applies to take a child into care, Cafcass’ job is to ensure that decisions are made in the child’s best interest. (1 mark)

The court will usually request for Cafcass to become involved in the case so that the Cafcass worker is known as a ‘children’s guardian’ (1 mark).

The guardian is the independent voice of the child in court (1 mark).

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6
Q

What does SDS-PAGE stand for?

A

Sodium dodecyl sulphate polyacrimide gel electrophoresis

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7
Q

How do Type V and Type I come together?

A

Type V and Type I collagen come together to form heterotypic fibrils

Type V collagen shown to regulate the diameter of the fibrils

Important as collagen needs to be densely packed

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8
Q

How many different types of conditions come under Ehlers Danlos?

A

13

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9
Q

Which type of collagen is most abundant in tissues?

A

Type I

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10
Q

Which type of collagen has been associated with Ehlers Danlos?

A

Type V

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11
Q

What kind of haploinsufficiency do you see in Classic Ehlers Danlos and what does this result in?
What does a COL5A1 mutation result in?

A

One gene of collagen V is functional and working well, the other is not

So you don’t have enough collagen V
Because you have a loss of function in COL5A1 mRNA and hence less of the alpha 1 (V) procollagen chains

Therefore get some normal and some abnormal collagen V

Irregular fibrils in the dermis

Less strength in connective tissues, skin etc and abnormal wound healing

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12
Q

What is Ehlers Danlos?

A

A collection of heritable connective tissues disorders classified according to its symptoms and signs

13 different types

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13
Q

What is a non-conservative missense mutation?

A

A point mutation that codes for a different amino acid with different properties

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14
Q

What is haploinsufficiency?

A

Only have one functional copy of a gene

Half the dose causing a pathological phenotype - cannot provide sufficient gene product

Often caused by a LOF mutation

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15
Q

What is the structure of Type V collagen?

A

It is made of 3 chains
2 alpha1 chains
1 alpha2 chain

Heterotrimer

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16
Q

What is the inheritance pattern of Ehlers Danlos?

A

Autosomal Dominant

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17
Q

How common is Ehlers Danlos?

A

1 in 5000 births

Rare

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18
Q

What is the major criteria for Ehlers Danlos?

A

Skin hyperextensibility

Widened atrophic scarring (due to tissue fragility)

Joint hypermobility

Positive family history

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19
Q

Name 5 minor criteria for Ehlers Danlos

A

Smooth velvety skin

Molluscoid pseudotumours (fleshy, heaped up lesions associated with scars over pressure points e.g. elbows and knees)

Subcutaneous spheroids (small, hard cyst-like nodules, freely moveable in the subcutis over the bony prominences of the legs and arms, which have an outer calcified layer with a translucent core on X-ray)

Complications of joint hyper-mobility (sprains, dislocations/subluxations and pes planus)

Muscle hypotonia, delayed gross motor development

Easy bruising

Manifestions of tissue extensibility and fragility (anal prolapse in childhood, hiatal hernia, cervical insufficiency)

Surgical complications (postoperative hernias)

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20
Q

Why is the skin so fragile and flexible?

A

Mutation in the collagen fibres so skin is very flexible

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21
Q

Why are the joints hypermobile?

A

Collagen is in the ECM of the tendons

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22
Q

Why do patients bruise easily?

A

Less collagen in the blood vessels so the blood becomes more leaky and the blood vessels get damaged easily

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23
Q

What does diagnosis of Ehlers Danlos require?

A

3 major criteria

1 minor criteria

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24
Q

What does culturing fibroblasts mean?

A

Take fibroblasts from Andreas’ cells and grow them on a petri dish

Process the fibroblasts for gel electrophoresis

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25
Q

Explain electrophoresis

A

Charged molecules move up a gel

Current passed through the gel and then the proteins move up depending on their size and shape (weight)

Collagen was processed from dermal fibroblasts

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26
Q

What does haematoma mean?

A

The abnormal collection of blood that has usually clotted outside of a blood vessel

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27
Q

What is a subcutaneous nodule?

A

A firm lump under the skin that is often the result of infection/inflammation

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28
Q

What does hyper-extensible mean?

A

Being able to be stretched to a greater than normal degree

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29
Q

What does episiotomy mean?

A

A surgical cut made in the perineum to enlarge the vaginal opening for childbirth

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30
Q

What is a skin biopsy?

A

A small sample of skin is removed and examined under an electron microscope

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31
Q

The results from this showed the electrophoretic pattern of the (pro)collagen type I, II and V proteins, secreted in the medium showed a normal profile.

What does the electrophoresis pattern show?

A

Normal

All (pro)collagen I, II, V proteins were shown to be normal

So all were present but doesn’t show the mutations

32
Q

What are other symptoms that might suggest Ehlers Danlos?

A

Fibromyalgia
IBS
Chronic pain
Gorlin’s sign (can touch your nose with your tongue)

Flying bird bands (hypermobility syndrome)

33
Q

What percentage of people who have Ehlers Danlos are diagnosed?

A

5%

Incidence thought to be 1:200 (found through sequencing data and people having the mutations but are not diagnosed)

34
Q

What is SDS-PAGE used for?

A

Proteins not genes

Doesn’t tell us if the proteins are mutated but tells us the amount of protein present

Can help detect severity of the symptoms or type

35
Q

What does Andreas’ electrophoresis show us?

A

Has reduced type III and reduced type V

Can’t tell if V is normal/functional or mutated

36
Q

What is a silent mutation?

A

You have a mutation in the triplet code and it produces the same amino acid

37
Q

However, sequence analysis of the entire coding region for COL5A1 (exons 1-66) and all intron-exon boundaries along the COL5A1 gene identified a heterozygous variant (c.379C>T) in exon 3, which is predicted to cause a nonsense mutation from the substitution of glutamine causing a premature stop codon and thus a truncated COL5A1 protein or reduced COL5A1 mRNA due to RNA decay confirming the clinical suspicion of classic Ehler-Danlos.

How does gene sequencing help the diagnosis of Andreas?

A

Electrophoresis shows us that the Collagen V is present and reduced but doesn’t tell us more

Gene-sequencing tells us that Collagen V is mutated and where and that it is truncated and non functional

38
Q

However, sequence analysis of the entire coding region for COL5A1 (exons 1-66) and all intron-exon boundaries along the COL5A1 gene identified a heterozygous variant (c.379C>T) in exon 3, which is predicted to cause a nonsense mutation from the substitution of glutamine causing a premature stop codon and thus a truncated COL5A1 protein or reduced COL5A1 mRNA due to RNA decay confirming the clinical suspicion of classic Ehler-Danlos.

What is the coding region of COL5A1?

A

Exons 1-66

39
Q

However, sequence analysis of the entire coding region for COL5A1 (exons 1-66) and all intron-exon boundaries along the COL5A1 gene identified a heterozygous variant (c.379C>T) in exon 3, which is predicted to cause a nonsense mutation from the substitution of glutamine causing a premature stop codon and thus a truncated COL5A1 protein or reduced COL5A1 mRNA due to RNA decay confirming the clinical suspicion of classic Ehler-Danlos

In which exon is the mutation?

A

33

40
Q

However, sequence analysis of the entire coding region for COL5A1 (exons 1-66) and all intron-exon boundaries along the COL5A1 gene identified a heterozygous variant (c.379C>T) in exon 3, which is predicted to cause a nonsense mutation from the substitution of glutamine causing a premature stop codon and thus a truncated COL5A1 protein or reduced COL5A1 mRNA due to RNA decay confirming the clinical suspicion of classic Ehler-Danlos.

What is the amino acid change?

A

Glutamine to a premature stop codon

CAA to TAA
CAG to TAG

41
Q

What does degeneracy in the genetic code mean?

A

More than one triplet code codes for an amino acid

42
Q

What is the role of Collagen V?

A

Regulates fibril formation and diameter of type I collagen fibrils

and co-polymerization of collagen Type I

43
Q

What are the different ways Andreas is diagnosed in this scenario?

A

Physical examination

Assess hypermobility using the Beighton criteria

Skin biopsy for collagen typing

Collagen gene mutation testing

44
Q

What are the steps of collagen formation?

A 
Procollagen
Fibril nucleation
Fibril intermediates
Linear fusions
Lateral fusions
Heterotypic fibril
45
Q

What normally makes Type I collagen fibrils strong?

A

Regular diameter

Regular length

46
Q

What is the result of haploinsufficiency of COL5A1?

A

Less Collagen V than there should be due to less [a1 (V) pro collagen chains]

The reduction of Collagen V cannot compensate so you have symptoms

47
Q

What percentage of Classic EDS cases have a haploinsufficiency of Collagen V?

A

30-50%

48
Q

What percentage of dry weight of skin is collagen?

A

70%

49
Q

What percentage of the collagen in the skin is Collagen I?

A

80%

50
Q

What percentage of the collagen in the skin is Collagen III?

A

15%

51
Q

What percentage of the collagen in the skin is Collagen V?

A

5%

52
Q

What chains is collagen made of?

A

3 alpha chains
2 a1, 1 a2
or 1a1 and 2a2

53
Q

Where is collagen synthesised and what is the starting product?

A

Pro collagen

In the rough endoplasmic reticulum

54
Q

After the rER where is the collagen synthesised?

A

It is secreted out of the cell and processes/aggregates outside the cell

At this point it is a mature collagen proteins

55
Q

What repeat do you have in the alpha chains of collagen?

A 
Triplet repeat
Predominantly glycine (every 3rd amino acid)

G X Y
Glycine - Proline - Y

Y = Hydroxyproline derived from proline
or Hydroxylysine derived from lysine

56
Q

How do the properties of glycine contribute to the structure of the alpha chain?

A

Smallest amino acids with no side chains (H)

Allows close association of collagen fibres facilitating hydrogen bonding

Strong molecules due to close packing

57
Q

What is the dermis like in EDS patients?

A

Looser with few bundles
Varying diameter
Abnormal wound healing

58
Q

What is the skin structure layers?

A

Epidermis and dermis

59
Q

What cells are in the epidermis?

A

Stratified squamous epithelium

Keratinocytes (Langerhans cells (dendritic cells - APCs) and melanocytes

60
Q

What cells are in the dermis?

A

Dense irregular connective
Fibroblasts

Not regular but random, gives the property of not tearing when pressure is applied

61
Q

What are the 4 stages of wound healing?

A
  1. Haemostasis (vascular constriction and clotting (platelets and fibrin))
  2. Inflammation (release of cytokines and growth factors, WBC to remove dead cells and provide defence against microbes)

Continues from start to day 10, redness around the wound

  1. Proliferation (fibroblasts and keratinocytes proliferate and start to make new ECM, initial formation of scar (epithelial cells are
  2. Remodelling (scar is 80% of normal skin strength) huge upregulation of collagen synthesis (I and V)

Balance between collagen synthesis and destruction

Changing of Collagen III to type I

Water is reabsorbed from this area to allow collagen to contract and become closer together

Wound contracts so the scar does not gape

62
Q

What happens in wound healing for EDS patients?

A

Wounds do not contract in EDS as collagen is not structurally sound

Mainly affecting the remodelling stage

Wounds are ‘gaping’ (doesn’t actually close properly) like a cigarette scar

Wounds are wide and thin

63
Q

Which stage of the wound healing process is predominantly effected in EDS patients?

A

Stage 4 - Remodelling

64
Q

What happens in the remodelling stage of Wound Healing?

A

Stage 4:
Remodelling (scar is 80% of normal skin strength) huge upregulation of collagen synthesis (I and V)

Balance between collagen synthesis and destruction

Changing of Collagen III to type I

Water is reabsorbed from this area to allow collagen to contract and become closer together

Wound contracts so the scar does not gape

65
Q

What happens in the Proliferation stage of Wound Healing?

A

Stage 3:
Proliferation (fibroblasts and keratinocytes proliferate and start to make new ECM, initial formation of scar (epithelial cells are

66
Q

What happens in the Inflammation stage of Wound Healing?

A

Stage 2:
Inflammation (release of cytokines and growth factors, WBC to remove dead cells and provide defence against microbes)

Continues from start to day 10, redness around the wound

67
Q

Why does the anaesthetic does not work?

A 
Not known
Sodium channels (Sodium 1.7 and 1.8) linked to pain could be linked to mutations in collagen V

May explain why the anaesthetic doesn’t interact with the sodium channels

68
Q

What is child abuse?

A

Any action by another person adult or another child that causes significant harm to a child

69
Q

What is neglect?

A

The failure of parent or another person with a responsibility for a child to provide food, clothing, shelter, medical care or supervision to degree of that child for health, safety and wellbeing so that they are threatened with harm

70
Q

Child

A

Under 18

71
Q

What are the sub topics of child abuse?

A 
Neglect
Physical abuse
Sexual abuse
Exploitation
Emotional abuse
Online cyberbullying
72
Q

What are the actual layers of the skin?

A
  1. Stratum corner (C)
  2. Stratum lucid (L)
  3. Stratum granulosom (G)
  4. Stratum spinous (S)
  5. Stratum basale (B)
  6. Dermis

Corny Lucy gets super baked

73
Q

Give three types of genetic point mutations briefly describe each

Which type is seen in this scenario? (3)

A
  1. Silent mutations: base changes but codes for the same amino acid
  2. Missense mutations: Codes for a different amino acid
  3. Nonsense mutations: Codes for a stop codon, resulting in early termination of transcription

This case is a nonsense mutation

74
Q

Which type of collagen is dominant in bone, tendon and skin?

Therefore explain what molecular abnormality causes the symptoms seen in classical EDS (4)

A

Collagen Type I

In Classical EDS, Type V is structurally abnormal and therefore cannot function optimally

Collagen V regulates fibril formation and copolymerisation of collagen I which is therefore effected in EDS

As Collagen I is the most abundant collagen in bone, tendon and skin, this results in weakness of these structures

This is shown in symptoms of hyper-extensile skin, hyper mobile joints and easy bruising

75
Q

Give 3 major and 1 minor diagnostic criteria of classical Ehlers Danlos Syndrome

A

Positive family history
Joint hyper-mobility
Skin hyper-extensibility
Atrophic scars

Easy bruising

PBLs FunMed (8 decks)

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