Brainscape's Knowledge GenomeTM

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


See full index

Sensory Neuroscience 316 > Lecture 25: Inner ear disease part 2 > Flashcards

Lecture 25: Inner ear disease part 2 Flashcards

1
Q

Of the 100 genes associated with congenital hearing loss, what do they mostly code for?

A

50% of these genes related to sensory hair cells.

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

How is HHL characterised?

A

Based on their mode of transmission;

  • Autosomal Dominant
  • Autosomal recessive
  • X chromosome linked
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What can HHL be further divided into?

A

Non-syndronic

Syndronic (other sensory organs are affected) - 30%

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

What can non-syndronic HHL be further categorised into?

A
  • Autosomal Dominant
  • Autosomal recessive (75-85%)
  • X chromosome linked (1-2%)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What can autosomal recessive, non-syndronic HHL be further categorized into?

A

Two mains causes;

  • DFNB1 (50%) Cnx 26 mutation
  • Other DFNB
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Genes that cause hearing loss are found on what chromosomes?

A

Nearly all somatic chromosomes and x chromosome.

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

Has genetic models of HHL being bale to be reproduced?

A

HHL can be modelled in mice sucessfully

These models point towards several developmental defects leading to hearing loss

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

What are the three types of HHL studied in this course?

A

DFNB9 form
Usher syndrome
DFNB1 form

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

What is DFNB9 also known as?

A

Inner hair cell synaptopathy

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

What is DFNB9 form?

A

An auditory neuropathy, defined as a heairng loss characterised by the absence of auditory brain stem responses with preserved function of the OHC

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

What causes DFNB9?

A

Due to a defect in the synaptic protein otoferlin expressed in the IHC

(inner hair cell synaptopathy)

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

What can be used to understand that pathogenesis of DFNB9?

A

Otoferlin knockout mice are key to understanding DFNB9 pathogenesis

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

Whats the function of otoferlin?

A

Acts as a Ca sensor,

Ca binds to otoferlin and it mediates the binding of synaptic vesicles to the membrane for neurotransmitter release

Without otoferlin, synaptic transmission cannot occur even though Ca currents are normal

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

Describe how DFNB9 hearing impairment occurs;

A
  •  Otoferlin involved in IHC synaptic vesicle exocytosis as a Ca2+ sensor
  •  Electrophysiological studies in Otof -/- mice: Ca2+ currents normal, but fail to trigger synaptic vesicle exocytosis
  •  Otoferlin triggers synaptic vesicle-plasma membrane fusion at the IHC ribbon synapse
  •  Otof -/- mice profoundly deaf, just like DFNB9 patients
  •  Degenerative process of the IHC active zone and some afferent neurones likely to take place in DFNB9 patients
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is expected to be a major help for DFNB9?

A

- Early cochlear implant expected to be of major help

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

What does usher syndrome affect?

A

Vision
Hearing
Balance

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

Describe the genetic cause of usher syndrome and what is affects?

A
  •  USH is a monogenic sensory disability (autosomal recessive transmission)
  •  Causes sensorineural hearing loss, retinitis pigmentosa and balance problems
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

How many people are affected by ushers syndrome?

A

- 3-6% of all children who are deaf and another 3-6% of children who are hard-of-hearing have Usher syndrome.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What are the types of usher syndrome?

A
  •  Three clinical subtypes: USH I, USH II, USH III

-  Types 1 and 2 are the most common and account for approximately 90-95% of all cases of children with USH.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What would lead you to suspect that someone has ushers syndrome?

A
  • Juvenile age of onset, differential degree of hearing loss and balance problems, night blindness, progressive decrease of visual acuity
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Describe USH 1 symptoms with regards to the respective sensory systems;

A

Hearing; Profound bilateral deafness from birth

Vision; decreased night vision before 10 years

Balance; Balance problems from birth

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Describe USH 2 symptoms with regards to the respective sensory systems;

A

Hearing; Moderate to severe hearing loss from birth

Vision; decreased night vision begins late childhood or teens

Balance; Normal

23
Q

Describe USH 3 symptoms with regards to the respective sensory systems;

A

Hearing; Normal at birth, progressive loss in childhood or teens

Vision; Varies in severity, night vision problems often begins in teens

Balance: Normal to near normal, chance of later problems

24
Q

How is usher syndrome diagnosed?

A

Evaluation of all three senses:

  • Eye evaluation: visual field test, retinal examination and an electroretinogram (ERG).
  • Hearing evaluation: audiometry

-Balance: An electronystagmogram (ENG) measures involuntary eye movements that could signify a balance problem.

- Early diagnosis of Usher syndrome is very important (to learn how to live with multiple sensory defects)

25
Q

How many genes encode for each usher syndrome?

A

USH 1 = 5 genes
USH 2 = 3 genes
USH 3 = 1 gene

26
Q

What do all usher causing genes do?

A

Encode for proteins involved in sensory hair bundles. (hair bundle anomalies) (typically IHC for the cochlea)

These abnormalities are present prior to birth.

Also effects the retina photoreceptors

27
Q

What are usher proteins?

A

Normally proteins that connect adjacent stereocilia

At birth we naturally reduce the number of hair bundle links

28
Q

What happens when their is a mutation in the usher proteins?

A

It loosens the connection between the stereocilia

Therefore cannot move in a coordinated manner and causes sensorineural heairng loss as sounds transduction does not occur

29
Q

Describe what mutations occur because of the five genes in USH 1?

A
  • a molecular motor (myosin VIIa)
  • transmembrane Ca2+ dependent adhesion proteins(cadherin23 and protocadherin-15)
  • PDZ proteins (harmonin and sans)

Hair cells are the primary target of the hearing deficit and developing hair bundle in particular

Mice have the hearing and balance problems but not visual loss.

30
Q

What are the treatments for usher syndrome?

A

No treatment

Best practice is to;

  • Identify early so edcuational programs can begin asap
  • cochlear implants, hearing aids
  • orientation and independent living training
  • High doses Vit A may slow retinitis pigmentosa progression
31
Q

What is the most common type of HHL due to?

A

Gap junction defects

32
Q

What are the fucntions of gap junctions in the ear, which ones play a key role?

A
  • Gap junctions play a key role in K+ cycling in the cochlea and maintenance of the endocochlear potential (EP)
  •  Cx26 and Cx30 the main connexins of the cochlear gap junctions forming two major cellular networks: epithelial and connective
33
Q

Mutations in what gap junctions may lead to deafness?

A
  • Mutation in connexin 26 (Cx26 or GJB2) and Cx30 (GJB6) the major cause of congenital hearing loss
  • Mutations in connexins 29, 31 and 32 also cause deafness
34
Q

What do gap junctions form in the cochlea?

A

Gap junction cellular networks

35
Q

What are the gap junction networks in the cochlea?

A

Connective tissue gap junction system
•Fibrocytes (SL)
•Strial basal and intermediate cells
•Limbal fibrocytes

The epithelial cell gap junction system
•Root cells
•Supporting cells
•Interdental cells

Only IHC and OHC that dont have gap junctions, gap junctions allow for K recycling once K is extruded from the sensory cells by pumps.

36
Q

What is the most common connexin defect?

A

CX26 defect

  • Causative gene for DFNB1 and DFNA3 (a rare dominant form of deafness)
  • Mutations in Cx26 highly prevalent in caucasian population and account for 30-50% of non-syndromic congenital hearing loss

-Cx26 and Cx30 located close together on the same chromosome, hence combined point mutations/deletions possible

37
Q

Describe Cx26 knockout mice;

A
  • Have to use conditional Cx26 knockout mice as Cx26 is global and essential
  • Only moderate hearing impairment
  • But significant decrease in endolymph K concentrations
  • EP reduced by 50+%
  • Thus apoptosis in the organ of corti from postnatal day 14 onwards
38
Q

What causes the apoptosis in the organ of corti in Cx26 knockout mice?

A

- The absence of Cx26 in the epithelial gap junction network results in a local increase in extracellular K+ concentration in the basal region of hair cells that might be excitotoxic.
-  Cx30 which colocalises with Cx26 in cochlear gap junctions is not able to compensate for the lack of Cx26

39
Q

Describe Cx30 knockout mice;

A

Can globally knockout Cx30

  • Results in profound deafness
  • P13 onwards shows complete loss of EP before and histological alterations
  • Substantial cell death affecting both sensory and supporting cells
40
Q

In transgenic mice who lack Cx30 how can their hearing be saved?

A

By over expressing Cx26

Therefore suggesting that Cx30 in quantitative not qualitative in function, i.e there to boost gap junction numbers.

41
Q

How is hearing loss caused by Cx26 mutations diagnosed?

A
  •  Hearing loss found at birth or in early childhood
  •  Hearing loss mild, moderate, severe or profound
  •  Hearing loss without any other medical problem (non-syndromic)
  •  Hearing loss without obvious cause
42
Q

What is the use of testing for Cx26 mutation?

A
  •  Identify the cause of hearing loss
  • Exclude a syndromic form of hearing loss
  • Predict the prognosis of hearing loss
43
Q

Vestibular disorders can be;

A

central or peripheral vestibular disorders

44
Q

What are common symptoms of vestibular disorders?

A

Dizziness, vertigo, disequilibrium

45
Q

What are the main causes of vertigo?

A 
benign paroxysmal
positional vertigo 
Ménière’s disease 
vestibular neuritis 
labyrinthitis
46
Q

What defines mineires disease?

A
  • Vertigo attacks
  •  Fluctuating hearing loss
  •  Tinnitus (ringing in the ear)
  •  Auricular plenitude sensation (fullness in the ear/pressure)

Can be unilateral or bilateral

47
Q

What are other symptoms of mineires disease?

A
  •  Diarrhoea
  •  Headaches
  •  Pain or discomfort in the abdomen
  •  Nausea and vomiting
  •  Nistagmus (uncontrollable eye movements) (thus defining a vestibular problem)
48
Q

What causes mineires disease?

A

Fluid accumulation in the scala media

The pathophysiology is commonly explained by a distension of membranous labyrinth by the endolymph, known as endolymphatic hydrops

Either by blocked endolymphatic drainage or overproduction of fluid by stria vacularis, pushes on scala vestibuli

49
Q

What are the eitiological factors of endolymphatic hydrops?

A 
Genetic
Infection
vascular
dietary
allergy
autonomic
endocrine
autoimmune

A AGE DIVA

50
Q

What is the pathophysiology of mineires disease?

A

No sign of sensory or neural losses in disease patients

Hydrops is the most consistent pathological abnormality

However is not conclusively the cause as some people have these and no symptoms and others dont have them but have the symptoms.

51
Q

What has animal studies indicated regarding menieres disease?

A

cytochemical and ultrastructural lesions
affecting the fibrocytes within the spiral ligament, hair cells, and cochlear neurons.

Occur before!!! development endolymphatic hydrops

52
Q

Additionally to endolymphatic hydrops what other pathology occurs?

A

Type I and II fibrocytes of the spiral ligament are the most severely affected cochlear cells

Changes in the cytochemistry of Type I and Type II fibrocytes and of nonsensory epithelial cells before the development of hydrops.

Staining found increased NaClK cotransporter presence and decreased JNK (kinase)

53
Q

What does increased NaClK and decreased JNK mean?

A

NKCC1 is involved in regulation of cellular
volume in response to osmotic stress.
Changes reflect compensatory mechanisms for regulation of cell volume.

JNK is known to be a critical player in many
forms of cellular stress responses.
The decrease in staining for JNK indicates that the fibrocytes are under stress.

Therefore
Hydrops is the result rather than the cause of disordered cochlear homeostasis.

54
Q

What other cytochemical abnormalities are present in meniers disease?

A

Studies on hydropic cochleae have demonstrated an increase in NOS II expression, oxidative stress and caspase 3 activation, leading to apoptosis in SGN.

i.e hydrops = cyotchrome c release =
Increased oxidative stress
Increase glutamate release and excitotoxicity
= resulting in Increased apoptosis

Sensory Neuroscience 316 (32 decks)

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