NOnsyndromic HL & Deafness Flashcards
1
Q
what is nonsyndromic hl
A
only hl is associated
2
Q
how many genetic deafness is nonsyndromic
A
75-85%
3
Q
DFN
A
deafness neurosensory
4
Q
dominant conditions are identified by symbol
A
DFNA1
5
Q
recessive conditions are identified by symbol
A
DFNB
6
Q
DFNB1A =
A
connexin 26
7
Q
DFNB1B =
A
connexin 26
8
Q
what is the gene mutation of connexin 26
A
GJB2 gene mutation – Cx26
GJB6 gene mutation – Cx26
9
Q
most common associated with nonsyndromic hl
A
GJB2 gene mutation – Cx26
GJB6 gene mutation – Cx26
10
Q
what do modifier genes do for HL
A
modify severity of HL, making it worse or mild
11
Q
how are modifier genes identified
A
with the primary AR or AD genes and explain intra-familial variability with identical mutations
12
Q
why do we see differences in expressivity and penetrance with recessive disorders
A
modifier genes
13
Q
what are transcription factors
A
proteins (excluding rna polymerase) involved in initiating and regulating trasncription of genes (DNA) to RNA
14
Q
Which is the primary mode of congenital nonsyndromic deafness
A
recessive
15
Q
what is the primary mod of later onset nonsyndromic deafness
A
dominant
16
Q
Almost all of the autosomal dominant conditions show
A
post-lingual progressive hearing loss
17
Q
post lingual
A
later on, after child has acquired the language
18
Q
almost all AD conditions of HL start in high frequencies but differ in
A
age of onset
rate of progression
ultimate degree of HL
vestibular involvement
19
Q
what is otosclerosis
A
specific to ossificatioin of footplate of the stapes and its ossification into the oval window
20
Q
later onset, increased chances of it being
A
dominant
21
Q
If otosclerosis inherited, then it is an
A
autosomal dominant disorder and exhibits incomplete penetrance
22
Q
what is post-lingual
A
- later on, after child has acquired the language
23
Q
what is otosclerosis
A
ossification of the stapes footplatend its ossification into the oval window
24
Q
Otosclerosis may look like it _________ even though they may have the gene
A
skips generations or members of the same generation
25
what most likely triggers otosclerosis
by a combination of genetic, environmental, hormonal, and/or other factors
26
when do we look at otosclerosis hormonal trigger?
when there is a gender difference
27
why is otosclerosis complex?
so many different genes and loci involved and most common is the OTSC gene
28
What is the site of lesion of otosclerosis
Starts around the otic capsule
only takes place at the otic capsule
after embryo structures are into place,no remodeling occurs following this development
so this happens post birth
usually once they are layed down, no new remodelig occurs but with this it does happen
29
Single most common cause of hearing loss in young adulthood
otosclerosis
30
In 50% of females, initial awareness or rapid acceleration of the hearing loss occurs during or immediately after
pregnancy
31
what can worsen otosclerosis
after menopause (because of change of hormones
32
who is most vulnerable population for otosclerosis?
young white females - we don’t know why
33
what is DFNA5
AD nonsyndromic progessive SNHL
34
what happens in DFNA5
Hearing loss is present in childhood and becomes worse as affected individuals grow older
35
is otosclerosis progressive
YES
Cna go from conducive to mixed
Usually doesn’t progress to deafness
36
> 50% of autosomal recessive nonsyndromic hearing loss is caused by
Connexin 26 (GJB2 gene) mutations
36
almost all recessive conditions are associated with
profound SNHL that is prelingual
37
what is connexin 26
protein found in cells throughout the body
38
where can connexin 26 be found
The inner ear (including utricle & saccule - nonsensory epithelia)
Skin
Liver
Bladder
Placenta
Breast
Brain
39
where in the ear are connexins found
not cochlear hair cells
in nonsensory epithelial cells and supporting cels
40
what is the best management for connexin?
CI's
41
most common connexin disorders
26, 30
42
what are the connexin proteins
connexin 26
connexin 30
43
what are the connexin deafness genes
GJB
44
What are DFNB1 & DFNB3
first and third recessive connexin deafness
45
what is the protein product of GJB2
connexin 26
46
what is the protein product of GJB6
Connexin 30
47
what is the gene for connexin 26
GJB2
48
what is the gene for connexin 30
GJB6
49
What is connexin
inherited nonsyndromic hearing loss (mild to severe) and deafness usually congenital
50
if a baby has connexin and isn't diagnosed until age 2, is it still congenital
yes it can be
51
98% connextin mutations are found
GJB2 (small gene with entire coding sequence in exon 2)
52
associated with >50% of nonsyndromic SNHL
connexin 26 (GJB2)
53
Mutations in the connexins are responsible for
diversity of diseases, including deafness and skin disorders
54
if it is recessive and more common in certain populations?
founder effect = consanguinity which is why we see it so much in the deaf communities
55
most frequent cause of AR deafness
mutations of the connexins
56
what is a gap junction
when two cells are very close, and they come together and through the ion channels, the ions are exchanged
57
what happens if connexin intercellular communication is mutated
If they are mutated, they will not open and close, then the gap junctio nis defected and K+ ions cannot go in or out (cannot regulate potassium or calcium ions)
Clinically results in deafness or severe to profound SNHL
58
what makes up a connexin
6 individual connexins
59
describe mendelians second mendelia law of independent assortment
one gene transmitted is not influenced by other genes on that chromosome unless they are very close
alleles of different genes assort independently of one another during gamete formation
60
what is an example of when mendelian law of independent assortment doesn't hold tru
connexin deafness
Because they are so closely linked to each other, when an individual has a specific type of mutation in GJB6, it can influence the expression of the GJB2 gene
As a result, individuals can have hearing loss when they have two mutations in the GJB2 gene or two mutations in the GJB6 gene, or one mutation in each of these genes
61
if there are two mutations in the GJB gene, chance of passing GJB2 or 6 to offspring rises
from 50% to 100%
62
very common for GJB2 & GJB6 to be transmitted ______
together
63
what is the mode of transmission of connexin?
AR
64
List the several connexin proteins that are involved in human deafness
Cx26 (DFNB1/DFNA3) (most common)
Cx30 (GJB6-DFNA3; also common)
Cx32 (DFN or DFNX, X-linked Charcot-Marie-Tooth Disease)
65
what is a deletion mutation
one base is deleted in the nucleotide
66
single most common mutation in Caucasians and Asians with Connexin 26
35delG
67
35delG mutation arises from
deletion - frameshift mutation
68
35delG causes
truncated proteins
69
How do connexin 26 present themselves?
congenital, recessive, bilateral
Born with a hearing loss
small % will lose hl soon after birth
mild to profound (depending on genotype)
most of the cases will progress so why we have to watch them
70
what are other connexin phenotypes
Skin diseases and deafness and GJB2 mutations
71
why are we concerned with skin issues?
treatment is CI’s because they have nothing else going on like cognitive impairment etc., but if they have skin issues and put the processor on it will rub on the skin and cause it to bleed, more likely to get infected
May not be candidates for it then because of this skin implication
What would you do to provide auditory input? They will fxn as deaf individuals, like sign lanaguage
72
what is an xlinked nonsyndromic HL
x linked congenital stapes fixation with perilymph gusher
73
what is the difference between congenital stapes fixation with perilymph gusher and otosclerosis
they are born with it fixated into the oval window
it is congenital
otosclerosis is developed over time
74
what is x linked congenital stapes fixation with perilymph gusher
mixed hl
increase in hl if surgery is performed
can be progressive
females have milder symptoms
75
why would hl increase if surgery occurs with x linked congenital stapes fixation with perilymph gusher
When you remove the footplate, the perilymph will gush out
Instead of correctible hearing loss with HA’s, there is a severe SNHL that may not be fixed with HA’s
76
what is x linked congenital stapes fixation with perilymph gusher commonly misdiagnosed as
otosclerosis
77
what is an example of mitorchondrial nonsyndromic HL
Aminoglycoside-induced ototoxicity
78
what is an Irreversible but preventable hearing loss
Aminoglycoside-induced ototoxicity
79
Mechanism of ototoxicity of aminoglycosides is due to
interference with the production of ATP in the mitochondria of cochlear hair cells
80
Patients may have sudden onset ________ when exposed to aminoglycosides, which is generally not progressive
severe/profound SNHL
81
is Aminoglycoside-induced ototoxicity dose dependent?
NO
they are not dose dependent
82
what is not dose dependent
can take one or two doses and see the effects
83
what is dose dependent
can take it a lot before seeing any issues
84
what are the 3 categories of genetic disease
complex genetic disorders
monogenic diseases
environmental diseases
85
what are complex diseases
caused in part by the environment and in part by genes as well as by an interaction between the two
86
what is monogenic disease
primarily caused by genes
The environment only plays a minor role
87
what is environmental diseases
primarily caused by the environment
Genes can play a minor role such as to determine a person’s susceptibility to being infected by certain infectious agents
88
risk of single genetic variance that results in increased risk
mendelian disease
89
a lot of variants are needed and the additive effect of a lot of variants cause the disorder
complex genetics
90
why is there no clear inheritance pattern for complex genetics
becuase there are several different variants responsible for the disease
91
what are many complex genetic diseases are due to
single nucleotide polymorphisms (SNPs)
92
what is an example of complex diseases
age related hearing loss
93
give an example of age related hl
Most 20-year-olds do not have a hearing loss but at least 50% of 70-year-olds do
There also is a difference between the best and worst hearing 70-year-olds
this is caused by genes and the environment
