NOnsyndromic HL & Deafness Flashcards
what is nonsyndromic hl
only hl is associated
how many genetic deafness is nonsyndromic
75-85%
DFN
deafness neurosensory
dominant conditions are identified by symbol
DFNA1
recessive conditions are identified by symbol
DFNB
DFNB1A =
connexin 26
DFNB1B =
connexin 26
what is the gene mutation of connexin 26
GJB2 gene mutation – Cx26
GJB6 gene mutation – Cx26
most common associated with nonsyndromic hl
GJB2 gene mutation – Cx26
GJB6 gene mutation – Cx26
what do modifier genes do for HL
modify severity of HL, making it worse or mild
how are modifier genes identified
with the primary AR or AD genes and explain intra-familial variability with identical mutations
why do we see differences in expressivity and penetrance with recessive disorders
modifier genes
what are transcription factors
proteins (excluding rna polymerase) involved in initiating and regulating trasncription of genes (DNA) to RNA
Which is the primary mode of congenital nonsyndromic deafness
recessive
what is the primary mod of later onset nonsyndromic deafness
dominant
Almost all of the autosomal dominant conditions show
post-lingual progressive hearing loss
post lingual
later on, after child has acquired the language
almost all AD conditions of HL start in high frequencies but differ in
age of onset
rate of progression
ultimate degree of HL
vestibular involvement
what is otosclerosis
specific to ossificatioin of footplate of the stapes and its ossification into the oval window
later onset, increased chances of it being
dominant
If otosclerosis inherited, then it is an
autosomal dominant disorder and exhibits incomplete penetrance
what is post-lingual
- later on, after child has acquired the language
what is otosclerosis
ossification of the stapes footplatend its ossification into the oval window
Otosclerosis may look like it _________ even though they may have the gene
skips generations or members of the same generation
what most likely triggers otosclerosis
by a combination of genetic, environmental, hormonal, and/or other factors
when do we look at otosclerosis hormonal trigger?
when there is a gender difference
why is otosclerosis complex?
so many different genes and loci involved and most common is the OTSC gene
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
Single most common cause of hearing loss in young adulthood
otosclerosis
In 50% of females, initial awareness or rapid acceleration of the hearing loss occurs during or immediately after
pregnancy
what can worsen otosclerosis
after menopause (because of change of hormones
who is most vulnerable population for otosclerosis?
young white females - we don’t know why
what is DFNA5
AD nonsyndromic progessive SNHL
what happens in DFNA5
Hearing loss is present in childhood and becomes worse as affected individuals grow older
is otosclerosis progressive
YES
Cna go from conducive to mixed
Usually doesn’t progress to deafness
> 50% of autosomal recessive nonsyndromic hearing loss is caused by
Connexin 26 (GJB2 gene) mutations
almost all recessive conditions are associated with
profound SNHL that is prelingual
what is connexin 26
protein found in cells throughout the body
where can connexin 26 be found
The inner ear (including utricle & saccule - nonsensory epithelia)
Skin
Liver
Bladder
Placenta
Breast
Brain
where in the ear are connexins found
not cochlear hair cells
in nonsensory epithelial cells and supporting cels
what is the best management for connexin?
CI’s
most common connexin disorders
26, 30
what are the connexin proteins
connexin 26
connexin 30
what are the connexin deafness genes
GJB
What are DFNB1 & DFNB3
first and third recessive connexin deafness
what is the protein product of GJB2
connexin 26
what is the protein product of GJB6
Connexin 30
what is the gene for connexin 26
GJB2
what is the gene for connexin 30
GJB6
What is connexin
inherited nonsyndromic hearing loss (mild to severe) and deafness usually congenital
if a baby has connexin and isn’t diagnosed until age 2, is it still congenital
yes it can be
98% connextin mutations are found
GJB2 (small gene with entire coding sequence in exon 2)
associated with >50% of nonsyndromic SNHL
connexin 26 (GJB2)
Mutations in the connexins are responsible for
diversity of diseases, including deafness and skin disorders
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
most frequent cause of AR deafness
mutations of the connexins
what is a gap junction
when two cells are very close, and they come together and through the ion channels, the ions are exchanged
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
what makes up a connexin
6 individual connexins
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
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
if there are two mutations in the GJB gene, chance of passing GJB2 or 6 to offspring rises
from 50% to 100%
very common for GJB2 & GJB6 to be transmitted ______
together
what is the mode of transmission of connexin?
AR
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)
what is a deletion mutation
one base is deleted in the nucleotide
single most common mutation in Caucasians and Asians with Connexin 26
35delG
35delG mutation arises from
deletion - frameshift mutation
35delG causes
truncated proteins
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
what are other connexin phenotypes
Skin diseases and deafness and GJB2 mutations
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
what is an xlinked nonsyndromic HL
x linked congenital stapes fixation with perilymph gusher
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
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
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
what is x linked congenital stapes fixation with perilymph gusher commonly misdiagnosed as
otosclerosis
what is an example of mitorchondrial nonsyndromic HL
Aminoglycoside-induced ototoxicity
what is an Irreversible but preventable hearing loss
Aminoglycoside-induced ototoxicity
Mechanism of ototoxicity of aminoglycosides is due to
interference with the production of ATP in the mitochondria of cochlear hair cells
Patients may have sudden onset ________ when exposed to aminoglycosides, which is generally not progressive
severe/profound SNHL
is Aminoglycoside-induced ototoxicity dose dependent?
NO
they are not dose dependent
what is not dose dependent
can take one or two doses and see the effects
what is dose dependent
can take it a lot before seeing any issues
what are the 3 categories of genetic disease
complex genetic disorders
monogenic diseases
environmental diseases
what are complex diseases
caused in part by the environment and in part by genes as well as by an interaction between the two
what is monogenic disease
primarily caused by genes
The environment only plays a minor role
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
risk of single genetic variance that results in increased risk
mendelian disease
a lot of variants are needed and the additive effect of a lot of variants cause the disorder
complex genetics
why is there no clear inheritance pattern for complex genetics
becuase there are several different variants responsible for the disease
what are many complex genetic diseases are due to
single nucleotide polymorphisms (SNPs)
what is an example of complex diseases
age related hearing loss
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
