nonsyndromic HL Flashcards
DFN
deafness neurosensory
for non-syndromic conditions what is the most sensible guess if you don’t know the inheritance pattern
recessive as this is the majority of the inheritance
non syndromic dominant conditions are identified by ____
DFNA
non syndromic recessive conditions are identified by ____
DFNB
DFNB1A =
connexin 26
DFNB1B =
connexin 26
what is the gene mutation of connexin 26
GJB2 gene mutation – Cx26
GJB6 gene mutation – Cx26
what do modifier genes do for HL
modify severity of HL, making it worse or mild
why do we see differences in expressivity and penetrance with recessive disorders
modifier genes
what is the primary mod of later onset nonsyndromic deafness
dominant
what do almost AD conditions show
post-lingual progressive HL but differ in :
-age of onset
-rate or progression
-ultimate degree of HL
-vestibular invovlement
AD non-syndromic HL examples
otosclerosis and DFNA5
otosclerosis
ossification of the stapes footplate and into the oval window
- incomplete penetrance and varying expressivity
-will commonly present as a complex genetic disorder
-genes affected cause abnormal bone metabolism but there are multiple genes that can be affected
what is otosclerosis triggered by
combination of genetics, environmental, hormonal and other factors
-can often present within pregnant women due to hormones
who is most vulnerable population for otosclerosis?
young white females - we don’t know why
pathogenesis of otosclerosis
a focal disease unique to the temporal bone
-disease of abnormal bone remodeling of the otic capsule
-no remodeling of the otic capsule occurs following embryologic development
site of lesion of otosclerosis
otic capsule
DFNA5
AD progressive SNHL
-HL is present in childhood and becomes worse with age
50% of AR non-syndromic HL is cuased by
connnexin 26 (GJB2 gene) mutation
what do AR conditions usually show
severe to profound SNHL that is pre-lingual in origin
-over 50% of AR HL is caused by connexin
what is connexin
a protein found in the cells throughout the body
NOT found in the cochlear hair cells
where can connexin 26 be found
The inner ear (including utricle & saccule - nonsensory epithelia)
Skin
Liver
Bladder
Placenta
Breast
Brain
where is connexin 26 not found
not found in the cochlear hair cells
what is the gene for connexin
GJB
GJB2, GJB6,
what is the protein product of GJB2
connexin 26 (Cx26)
what is the protein product of GJB6
connexin 30 (Cx30)
what is the best management for connexin?
CI
what does the gap junction do in terms of connexin
permits ion transfer between cytoplasm of cells
-when opens the potassium goes through
-when closed potassium does not go through
what happens to the gap when connexin is mutated
the gap junctions will not open or close which results in no regulation
how does the mendelian law’s relate to connexin
second law (independent assortment) - separate genes for separate traits
-connexin is an example of how this law does not hold to be true due to the close relation of the genes for connexin 26 and 30 one can influence the expression of the other
2nd law remidner card
law of independent assortment
-separate genes for separate traits are passed from parents to offspring independently of one another
-biological selection of one gene has nothing to do with the selection of the other gene
connexin’s structures
hexagonal array of proteins within the membrane of each cell that when lined up together can create a gap junction
-groups of 6 and wrapped around the connexon
what connexin proteins are involved in deafness
- Cx26 (DFNB1/DFNA3) (most common)
- Cx36
- Cx30 (GJB6-DFNA3; also common)
- Cx31
- Cx32 (DFN or DFNX, X-linked Charcot-Marie-Tooth Disease)
what is the most common allele mutation in connexin 26
35delG
-a frameshit mutation that will code for a different protein
audiologic findings with connexin 26
congenital HL
-severity of HL can be mild to profound
-usually bilateral
-wide variability
-sudden HL can occur
what else can occur with certain connexin phenotypes
skin diseases
-this is due to the protein being found throughout the body
-causes some patients to not be good CI candidates due to skin fragillity
what is usually the best intervention for patients with Cx26
CIs
-speech intervention needs to occur as well
x-linked non-syndromic HL examples
stapes fixation with perilymph gusher
stapes fixation with perilymph gusher
occurs when you are born with the stapes footplate within the oval window
-gusher: occurs during surgery to fix stapes and perilymph leaks out causing sudden HL
-without the surgery, HL can be mixed or progressive
mitochondrial non-syndromic HL examples
aminoglycoside induced ototoxicity
amunoglycoside induced ototoxicity
occurs when certain people take doses of this group of antibiotics and it causes irreversible HL
-occurs due to a mutation and the problem arises with not knowing you have the mutation
-experience sudden onset severe/profound SNHL when exposed to this medication
-not dose dependent
what are the 3 categories of genetic disease
- complex genetic disorders
- monogenic diseases
- environmental diseases
complex genetics
causes due to an interaction between genetics and the environment
monogenic
primarily caused by genes
The environment only plays a minor role
environmental diseases
you may have the disease but it wont manifest itself until environmental factors come into play
why is there no clear inheritance pattern for complex genetics
becuase there are several different variants responsible for the disease
what is an example of complex genetics
age related HL
-due to the root of the cause being hard to determine
age-related HL
not every older adult will have HL
-could be due to genetics, environmental factors, social life aspects
-multiple genes at play
-there is no diagnostic value
first & third recessive deafness (connexin deafness
DFNB1 & DFNB3
