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AUDE 5310 > nonsyndromic conditions > Flashcards

nonsyndromic conditions Flashcards

1
Q

what are nonsyndromic conditions?

A

HL alone, nothing else is seen

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2
Q

how many genetic deafness is nonsyndromic

A

75-85%

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3
Q

what does DFN stand for ?

A

deafness neurosensory

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4
Q

what are dominant conditions is written in deafness neurosensory

A

DFNA1

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5
Q

how are recessive conditions written in deafness neurosensory?

A

DFNB1A = Connexin 26 (GJB2 gene mutation – Cx26)
DFNB1B = Connexin 26 (GJB6 gene mutation – Cx26)
*NOTICE HOW THE GENE IS DIFFERENT AND ONE ENDS IN A AND THE OTHER ENDS IN B

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6
Q

how are x linked conditions written in deafness neurosensory?

A

DFN or DFNX1-7 (7 loci - 3 genes)

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7
Q

how are y linked conditions written

A

DFNY (2 loci and 1 known gene)
theyre rare tho

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8
Q

how do modifier genes affect nonsyndromic conditions

A

-Modifier genes modify severity of HL, making it worse or mild
-They are identified with the primary AR or AD genes and explain intra-familial variability with identical mutations

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9
Q

what are the percentages in nonsyndromic deafness in being recess, dome or x linked

A

~ 15 - 24% are inherited in a dominant fashion
~ 75 - 85% are inherited in a recessive fashion
~ 1 - 2% are X-linked or have other (primarily mitochondrial) modes of inheritance
notice how the majority are recessive

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10
Q

how are many forms of deafness a result from?

A

-Several forms of deafness are known to occur as a result of mutations of transcription factors
-Theses are proteins (excluding RNA polymerase) involved in initiating and regulating transcription of genes (DNA) to RNA

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11
Q

how are dominant conditions typically seen in?

A

post-lingual progressive hearing loss starting in the high frequencies

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12
Q

how do dominant nonsyndromic conditions differ?

A

-Age of onset
-Rate of progression
-Ultimate degree of hearing loss
-Vestibular involvement

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13
Q

what must you do in order to diagnosis a dominant nonsryndromic HL

A

-Diagnosis in all cases must first exclude nongenetic causes as well as other nonsyndromic hearing loss
-Generally, an autosomal dominant pattern is readily apparent

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14
Q

is otosclerosis dom or recessive?

A

dom

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15
Q

is the penetrance complete or incomplete in otosclerosis ?

A

-it’s incomplete
-Otosclerosis may look like it skips generations or members of the same generation even though they may have the gene

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16
Q

how does otosclerosis present as ?

A

-it presents as complex genetic disorder because they’re multiple factors, the genetic component isn’t enoughto set the disease in motion
-Otosclerosis may look like it skips generations or members of the same generation even though they may have the gene
-it’s complex because multiple genes are involved

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17
Q

what is the pathology in otosclerosis?

A

It is a disease of abnormal bone remodeling (bone metabolism to form new bone) of the otic capsule (how it affects the ear)

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18
Q

where is the site of lesion in otosclerosis ?

A

the site of lesion starts around the optic capsle (because thats where the bone remodeling is

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19
Q

how often does otoclerosis happen?

A

0.3 to 0.4 %

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20
Q

how is each age group affected in otosclerosis?

A

Single most common cause of hearing loss in young adulthood
Mean age of onset is between 20 to 30 years
90% of affected individuals are < 50 years at the time of diagnosis
~ 10% develop profound SNHL across all frequencies

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21
Q

do men or women get otosclerosis ?

A

female get it more ?

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22
Q

what race is more at risk with otosclerosis?

A

-at risk: white
-not at risk:black hispanic asians

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23
Q

what is DFNA5 ?

A

Single most common cause of hearing loss in young adulthood
Mean age of onset is between 20 to 30 years
90% of affected individuals are < 50 years at the time of diagnosis
~ 10% develop profound SNHL across all frequencies
THAT “A” AFTER THE “N” STANDS FOR DOMINANT!!!!!

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24
Q

how is autosomal recessive conditions associated with ?

A

-severe to profound SNHL
-prelingual !

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25
Q

connexin is a mutation of what?

A

GJB2 gene mutation

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26
Q

is connexin 26 (GJB2) recess or dom

A

recess

27
Q

how much of does connexin (GJB2 gene) contribute to hearing loss

A

50%!!!!!

28
Q

what is connexin 26?

A

Connexin 26 is a protein found in cells throughout the body, including :
-The inner ear (including utricle & saccule - nonsensory epithelia)
-Skin
-Liver
-Bladder
-Placenta
-Breast
-Brain
-it’s not found in the cochlea HC but it’s found in the supporting cells and nonsensory epithelial cells (ion channels)

29
Q

connexin can range from what type of hearing loss?

A

mild to severe & DEAF (that typically starts at birth)

30
Q

how many terms are there for connexin and do the represent the same thing?

A

Three different term are used interchangeably for connexin deafness, but they represent different things

31
Q

what are the 3 terms used interchangeably for connexin?

A

-DFNB1 and DFNB3 = First and third recessive deafness (connexin deafness)
-GJB = Genes for connexin deafness
-Protein = Connexin 26 (Cx26) = Protein product of GJB2 gene
-Protein = Connexin 30 (Cx30) = Protein product of GJB6 gene
*the 2 protein ones are the most common

32
Q

what is connexin pt 2

A

Connexins are a hexagonal array of proteins in the membrane of each cell that line up to the corresponding connexin proteins of the adjacent cell forming a channel –gap junction – that permits ion transfer between cytoplasm of cells without entering the extracellular fluid

33
Q

why is connexin important ?

A

-The connexins are important to intercellular communication
Current research indicates that Cx26:
1)Provides a structural basis of recycling K+ back to endolymph of scala media after hair cell stimulation
2)Is responsible for intercellular calcium signaling
3)Causes electrical coupling to support cochlear amplification

34
Q

what is the second law of mendelian’s law?

A

-It states that separate genes for separate traits are passed from parents to offspring independently of one another
-More precisely, the law states that alleles of different genes assort independently of one another during gamete formation

35
Q

where is GJB2 sequence coded located, and how many mutations are there?

A

GJB2 is small gene with the entire coding sequence in exon 2 where 98% mutations are found
-on exon 2 and 98% of mutations are found here

36
Q

in 1996, what chromosome was conexin 26 associated too

A

Cx26 (GJB2) was assigned to 13q11-q12

37
Q

in 1997, how was connexin identified

A

Cx26 (GJB2) was identified as the causative gene in the DFNBI locus and was associated with >50% of nonsyndromic SNHL

38
Q

mutations in connexins can lead to what?

A

deafness and skin disorders

39
Q

how many connexins are known to be expressed in the ear

A

at least 4

40
Q

In many populations, mutations of the connexins are the most frequently caused by?

A

Autosomal recessive deafness

41
Q

does mendelians second law affect connexin ?

A

Connexin deafness is an example where the Mendelian law of independent assortment does not hold true

42
Q

why does mendelians second law not effect connexin?

A

-The genes GJB2 and GJB6, which code for the protein Connexin 26 and Connexin 30 respectively, are closely link to each other on chromosome 13
-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 then the chance of passing a mutated GJB2 or GJB6 gene to offspring(s) rises from 50% to 100%

43
Q

what are common mutations seen of connexin 26 ?

A

1)35delG single most common mutation in Caucasians and Asians
-Causes ~ 70% of all mutations in the Western world (1/31 in Caucasians)

2)167delT mutation in Ashkenazi Jews (~ 4% carrier frequency)

3)235delC mutation common in East Asian population

Generally, Cx26 mutations are much less common in Hispanics and African-Americans

44
Q

why can connexin all of as sudden appear in families with no history of deafness

A

because it’s recessive

45
Q

what are the connexin proteins involved in human deafness?

A

-Cx26 (DFNB1/DFNA3) (most common) KNOW
-CX36 (also called GJD2 - also common)
-Cx30 (GJB6-DFNA3; also common)KNOW
-Cx31 (DFNA2)
-Cx32 (DFN or DFNX, X-linked Charcot-Marie-Tooth Disease)

46
Q

what are audiologic phenotypes in connexin 26?

A

-congenital HL
-can pass newborn hearing screening and normal ABR and still get HL
-it can be mild to profound HL, depending on the genotype
-bilateral HL (rarely unilateral)
-sudden hearing
-vestibular symptoms (vertigo/tinnitus)

just know its congenital, bilateral, and recessive

47
Q

how is the skin and connexin associated ?

A

-Skin diseases and deafness and GJB2 mutations:
-Connexins are expressed in the skin too so there can be syndromic conditions that have predominantly skin issues with hearing loss
-These patients may not be tested for Connexin 26 because of the associated skin condition

48
Q

why wouldnt some deaf connexin people not be a condidate for a CI

A

because of the fragility of the skin

49
Q

is intellectual blindness or intellectual disabilities seen in connexin 26?

A

no

50
Q

is genetic testing available for connexin?

A

no

51
Q

do connexin patient get benefit more from CI in comparison to other pathologies?

A

yes

52
Q

what is anexample of x linked nonsyndromic HL?

A

X-linked Congenital Stapes Fixation with Perilymph Gusher

53
Q

what are some findings seen in X-linked Congenital Stapes Fixation with Perilymph Gusher?

A

-mixed HL
-progressive
-Increased hearing loss if middle ear surgery is performed to correct stapes fixation (mistaken for otosclerosis)
-May result in massive & sudden loss of inner ear fluid (perilymph) because it gets confused with otosclerosis
-females have milder symptoms

54
Q

what is an example of mitocondrial nonsyndromic HL?

A

Aminoglycoside-induced ototoxicity

55
Q

what are some findings seen in Aminoglycoside-induced ototoxicity?

A

-Irreversible but preventable hearing loss
-Avoid aminoglycoside use in patients with +ve mutation
-Medic Alert bracelet provided to those individuals with mutation
-when people with this get exposed to aminoglycoside, they can have a sudden severe/profound SNHL (but it’s not progressive)

56
Q

what are the 3 categories of genetic diseases?

A

1)Complex genetic disorders
2)Monogenic diseases
3)Environmental diseases

57
Q

what caused an complex genetic disorder?

A

caused in part by the environment and in part by genes as well as by an interaction between the two
-enviro and genetic

58
Q

what causes monogenic diseases?

A

genes

59
Q

what causes a enviromental disease

A

enviro

60
Q

why are genetic disorders different from mendelian disorders?

A

-In complex genetics, a lot of variants are needed and the additive effect of a lot of variants cause the disorder (alot of varients are needed and the effect of the vareints cause the disease for complex diseases)
Because there are several different variants that are responsible for a disease, there is no clear inheritance pattern

61
Q

how might complex disorders appear on a pedigree?

A

-There is never a clear autosomal dominant pedigree or a clear autosomal recessive pedigree
-There might be familial clustering of the disease, but the inheritance pattern is never clear from these families
-Instead of just one gene per family, there will be many genes or in most cases, genes and the environment are involved

62
Q

what are causes complex genetic diseases?

A

single nucleotide polymorphisms (SNPs)

63
Q

is age related hearing loss a complex disease?

A

yes
ex.The difference between these two 70-year-old groups is partly environmental factors, but also partly genes

64
Q

does genetic testing help analyze age related HL?

A

no

AUDE 5310 (4 decks)

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