cmv and connexin 26 frontiers of research and therapy for
TRANSCRIPT
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CMV and Connexin 26 Frontiers of Research and Therapy for Congenital Hearing Loss
Dylan K. Chan, MD, PhD, FAAPAssistant ProfessorPediatric Otolaryngology-Head and Neck SurgeryDirector, Children’s Communication CenterUniversity of California, San [email protected]
UCSF Audiology Update XIINovember 4, 2016
CMV and Cx26 Hearing Loss
Background – Congenital hearing lossPrevalence and impactDiagnostic testing
CMV-associated SNHLOverviewDiagnostic testingTreatmentCurrent management
Cx26-associated SNHLClinical overviewResearch
CMV and Cx26 Hearing Loss
Background – Congenital hearing lossPrevalence and impactDiagnostic testing
CMV-associated SNHLOverviewDiagnostic testingTreatmentCurrent management
Cx26-associated SNHLClinical overviewResearch
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Childhood hearing loss Definition
Permanent Childhood Hearing Impairment (PCHI)
Childhood hearing loss Definition
Permanent Childhood Hearing Impairment (PCHI)
Mild to profoundBilateral or unilateral
All frequencies or some frequenciesStable or progressive
Sensorineural or conductive
All are eligible by law for services to prevent developmental delay
Childhood hearing loss Prevalence
How common is PCHI?
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Childhood hearing loss Prevalence
Prevalence depends on your exact definition:
From newborn/school/pediatrician screening
1:500 newborns (> 40 dB HL)1:300 by age 9 (> 40 dB HL)
From NHANES survey
1:100 by age 19 (> 25 dB HL, bilateral)1:5 by age 19 (> 15 dB HL, any kind, laterality, or frequency)
Shargorodsky, 2010
Mild/unilateral hearing loss Impact
Children with mild or unilateral hearing loss have impaired school performance, behavior, and psychosocial well-being
Mild/moderate hearing lossBess 1998
1200 students, 5.5% with mild SNHLWorse on general education, educational risk, behavior, physical/emotional/social function
Unilateral hearing lossLieu 2010/2012
74 children, case-control studyChildren with UHL had significantly worse speech and language with persistent delays in academic and behavioral performance after 6 years
Childhood hearing loss Economic impact
Economic cost to the public for an untreated child with hearing loss:
• $652 million: total cost in the US for education for DHH children ($11,006/ child)• $115,600: lifetime direct educational costs for 1 DHH child• $420,000: additional direct educational costs (if untreated)• $1,000,000: total lifetime (educational costs + lost productivity)• $2.1 billion: economic cost to the public for a one-year cohort of DHH children• $10 billion: cost if untreated
• Estimated lifetime costs for all 380,000 children born in one year with asthma• $7 billion
Johnson, 1993Corso, 2009http://www.cdc.gov/ncbddd/hearingloss/data.html
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Early Intervention Timing matters
Yoshinaga-Itano, 1998
Newborn Hearing Screening 1-3-6
Birth AABR or DPOAE- based screen
By 1 month Outpatient screen/rescreen
By 3 monthsDiagnostic audiology evaluation (ABR)
By 6 monthsEarly intervention services initiatedOtolaryngology evaluationOngoing audiology management
REFER
REFER
Confirmed hearing
loss
Goal Diagnosis, medical treatment, and early intervention initiated by 6 months
CMV and Cx26 Hearing Loss
Background – Congenital hearing lossPrevalence and impactDiagnostic testing
CMV-associated SNHLOverviewDiagnostic testingTreatmentCurrent management
Cx26-associated SNHLClinical overviewResearch
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All children with congenital SNHL
50% acquired 50% genetic
67% non-syndromic33% syndromic
50% GJB2
50%Non-GJB2
Congenital SNHL Diagnostic workup
Pendred’sUsher’s
CMV
TORCH infections
Congenital SNHL Why test?
Knowledge Why can’t my child hear?
Prognosis Is the hearing going to get worse?
Exclusion of other causes What else is wrong with my child?
Family counseling What does this mean for my other kids?
Intervention What can we do about it?
hearing.siemens.com
Congenital SNHL Diagnostic workup
HistoryPhysical ExamDiagnostic Tests
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History Syndromic hearing loss
Associations with syndromic SNHL apparent from personal or family history
Visual impairment Usher’sBranchial cleft anomalies Branchio-oto-renalThyroid dysfunction/goiter Pendred’sSudden death/arrhythmia Jervell Lange-NielsenRenal/urinary complaints Alport’s, branchio-oto-renalPigmentation disorders Waardenburg
Unsure?? Refer to genetics
Physical Exam Syndromic hearing loss
Associations with syndromic SNHL apparent from physical exam
GoiterPendred’s
Craniofacial abnormalitiesMultiple
Branchial cleft anomalies/preauricular pitsBranchio-oto-renal
Pigmentation abnormalitiesWaardenburg’s
adhb.govt.nz
www.motownsports.comwww.chargesyndrome.org
www.thyroidmanager.org
History Non-syndromic hearing loss
Causes of non-syndromic SNHL apparent from history
Infectious Toxoplasmosis, syphilis, rubella, CMV, HSV, meningitis
Ototoxic drugs Gentamicin, cisplatinGenetic Family history, consanguinityHyperbilirubinemia JaundiceTrauma EVA-related sudden hearing loss
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Idiopathic Non-syndromic SNHL Core diagnostic tests
1) Imaging1) CT2) MRI
2) Genetic testing1) Connexin 26/302) Complete hearing loss gene array testing
3) CMV testing1) Urine PCR (active infection)2) Newborn blood spot PCR (congenital infection)
Idiopathic Non-syndromic SNHL Core diagnostic tests
1) Imaging1) CT2) MRI
2) Genetic testing1) Connexin 26/302) Complete hearing loss gene array testing
3) CMV testing1) Urine PCR (active infection)2) Newborn blood spot PCR (congenital infection)
Imaging Impact
How does information gleaned from imaging affect patient management?
Cochlear nerve hypoplasia cochlear implant candidacy
Temporal-bone abnormalities surgical planning
EVA recommendations regarding head traumaYan et al., 2013
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EVA Head trauma
2015 Meta-analysis of EVA, head trauma, and progressive hearing loss
- EVA is associated with 40% risk of long-term progressive SNHL- There is no association between head trauma and risk for long-term
progression of hearing loss in people with EVA- I do NOT recommend special precautions for head trauma relating to EVA
Alemi, 2015
Imaging Recommendations
1) Cochlear implant candidates MRI with or without CT
2) All others MRI or CT after discussion with parents(age, cost, anxiety)
3) No special precautions for head trauma relating to EVA
Idiopathic Non-syndromic SNHL Core diagnostic tests
1) Imaging1) CT2) MRI
2) Genetic testing1) Connexin 26/302) Complete hearing loss gene array testing
3) CMV testing1) Urine PCR (active infection)2) Newborn blood spot PCR (congenital infection)
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Genetic Testing Impact
Any cause identified genetic counseling/family planning
Syndromic association identified careful screening for associated phenotype
Specific mutations increased risk of progressive hearing loss, ototoxicity
Future therapeutic options gene therapy
Genetic testing Available tests
Test Location #genes tested
Turnaround time
Cost/insurance Indication
GJB2/GJB6 (Connexin26/30)
Multiple (Quest)
2 1-3 wks $300 / yes Non-syndromicSNHL
Pendred’s/ SLC26A4
Stanford, Cincinnati, Boston
1-3 4 wks $1100 / yes SNHL + EVA or thyroiddysfunction
Usher’s panel Cincinnati,Boston
9 8-12 wks $2500 / yes SNHL + visual dysfunction
OtoScope Iowa 133 3 months $1500 / no Any congenital hearing loss
Exome sequencing
Referral to genetics
All Varies Varies / no Any congenital hearing loss
Genetic testing Available tests
Test Location #genes tested
Turnaround time
Cost/insurance Indication
GJB2/GJB6 (Connexin26/30)
Multiple (Quest)
2 1-3 wks $300 / yes Non-syndromicSNHL
Pendred’s/ SLC26A4
Stanford, Cincinnati, Boston
1-3 4 wks $1100 / yes SNHL + EVA or thyroiddysfunction
Usher’s panel Cincinnati,Boston
9 8-12 wks $2500 / yes SNHL + visual dysfunction
OtoScope Iowa 133 3 months $1500 / no Any congenital hearing loss
Exome sequencing
Referral to genetics
All Varies Varies / no Any congenital hearing loss
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Genetic testing Available tests
Test Location #genes tested
Turnaround time
Cost/insurance Indication
GJB2/GJB6 (Connexin26/30)
Multiple (Quest)
2 1-3 wks $300 / yes Non-syndromicSNHL
Pendred’s/ SLC26A4
Stanford, Cincinnati, Boston
1-3 4 wks $1100 / yes SNHL + EVA or thyroiddysfunction
Usher’s panel Cincinnati,Boston
9 8-12 wks $2500 / yes SNHL + visual dysfunction
OtoScope Iowa 133 3 months $1500 / no Any congenital hearing loss
Exome sequencing
Referral to genetics
All Varies Varies / no Any congenital hearing loss
Genetic testing Available tests
Test Location #genes tested
Turnaround time
Cost/insurance Indication
GJB2/GJB6 (Connexin26/30)
Multiple (Quest)
2 1-3 wks $300 / yes Non-syndromicSNHL
Pendred’s/ SLC26A4
Stanford, Cincinnati, Boston
1-3 4 wks $1100 / yes SNHL + EVA or thyroiddysfunction
Usher’s panel Cincinnati,Boston
9 8-12 wks $2500 / yes SNHL + visual dysfunction
OtoScope Iowa 133 3 months $1500 / no Any congenital hearing loss
Exome sequencing
Referral to genetics
All Varies Varies / no Any congenital hearing loss
Genetic testing Available tests
Test Location #genes tested
Turnaround time
Cost/insurance Indication
GJB2/GJB6 (Connexin26/30)
Multiple (Quest)
2 1-3 wks $300 / yes Non-syndromicSNHL
Pendred’s/ SLC26A4
Stanford, Cincinnati, Boston
1-3 4 wks $1100 / yes SNHL + EVA or thyroiddysfunction
Usher’s panel Cincinnati,Boston
9 8-12 wks $2500 / yes SNHL + visual dysfunction
OtoScope Iowa 133 3 months $1500 / no Any congenital hearing loss
Exome sequencing
Referral to genetics
All Varies Varies / no Any congenital hearing loss
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Idiopathic Non-syndromic SNHL Core diagnostic tests
1) Imaging1) CT2) MRI
2) Genetic testing1) Connexin 26/302) Complete hearing loss gene array testing
3) CMV testing1) Urine PCR (active infection)2) Newborn blood spot PCR (congenital infection)
CMV Congenital Hearing Loss
15-20% of all congenital hearing loss
More common in lower socioeconomic strata
Often progressive
May be syndromic
Can be treated
Core diagnostic tests How to choose?
Neonates < 2 weeks old CMV testing ASAP
Cochlear implant candidate MRI -> Cx26/CMV*
Unilateral CMV* -> imaging at appropriate age -> Cx26
All others Cx26/CMV* -> imaging at appropriate age
* CMV testing only by dried blood spot if > 2 weeks. If unable, skip** If no findings from core testing, consider full genetic array testing
Order and type of testing depends on many patient factors, systems consideration, and family preference
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CMV and Cx26 Hearing Loss
Background – Congenital hearing lossPrevalence and impactDiagnostic testing
CMV-associated SNHLOverviewDiagnostic testingTreatmentCurrent management
Cx26-associated SNHLClinical overviewResearch
CMV and Cx26 Hearing Loss
Background – Congenital hearing lossPrevalence and impactDiagnostic testing
CMV-associated SNHLOverviewDiagnostic testingTreatmentCurrent management
Cx26-associated SNHLClinical overviewResearch
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CMV-associated SNHL noted to progress and/or newly develop up to teenage years
20-30% of CMV(+) will have SNHL0.2-0.6/1000 live births = 1000 new cases/year in the US
May be vastly underestimated
Take home point 1 – CMV-associated hearing loss
• Highly variable
• Frequently progressive
• Onset/progression throughout childhood
• Occurs with or without other symptoms
• ONLY occurs with prenatal transmission
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CMV and Cx26 Hearing Loss
Background – Congenital hearing lossPrevalence and impactDiagnostic testing
CMV-associated SNHLOverviewDiagnostic testingTreatmentCurrent management
Cx26-associated SNHLClinical overviewResearch
Prenatal screening healthy pregnant women - not routinely done
Newborn screening saliva PCR assays - not routinely done
Neonatal (up to 2-3 weeks) culture or PCR from urine or blood- gold standard
Postnatal PCR assay from dried newborn blood spots- 99% specificity- 30% sensitivity
CMV Testing
SNHL CMV DBS testing
Boppana et al., JAMA 2010
DBS CMV PCR (vs saliva culture)
34.4% sensitivity99.9% specificity
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Take home point 2 – CMV testing
• CMV testing (CMV PCR/culture)
• is sensitive and specific before 3 weeks• Is sensitive but NOT specific after 3 weeks
• CMV DBS testing
• Is specific but NOT sensitive• Is the only specific test after 3 weeks
Question:
What is the best testing/screening paradigm to efficiently and accurately identify congenital CMV-associated hearing loss?
1) Universal neonatal CMV screening2) Hearing-targeted CMV screening
NHS and CMV screening CHIMES data
• Ross (UAB) – AAP NCE 2014
• CMV and newborn hearing screening (NHS) in 100,000 newborns
CMV - CMV +
NHS PASS
97,571 429
NHS REFER
1967 33 21 SNHL12 No SNHL
Hearing unknown
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NHS and CMV screening CHIMES data +
63% SNHL21
All asymptomatic neonates100,000
2% refer NHS2000
1.6% + CMV33
98% pass NHS98,000
0.4% + CMV429
98.4% ‐ CMV1967
99.6% ‐ CMV97,571
15% SNHL(295)
7‐15% SNHL(30‐60)
0.1‐0.3% SNHL(100‐300)
NHS and CMV screening CHIMES data +
63% SNHL21
All asymptomatic neonates100,000
2% refer NHS2000
1.6% + CMV33
98% pass NHS98,000
0.4% + CMV429
98.4% ‐ CMV1967
99.6% ‐ CMV97,571
15% SNHL(295)
7‐15% SNHL(30‐60)
0.1‐0.3% SNHL(100‐300)
NNT = 100 to identify one case of congenital CMV‐associated SNHL for treatment
NHS and CMV screening Criticism
63% SNHL21
All asymptomatic neonates100,000
2% refer NHS2000
1.6% + CMV33
98% pass NHS98,000
0.4% + CMV429
98.4% ‐ CMV1967
99.6% ‐ CMV97,571
15% SNHL(295)
7‐15% SNHL(30‐60)
0.1‐0.3% SNHL(100‐300)
This method will miss CMV +children who pass NHS and later develop progressive SNHL
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NHS and CMV screening Criticism
63% SNHL21
All asymptomatic neonates100,000
2% refer NHS2000
1.6% + CMV33
98% pass NHS98,000
0.4% + CMV429
98.4% ‐ CMV1967
99.6% ‐ CMV97,571
15% SNHL(295)
7‐15% SNHL(30‐60)
0.1‐0.3% SNHL(100‐300)
Is this method an effective means for identifying babies at risk for congenital CMV?Yield of CMV + is 1.6% vs 0.4%. But still misses 93% of CMV + babies.
Take home point 3 – identification of CMV-associated hearing loss
• Universal CMV screening would be ideal
• Hearing-targeted CMV screening misses many potential cases, but is the best current option
CMV and Cx26 Hearing Loss
Background – Congenital hearing lossPrevalence and impactDiagnostic testing
CMV-associated SNHLOverviewDiagnostic testingTreatmentCurrent management
Cx26-associated SNHLClinical overviewResearch
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Treatment Valganciclovir for CMV hearing loss
NIAID Collaborative Antiviral Study GroupKimberlin et al., NEJM 372(10):933-43
Multinational 31-institution Phase III randomized, controlled clinical trial
109 infants < 30 days old Symptomatic congenital CMV43% with baseline hearing loss
6 wks vs. 6 mos PO valganciclovir24-month follow up
Significantly increased odds of hearing improvement or stabilization of normal hearing with 6-month course (OR (1.02-6.91) at 24 months)
V-GCV for congenital CMV Utah study
HT-CMV screening-directed treatment for congenital CMV-associated hearing loss
Study sites25 sites; coordinator Albert Park (OHNS, University of Utah);
InclusionReferred NHS and subsequent CMV + by urine/saliva PCR or culture
GoalDetermine hearing, speech, language, developmental outcomes of infants with referred NHS entered into a pathway of early CMV screening and subsequent treatment (placebo vs. valganciclovir)
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NCT01649869 (Valgan Toddler Study)
Multi-institution Phase II randomized, controlled clinical trial
6 wks PO valganciclovir vs. placeboAge 1 month – 4 years with sensorineural hearing loss
Congenital CMV by neonatal urine CMV or dried blood spot CMV
CMV-associated SNHL New Kimberlin study
Take home point 4
• CMV treatment (6 months valganciclovir)
• Can prevent progression of hearing loss
• Is of unknown efficacy in kids with isolated CMV-associated hearing loss AND in older kids
CMV and Cx26 Hearing Loss
Background – Congenital hearing lossPrevalence and impactDiagnostic testing
CMV-associated SNHLOverviewDiagnostic testingTreatmentCurrent management
Cx26-associated SNHLClinical overviewResearch
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Babies under 3 weeks of age with referred NHS- CMV testing (urine/saliva PCR or culture)- Diagnostic audiologic testing
Babies over 3 weeks of age with referred NHS- Diagnostic audiologic testing
Babies and children over 3 weeks of age up to 4 years of age with confirmed SNHL- CMV DBS testing (as part of diagnostic workup for SNHL)- Consider V-GCV if positive
Children over 4 years of age with confirmed SNHL- CMV DBS testing (purely for diagnostic workup for SNHL)
CMV-associated SNHL Practice guidelines
1) Babies under 3 weeks of age with referred NHS- CMV testing (urine/saliva PCR or culture)- Diagnostic audiologic testing
2) Babies over 3 weeks of age with referred NHS- Diagnostic audiologic testing
3) Babies and children over 3 weeks of age with confirmed SNHL- CMV DBS testing (as part of diagnostic workup for SNHL)- Consider V-GCV if positive
Hearing-targeted CMV screening
State law in UT, CT, MN, IL
CMV-associated hearing loss Take-home
If you see a baby < 3 weeks old for a referred newborn hearing screen, recommend discussion with pediatrician/OHNS about CMV testing
If you are involved with your hospital’s NHS program, consider hearing-targeted CMV testing
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CMV and Cx26 Hearing Loss
Background – Congenital hearing lossPrevalence and impactDiagnostic testing
CMV-associated SNHLOverviewDiagnostic testingTreatmentCurrent management
Cx26-associated SNHLClinical overviewResearch
Cx26 hearing loss Prevalence among all hearing impaired
54 countries141 studies23093 hearing-loss probands4064 GJB2 biallelic probandsFrequency = 18%
0-10%
>40%
10-20%20-30%30-40%
Chan and Chang, 2015
0%
50%
100%
T/T NT/T NT/NT
profound
severe
moderate
mild
1531 probandsSnoeckx et al., 2006
Per
cent
of i
ndiv
idua
ls
Genotype
Cx26 hearing loss Severity
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Initial audiogram
Final audiogram
0
20
40
Pure‐tone threshold (dB)
60
0.5 1 2 4 8
Frequency (kHz)
Thresholds averaged from 7 V37I/V37I individuals with progressive hearing loss
Cx26 hearing loss Progression and V37I
CMV and Cx26 Hearing Loss
Background – Congenital hearing lossPrevalence and impactDiagnostic testing
CMV-associated SNHLOverviewDiagnostic testingTreatmentCurrent management
Cx26-associated SNHLClinical overviewResearch
gene GJB2 (gap junction protein, beta 2)Chromosome location13q11-q12
protein Connexin 26Expressed in cochlea and epidermisForms heteromeric/heterotypic gap-junction channels
and apical hemichannels with Connexin 30
Ions, small molecules, electrical currents, cell adhesion
Cx26 GJB2
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Connexin function K+ recycling
K+
K+ K+
K+
Connexin independentConnexin dependent
Noise
Connexin function Noise detection
ATP
Ca2+ waves MAPKConnexin independentConnexin dependent
Cx26 dysfunction Animal models
Mouse (genetic model) Gerbil (physiologic model)
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Cx26 dysfunction Animal models
Mouse (genetic model) Gerbil (physiologic model)
CreER loxP loxP
Cx26
TMX
Mouse Inducible Cx26 KO
ER-Cre/Cx26-lox
TMX-inducible Cx26 cKO Progressive hearing loss
Zhu, 2015
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TMX-inducible Cx26 cKO Noise-induced hearing loss
Baseline Days Permanent shift
Clic
k A
BR
thre
shol
d (d
B S
PL)
103 dB, 2 hr octave-band noise
20
30
40
50
60
70
80
0 2 4 6 8 10 12 14 16
WT
Cx26
Wild-typeConnexin-26 knockout
Cx26 dysfunction Animal models
Connexin 26‐deficient mice have increased susceptibility to age‐ and noise‐induced
hearing loss
Cx26 dysfunction Animal models
Connexin 26‐deficient mice have increased susceptibility to age‐ and noise‐induced
hearing loss
Connexin 26 may protect against cochlear trauma
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Cx26 dysfunction Animal models
Connexin 26‐deficient mice have increased susceptibility to age‐ and noise‐induced
hearing loss
Connexin 26 may protect against cochlear trauma
How?
Cx26 dysfunction Animal models
Mouse (genetic model) Gerbil (physiologic model)
Acoustic stimulus
Endolymph
Perilymph
Endocochlearpotential
Microphonicpotential
Calcium imagingCochlear stroboscopy
Adult gerbil cochlear physiology in vitro
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DorsalVentral
Lateral
Medial
50 µm
In vitro Cochlear explant
Chan and Hudspeth, 2005
10 µm
Lateral
Medial
In vitro Cochlear explant
Chan and Hudspeth, 2005
Chan and Hudspeth, 2006
Noise-exposure Cochlear stroboscopy
1000 Hz, 100 dB SPL
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Noise exposure Intercellular Ca2+ signalling
AAA
0.4
0.5
0.6
0.7
0.8
0.9
Rat
io (
340
/387
)
slope = 6.2 m/s
0
10
20
30
40
50
60
70
80
90
0 5 10 15Time (s)
Dis
tanc
e (m
m)
10 s
OHCs
50 M
A B DC
E F
Adult gerbil cochlear explant
Cx26 dysfunction Animal models
Connexin 26 protects against cochlear
trauma
Calcium signalling in cochlear supporting cells is involved
Cx26 dysfunction From rodents to humans
Are people with Connexin 26 mutations more susceptible to
NIHL?
Could calcium regulation in the cochlea be a potential drug
target?
What about gene therapy?
Connexin 26 protects against cochlear
trauma
Calcium signalling in cochlear supporting cells is involved
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Connexin 26 Gene therapy
What about gene therapy?
Normal cochlea Long-deafened cochlea
Connexin 26 Gene therapy
The risks and benefits of intervention now are unclear with respect to future therapies
We need to support your child’s hearing and communication development now
Connexin 26 Gene therapy
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Connexin 26 is the most common gene affected in congenital SNHL and has highly variable presentation
Connexin 26-associated hearing loss may be due to changes in calcium regulation in the cochlea that make it break down more easily
This may lead to new drug targets or gene therapy in the future
Let’s take care of our kids now
Cx26 hearing loss Summary
Thanks
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Cochlear implantation Cost effectiveness
Unilateral Cochlear Implant
Estimated cost per QALY: $9,000
Once accounting for indirect costs (including reduced educational expenses): Savings of $53,000 per child
Cheng, 2000Lammers, 2011
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Early Intervention Timing matters
Cochlear implantation at< 18 months18-36 months>36 months
Niparko, JAMA 2010
Receptive language Expressive language
How was hearing loss detected?
Unresponsive to sound
Speech/language
Education/behavior
Newborn Infant Preschooler Schoolchild
Profound Moderate Mild/unilateral
Age
Degree
Sign
How was hearing loss detected?
Unresponsive to sound
Speech/language
Education/behavior
Newborn Infant Preschooler Schoolchild
Profound Moderate Mild/unilateral
Age
Degree
Sign
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Diagnostic tests Congenital hearing loss
What next?
1) Work up potential causes revealed in H&P• Visual loss -> ophthalmology consult• Urinary problems -> renal US• Branchial cleft anomalies -> renal US• Goiter or thyroid problems -> TFTs, genetic testing (SLC26A4), imaging
(EVA)• History of syncope or arrhythmia -> EKG• ANY syndromic association -> genetics consult
Unsure?? Refer to genetics
Diagnostic tests Congenital hearing loss
What next?
1) Work up potential causes revealed in H&P• Visual loss -> ophthalmology consult• Urinary problems -> renal US• Branchial cleft anomalies -> renal US• Goiter or thyroid problems -> TFTs, genetic testing (SLC26A4), imaging
(EVA)• History of syncope or arrhythmia -> EKG• ANY syndromic association -> genetics consult
2) If H&P/genetics evaluation unrevealing:• do NOT empirically pursue these tests for specific syndromic causes.• DO consider one of three core diagnostic tests
Imaging CT vs MRI
Right: http://www.nidcd.nih.gov/health/hearing/pages/eva.aspx
CT
Better bony anatomy+ radiationLess sedationLess expensiveLess incidental findings
MRI
Better neural anatomyNo radiationMore sedationMore expensiveMore incidental findings
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Genetic testing Recommendations
1) GJB2/Connexin 26 testing
2) Refer to genetics for consideration of other testing