10/26/2016 CMV and Connexin 26 Frontiers of Research and Therapy - - PDF document

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CMV and Connexin 26 Frontiers of Research and Therapy for Congenital Hearing Loss

Dylan K. Chan, MD, PhD, FAAP Assistant Professor Pediatric Otolaryngology-Head and Neck Surgery Director, Children’s Communication Center University of California, San Francisco dylan.chan@ucsf.edu UCSF Audiology Update XII November 4, 2016

CMV and Cx26 Hearing Loss

Background – Congenital hearing loss Prevalence and impact Diagnostic testing CMV-associated SNHL Overview Diagnostic testing Treatment Current management Cx26-associated SNHL Clinical overview Research

CMV and Cx26 Hearing Loss

Background – Congenital hearing loss Prevalence and impact Diagnostic testing CMV-associated SNHL Overview Diagnostic testing Treatment Current management Cx26-associated SNHL Clinical overview Research

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Childhood hearing loss Definition

Permanent Childhood Hearing Impairment (PCHI)

Childhood hearing loss Definition

Permanent Childhood Hearing Impairment (PCHI) Mild to profound Bilateral or unilateral All frequencies or some frequencies Stable 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 loss Bess 1998 1200 students, 5.5% with mild SNHL Worse on general education, educational risk, behavior, physical/emotional/social function Unilateral hearing loss Lieu 2010/2012 74 children, case-control study Children 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, 1993 Corso, 2009 http://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 months Diagnostic audiology evaluation (ABR) By 6 months Early intervention services initiated Otolaryngology evaluation Ongoing 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 loss Prevalence and impact Diagnostic testing CMV-associated SNHL Overview Diagnostic testing Treatment Current management Cx26-associated SNHL Clinical overview Research

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All children with congenital SNHL 50% acquired 50% genetic 67% non-syndromic 33% syndromic 50% GJB2 50% Non-GJB2

Congenital SNHL Diagnostic workup

Pendred’s Usher’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

History Physical Exam Diagnostic Tests

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History Syndromic hearing loss

Associations with syndromic SNHL apparent from personal or family history Visual impairment Usher’s Branchial cleft anomalies Branchio-oto-renal Thyroid dysfunction/goiter Pendred’s Sudden death/arrhythmia Jervell Lange-Nielsen Renal/urinary complaints Alport’s, branchio-oto-renal Pigmentation disorders Waardenburg Unsure?? Refer to genetics

Physical Exam Syndromic hearing loss

Associations with syndromic SNHL apparent from physical exam

Goiter Pendred’s Craniofacial abnormalities Multiple Branchial cleft anomalies/preauricular pits Branchio-oto-renal Pigmentation abnormalities Waardenburg’s

adhb.govt.nz www.motownsports.com www.chargesyndrome.o rg 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, cisplatin Genetic Family history, consanguinity Hyperbilirubinemia Jaundice Trauma EVA-related sudden hearing loss

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Idiopathic Non-syndromic SNHL Core diagnostic tests

1) Imaging 1) CT 2) MRI 2) Genetic testing 1) Connexin 26/30 2) Complete hearing loss gene array testing 3) CMV testing 1) Urine PCR (active infection) 2) Newborn blood spot PCR (congenital infection)

Idiopathic Non-syndromic SNHL Core diagnostic tests

1) Imaging 1) CT 2) MRI 2) Genetic testing 1) Connexin 26/30 2) Complete hearing loss gene array testing 3) CMV testing 1) 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 trauma

Yan 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) Imaging 1) CT 2) MRI 2) Genetic testing 1) Connexin 26/30 2) Complete hearing loss gene array testing 3) CMV testing 1) 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 (Connexin 26/30) Multiple (Quest) 2 1-3 wks $300 / yes Non- syndromic SNHL Pendred’s/ SLC26A4 Stanford, Cincinnati, Boston 1-3 4 wks $1100 / yes SNHL + EVA

• r thyroid

dysfunction 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 (Connexin 26/30) Multiple (Quest) 2 1-3 wks $300 / yes Non- syndromic SNHL Pendred’s/ SLC26A4 Stanford, Cincinnati, Boston 1-3 4 wks $1100 / yes SNHL + EVA

• r thyroid

dysfunction 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 (Connexin 26/30) Multiple (Quest) 2 1-3 wks $300 / yes Non- syndromic SNHL Pendred’s/ SLC26A4 Stanford, Cincinnati, Boston 1-3 4 wks $1100 / yes SNHL + EVA

• r thyroid

dysfunction 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 (Connexin 26/30) Multiple (Quest) 2 1-3 wks $300 / yes Non- syndromic SNHL Pendred’s/ SLC26A4 Stanford, Cincinnati, Boston 1-3 4 wks $1100 / yes SNHL + EVA

• r thyroid

dysfunction 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 (Connexin 26/30) Multiple (Quest) 2 1-3 wks $300 / yes Non- syndromic SNHL Pendred’s/ SLC26A4 Stanford, Cincinnati, Boston 1-3 4 wks $1100 / yes SNHL + EVA

• r thyroid

dysfunction 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) Imaging 1) CT 2) MRI 2) Genetic testing 1) Connexin 26/30 2) Complete hearing loss gene array testing 3) CMV testing 1) 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 loss Prevalence and impact Diagnostic testing CMV-associated SNHL Overview Diagnostic testing Treatment Current management Cx26-associated SNHL Clinical overview Research

CMV and Cx26 Hearing Loss

Background – Congenital hearing loss Prevalence and impact Diagnostic testing CMV-associated SNHL Overview Diagnostic testing Treatment Current management Cx26-associated SNHL Clinical overview Research

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CMV-associated SNHL noted to progress and/or newly develop up to teenage years

20-30% of CMV(+) will have SNHL 0.2-0.6/1000 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 loss Prevalence and impact Diagnostic testing CMV-associated SNHL Overview Diagnostic testing Treatment Current management Cx26-associated SNHL Clinical overview Research 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% sensitivity 99.9% 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 screening 2) 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 SNHL 12 No SNHL Hearing unknown

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NHS and CMV screening CHIMES data +

63% SNHL 21 All asymptomatic neonates 100,000 2% refer NHS 2000 1.6% + CMV 33 98% pass NHS 98,000 0.4% + CMV 429 98.4% ‐ CMV 1967 99.6% ‐ CMV 97,571 15% SNHL (295) 7‐15% SNHL (30‐60) 0.1‐0.3% SNHL (100‐300)

NHS and CMV screening CHIMES data +

63% SNHL 21 All asymptomatic neonates 100,000 2% refer NHS 2000 1.6% + CMV 33 98% pass NHS 98,000 0.4% + CMV 429 98.4% ‐ CMV 1967 99.6% ‐ CMV 97,571 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% SNHL 21 All asymptomatic neonates 100,000 2% refer NHS 2000 1.6% + CMV 33 98% pass NHS 98,000 0.4% + CMV 429 98.4% ‐ CMV 1967 99.6% ‐ CMV 97,571 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% SNHL 21 All asymptomatic neonates 100,000 2% refer NHS 2000 1.6% + CMV 33 98% pass NHS 98,000 0.4% + CMV 429 98.4% ‐ CMV 1967 99.6% ‐ CMV 97,571 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 loss Prevalence and impact Diagnostic testing CMV-associated SNHL Overview Diagnostic testing Treatment Current management Cx26-associated SNHL Clinical overview Research

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Treatment Valganciclovir for CMV hearing loss

NIAID Collaborative Antiviral Study Group Kimberlin et al., NEJM 372(10):933-43 Multinational 31-institution Phase III randomized, controlled clinical trial 109 infants < 30 days old Symptomatic congenital CMV 43% with baseline hearing loss 6 wks vs. 6 mos PO valganciclovir 24-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 sites 25 sites; coordinator Albert Park (OHNS, University of Utah); Inclusion Referred NHS and subsequent CMV + by urine/saliva PCR or culture Goal Determine 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. placebo Age 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 loss Prevalence and impact Diagnostic testing CMV-associated SNHL Overview Diagnostic testing Treatment Current management Cx26-associated SNHL Clinical overview Research

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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 loss Prevalence and impact Diagnostic testing CMV-associated SNHL Overview Diagnostic testing Treatment Current management Cx26-associated SNHL Clinical overview Research

Cx26 hearing loss Prevalence among all hearing impaired

54 countries 141 studies 23093 hearing-loss probands 4064 GJB2 biallelic probands Frequency = 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 probands Snoeckx et al., 2006 Percent of individuals

Genotype

Cx26 hearing loss Severity

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Initial audiogram Final audiogram 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 loss Prevalence and impact Diagnostic testing CMV-associated SNHL Overview Diagnostic testing Treatment Current management Cx26-associated SNHL Clinical overview Research gene GJB2 (gap junction protein, beta 2) Chromosome location13q11-q12 protein Connexin 26 Expressed in cochlea and epidermis Forms 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 independent Connexin dependent

Noise Connexin function Noise detection ATP

Ca2+ waves

MAPK

Connexin independent Connexin 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) Cre ER 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 Click ABR threshold (dB SPL) 103 dB, 2 hr octave-band noise

20 30 40 50 60 70 80 2 4 6 8 10 12 14 16 WT Cx26

Wild-type Connexin-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 Endocochlear potential Microphonic potential Calcium imaging Cochlear stroboscopy

Adult gerbil cochlear physiology in vitro

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Dorsal Ventral 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

A A A

0.4 0.5 0.6 0.7 0.8 0.9 Ratio (340/387) slope = 6.2 m/s 10 20 30 40 50 60 70 80 90 5 10 15 Time (s) Distance (mm) 10 s OHCs 50 M

A B D C 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, 2000 Lammers, 2011

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Early Intervention Timing matters

Cochlear implantation at < 18 months 18-36 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 + radiation Less sedation Less expensive Less incidental findings MRI Better neural anatomy No radiation More sedation More expensive More incidental findings

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Genetic testing Recommendations

1) GJB2/Connexin 26 testing 2) Refer to genetics for consideration of other testing